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  • 1.
    Andersson, Emma K.
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Bengtsson, Christoffer
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Evans, Margery L.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Sellstedt, Magnus
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Lindgren, Anders E.G.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Hufnagel, David A.
    Bhattacharya, Moumita
    Tessier, Peter M.
    Wittung-Stafshede, Pernilla
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Chapman, Matthew R.
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). University of Michigan, USA.
    Modulation of Curli Assembly and Pellicle Biofilm Formation by Chemical and Protein Chaperones2013Inngår i: Chemistry and Biology, ISSN 1074-5521, E-ISSN 1879-1301, Vol. 20, nr 10, s. 1245-1254Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Enteric bacteria assemble functional amyloid fibers, curli, on their surfaces that share structural and biochemical properties with disease-associated amyloids. Here, we test rationally designed 2-pyridone compounds for their ability to alter amyloid formation of the major curli subunit CsgA. We identified several compounds that discourage CsgA amyloid formation and several compounds that accelerate CsgA amyloid formation. The ability of inhibitor compounds to stop growing CsgA fibers was compared to the same property of the CsgA chaperone, CsgE. CsgE blocked CsgA amyloid assembly and arrested polymerization when added to actively polymerizing fibers. Additionally, CsgE and the 2-pyridone inhibitors prevented biofilm formation by Escherichia coli at the air-liquid interface of a static culture. We demonstrate that curli amyloid assembly and curli-dependent biofilm formation can be modulated not only by protein chaperones, but also by "chemical chaperones."

  • 2.
    Andréasson, Måns
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bhuma, Naresh
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Pemberton, Nils
    AstraZeneca, Mölndal, Gothenburg, Sweden.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Using Macrocyclic G-Quadruplex Ligands to Decipher the Interactions Between Small Molecules and G-Quadruplex DNA2022Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 28, nr 65, artikkel-id e202202020Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This study aims to deepen the knowledge of the current state of rational G4-ligand design through the design and synthesis of a novel set of compounds based on indoles, quinolines, and benzofurans and their comparisons with well-known G4-ligands. This resulted in novel synthetic methods and G4-ligands that bind and stabilize G4 DNA with high selectivity. Furthermore, the study corroborates previous studies on the design of G4-ligands and adds deeper explanations to why a) macrocycles offer advantages in terms of G4-binding and -selectivity, b) molecular pre-organization is of key importance in the development of strong novel binders, c) an electron-deficient aromatic core is essential to engage in strong arene-arene interactions with the G4-surface, and d) aliphatic amines can strengthen interactions indirectly through changing the arene electrostatic nature of the compound. Finally, fundamental physicochemical properties of selected G4-binders are evaluated, underscoring the complexity of aligning the properties required for efficient G4 binding and stabilization with feasible pharmacokinetic properties.

    Fulltekst (pdf)
    fulltext
  • 3.
    Andréasson, Måns
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Donzel, Maxime
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Abrahamsson, Alva
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Berner, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Doimo, Mara
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Clinical Genetics Unit, Department of Women and Children’s Health, Padua University, Padua, Italy.
    Quiroga, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Eriksson, Anna U.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chao, Yu-Kai
    Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge, United Kingdom.
    Overman, Jeroen
    Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge, United Kingdom.
    Pemberton, Nils
    Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), Bio Pharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Exploring the dispersion and electrostatic components in arene-arene interactions between ligands and G4 DNA to develop G4-ligands2024Inngår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 67, nr 3, s. 2202-2219Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    G-Quadruplex (G4) DNA structures are important regulatory elements in central biological processes. Small molecules that selectively bind and stabilize G4 structures have therapeutic potential, and there are currently >1000 known G4 ligands. Despite this, only two G4 ligands ever made it to clinical trials. In this work, we synthesized several heterocyclic G4 ligands and studied their interactions with G4s (e.g., G4s from the c-MYC, c-KIT, and BCL-2 promoters) using biochemical assays. We further studied the effect of selected compounds on cell viability, the effect on the number of G4s in cells, and their pharmacokinetic properties. This identified potent G4 ligands with suitable properties and further revealed that the dispersion component in arene-arene interactions in combination with electron-deficient electrostatics is central for the ligand to bind with the G4 efficiently. The presented design strategy can be applied in the further development of G4-ligands with suitable properties to explore G4s as therapeutic targets.

    Fulltekst (pdf)
    fulltext
  • 4.
    Andréasson, Måns
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Donzel, Maxime
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Abrahamsson, Alva
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Berner, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Doimo, Mara
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Quiroga, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Pemberton, Nils
    AstraZeneca, Gothenburg, Sweden.
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    The Synergism of the Dispersion and Electrostatic Components in the Arene-Arene Interactions Between Ligands and G4 DNAManuskript (preprint) (Annet vitenskapelig)
  • 5. Bengtsson, Christoffer
    et al.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Krishnan, Syam
    Banchelin, Thomas Sainte-Luce
    Gustafson, Karl
    Das, Pralay
    Sinha, Arun K
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Synthesis of a bromomethyl substituted bicyclic 2-pyridone scaffold2013Inngår i: Abstracts of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 245Artikkel i tidsskrift (Fagfellevurdert)
  • 6.
    Berner, Andreas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Das, Rabindra Nath
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bhuma, Naresh
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Golebiewska, Justyna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Abrahamsson, Alva
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Andréasson, Måns
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chaudhari, Namrata
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Doimo, Mara
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Bose, Partha Pratim
    Department of Biosciences and Nutrition, Karolinska Institutet, Neo, Huddinge, Sweden.
    Chand, Karam
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Strömberg, Roger
    Department of Biosciences and Nutrition, Karolinska Institutet, Neo, Huddinge, Sweden.
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    G4-ligand-conjugated oligonucleotides mediate selective binding and stabilization of individual G4 DNA structures2023Inngår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 146, nr 10, s. 6926-6935Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    G-quadruplex (G4) DNA structures are prevalent secondary DNA structures implicated in fundamental cellular functions, such as replication and transcription. Furthermore, G4 structures are directly correlated to human diseases such as cancer and have been highlighted as promising therapeutic targets for their ability to regulate disease-causing genes, e.g., oncogenes. Small molecules that bind and stabilize these structures are thus valuable from a therapeutic perspective and helpful in studying the biological functions of the G4 structures. However, there are hundreds of thousands of G4 DNA motifs in the human genome, and a long-standing problem in the field is how to achieve specificity among these different G4 structures. Here, we developed a strategy to selectively target an individual G4 DNA structure. The strategy is based on a ligand that binds and stabilizes G4s without selectivity, conjugated to a guide oligonucleotide, that specifically directs the G4-Ligand-conjugated oligo (GL-O) to the single target G4 structure. By employing various biophysical and biochemical techniques, we show that the developed method enables the targeting of a unique, specific G4 structure without impacting other off-target G4 formations. Considering the vast amount of G4s in the human genome, this represents a promising strategy to study the presence and functions of individual G4s but may also hold potential as a future therapeutic modality.

    Fulltekst (pdf)
    fulltext
  • 7. Bhattacharjee, Snehasish
    et al.
    Chakraborty, Sandipan
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sengupta, Pradeep K.
    Bhowmik, Sudipta
    Importance of the hydroxyl substituents in the B-ring of plant flavonols on their preferential binding interactions with VEGF G-quadruplex DNA: Multi-spectroscopic and molecular modeling studies2018Inngår i: International Journal of Biological Macromolecules, ISSN 0141-8130, E-ISSN 1879-0003, Vol. 118, s. 629-639Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    G-quadruplex (G4) structures are known to be promising anticancer drug targets and flavonols (an important class of fiavonoids) are small molecules reported to possess several health-promoting properties including those of anticancer activities. In this work, we explored the interactions of the structurally related plant flavonols kaempferol (KAE; 3,5,7,4'-OH flavone) and morin (MOR; 3,5,7,2',4'-OH flavone) with various G4-DNA sequences along with duplex DNA using a combination of spectroscopic and molecular docking studies. Our results revealed that KAE shows preferential interaction with VEGF G4-DNA in comparison to the other G4 sequences and duplex DNA. Moreover, KAE enhances the thermal stability of VEGF G4-DNA. In contrast, MOR exhibits an appreciably weaker level of interaction with both duplex and various G4-DNAs, with no significant structural specificity. The contrasting DNA binding behaviors suggest a crucial role of the 2'-OH substituent in the Bring of flavonol moiety. While KAE is relatively planar, MOR adopts a significantly non-planar conformation attributable to steric hindrance from the additional 2'-OH substituent. This small structural difference is apparently very important for the ability of KAE and MOR to interact with VEGF G4-DNA. Thus, KAE (but not MOR) appears to be an effective ligand for VEGF G4-DNA, opening up possibilities of its application for regulation of gene expression in cancer cells. 

  • 8.
    Bhuma, Naresh
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chand, Karam
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Department of Medicinal Chemistry, Uppsala University, BMC, Uppsala, Sweden.
    Andréasson, Måns
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Mason, James E.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Das, Rabindra Nath
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Department of Chemistry, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India.
    Patel, Ankit Kumat
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Öhlund, Daniel
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    The effect of side chain variations on quinazoline-pyrimidine G-quadruplex DNA ligands2023Inngår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 248, artikkel-id 115103Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    G-quadruplex (G4) DNA structures are involved in central biological processes such as DNA replication and transcription. These DNA structures are enriched in promotor regions of oncogenes and are thus promising as novel gene silencing therapeutic targets that can be used to regulate expression of oncoproteins and in particular those that has proven hard to drug with conventional strategies. G4 DNA structures in general have a well-defined and hydrophobic binding area that also is very flat and featureless and there are ample examples of G4 ligands but their further progression towards drug development is limited. In this study, we use synthetic organic chemistry to equip a drug-like and low molecular weight central fragment with different side chains and evaluate how this affect the compound's selectivity and ability to bind and stabilize G4 DNA. Furthermore, we study the binding interactions of the compounds and connect the experimental observations with the compound's structural conformations and electrostatic potentials to understand the basis for the observed improvements. Finally, we evaluate the top candidates' ability to selectively reduce cancer cell growth in a 3D co-culture model of pancreatic cancer which show that this is a powerful approach to generate highly active and selective low molecular weight G4 ligands with a promising therapeutic window.

    Fulltekst (pdf)
    fulltext
  • 9.
    Broman, Karolina
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för naturvetenskapernas och matematikens didaktik.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Holmboe, Michael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Combining Virtual Reality and Zoom to visualize chemical structures in 3D and develop the spatial ability of university chemistry students2021Inngår i: Book of abstracts: 9th European Variety in University Chemistry Education Conference EUROVARIETY 2021, University of Ljubljana , 2021, s. -60Konferansepaper (Fagfellevurdert)
  • 10.
    Broman, Karolina
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för naturvetenskapernas och matematikens didaktik.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Holmboe, Michael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Virtual Reality and Zoom in combination to visualise chemical structures and develop students' spatial ability during the Corona pandemic2021Inngår i: Den 8:e utvecklingskonferensen för Sveriges ingenjörsutbildningar: Detaljerat program, Karlstads universitet , 2021Konferansepaper (Fagfellevurdert)
    Abstract [en]

    In chemistry education, students need to develop their competence to visualise chemical structures and reaction mechanisms, for example, to be able to predict how chemical compounds react. As a chemistry or biotechnology engineering student, this competence needs to be practiced. In our project, students have since 2018 used Virtual Reality (VR) to learn to “see” chemistry, and to move between 2D and 3D representations, i.e., spatial ability or spatial thinking. During the Corona pandemic, several teaching challenges have had to be handled, and Zoom has become the most common teaching and communication platform in Sweden. When combining VR with Zoom, students had a possibility to develop their spatial ability even though distance teaching, something described in this paper. The combination of VR and Zoom is explored further for future teaching implications even post-Covid.

    Fulltekst (pdf)
    fulltext
  • 11.
    Broman, Karolina
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för naturvetenskapernas och matematikens didaktik.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Holmboe, Michael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Magkakis, Konstantinos
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Virtual Reality to visualise chemistry in higher education: Digital tools to enhance student learning2022Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Visualisation of molecular representations is an important area within chemistry education that has been explored for a long time, from several different perspectives. In the 1950s, Linus Pauling and Robert Koltun defined the CPK-model, describing the colours of the different atoms used in wood or plastic ball-and-stick models, for example, the black carbon, the white hydrogen, and the red oxygen. These analogue ball-and-stick models (e.g., MolyMod) are still used both in schools and at universities to help students “see” chemistry in three dimensions (3D). Today, with digitalisation, new tools are available to represent and visualise chemistry(Bernholt, Broman, Siebert, & Parchmann, 2019). With these modern digital tools, there are less limitations in molecular size to represent molecules, and even large structures and reaction mechanisms can be explored (Won, Mocerino, Tang, Treagust, & Tasker, 2019). In our project, interventions applying Virtual Reality (VR) as the digital tool during organic chemistry workshops and tutorials, have been explored related to cognitive and affective learning.

    VR gives students the possibility to practice spatial ability, i.e., to move between 2D and 3D. In textbooks, chemistry is presented in 2D using, for example, Lewis structures. However, in real life, chemistry is three-dimensional, and the move between 2D and 3D is something students, as novices, need to practice to understand why and how chemicals react. In our project, university students practice their spatial ability through the application of VR. This on-going project started in 2018, and different workshops and tutorials have been implemented in different chemistry courses for bachelor, master, and engineering students. As presented in previous recent research from Brown and colleagues (2021), our students were very positive, enthusiastic and engaged to work with VR to develop their spatial ability and to visualise chemistry. In the presentation, we will give examples on how students can improve their learning and interest with the use of VR to represent chemical structures.

  • 12.
    Broman, Karolina
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för naturvetenskapernas och matematikens didaktik.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Holmboe, Michael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Magkakis, Konstantinos
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Virtual Reality: visualization of chemical structures to enhance student interest and learning2022Inngår i: ECRICE 2022: chemistry teaching and learning in a global unified world: abstract book, Weizmann Institute of Science , 2022Konferansepaper (Fagfellevurdert)
    Abstract [en]

    One of the fundamental aspects of chemistry learning is to visualize chemical structures. Through the application of Alex Johnstone's (1991) multilevel thought, the submicroscopic level is often a challenge for students, especially the shift between 2D and 3D, i.e., spatial thinking or spatial ability (Harle & Towns, 2011). With small molecules, plastic ball-and-stick models are commonly used, but on university level, the structures are often larger. By applying digital tools and techniques, as Virtual Reality (VR), there are less limitations in size to represent molecules, and even large structures and reaction mechanisms can be explored (Won et al., 2019). In a five-year design-based research project (Anderson & Shattuck, 2012), a collaboration between university chemistry teachers and a chemistry education researcher, has had an aim to develop university chemistry students' spatial thinking.

    Students and teachers have, in workshops and tutorials, applied VR with both simple and more advanced tools, see figures 1 and 2. Empirical data has been collected using surveys, interviews, and observations. Standard ethical considerations have been considered throughout the whole project.

    In this presentation, students' cognitive and affective learning related to spatial thinking will be discussed, as well as students', teachers', and researcher’s perspectives from the application of VR to visualize chemistry will be elaborated further. Implications for chemistry teaching at all levels will also be explored.

  • 13.
    Broman, Karolina
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för naturvetenskapernas och matematikens didaktik.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Holmboe, Michael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Mårell-Olsson, Eva
    Umeå universitet, Samhällsvetenskapliga fakulteten, Pedagogiska institutionen.
    Zoom combined with Virtual Reality (VR) to visualize chemical structures inorganic chemistry2021Inngår i: Universitetspedagogiskakonferensen 2021: den goda utbildningsmiljön 2.1, Umeå: Universitetspedagogik och lärandestöd (UPL), Umeå universitet , 2021, s. 12-13Konferansepaper (Fagfellevurdert)
    Abstract [en]

    The ability to visualize chemistry and to move between two-dimensional (2D) representations presented in textbooks, and three-dimensional (3D) representations of the real molecular structures and mechanisms, is an important competence to master in university chemistry. In research, this is called spatial thinking or spatial ability (Hegarty, 2014). Through spatial thinking, chemists can predict how and why chemical compounds react. Chemistry experts are used to apply this spatial thinking, i.e., visualization through the move between 2D and 3D, without realizing it, whereas novices as students often find spatial thinking or spatial ability challenging (Harle & Towns, 2011). Spatial ability is a competence that is possible to develop through practice (Kozma & Russel, 2005), and in this project, chemistry students had the possibility to use virtual reality, VR, to visualize organic molecular structures and improve their spatial thinking. VR has a potential as a digital learning tool to explore 3D representation  During the last one and a half years, Covid 19 has influenced teaching strategies at universities, and Zoom has become the most common software to teach students. At a first-cycle chemistry course in biological chemistry within a bachelor programme in life science, students were given the opportunity to visualize 3D representations of chemical structures. Due to the Covid 19 restrictions, the teachers could not help students attending the course to be active VR users. Instead, one teacher applied the VR application, Oculus Rift combined with Nanome software (https://nanome.ai), and streamed the visualization over Zoom. The second university chemistry teacher, and the students, used simple VR glasses with their smartphones to visualize the 3D projected molecules, and the teacher explained what was presented. This design-based research project (Anderson & Shattuck, 2012), where the university chemistry teachers collaborated with a chemistry education researcher and a digitalization researcher, will elaborate further on how Zoom as a digital teaching tool also can be applied to facilitate spatial thinking for students even post-Covid. The chemistry teachers and chemistry education researcher designed an intervention from where examples of the visualizations will be presented together with survey results on students’ responses of the application of digital techniques as a way to practice their visualization competence and spatial ability. Preliminary results show that students find this visualization combining VR and Zoom valuable to practice their spatial thinking, and examples of teaching activities will be presented.

    For more information about the project, see https://www.umu.se/en/feature/vr-glasses-help-students-visualize-molecules-/or https://www.umu.se/reportage/vr-glasogon-hjalper-studenter-visualisera-molekyler/

    Fulltekst (pdf)
    fulltext
  • 14.
    Broman, Karolina
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för naturvetenskapernas och matematikens didaktik.
    Mårell-Olsson, Eva
    Umeå universitet, Samhällsvetenskapliga fakulteten, Institutionen för tillämpad utbildningsvetenskap, Interaktiva medier och lärande (IML).
    Johnels, Dan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Andersson, C. David
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Westerlind, Ulrika
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Boström, Jonas
    Norrby, Magnus
    Spatial Ability in Organic Chemistry: Can Virtual and Augmented Reality be Valuable?2019Inngår i: 7:e Utvecklingskonferensen för Sveriges ingenjörsutbildningar, Luleå tekniska universitet , 2019Konferansepaper (Annet vitenskapelig)
    Abstract [en]

    In this paper, the roles of digital technologies as Virtual Reality (VR), and Augmented Reality (AR), are discussed to explore how biotechnology engineering students develop their spatial ability in organic chemistry. We have, through stereochemistry workshops, followed how students, in specific, visualise and rotate molecular representations and how the use of digital tools influences the students’ interest.

    Fulltekst (pdf)
    fulltext
  • 15.
    Cegelski, Lynette
    et al.
    Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA..
    Pinkner, Jerome S
    Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.
    Hammer, Neal D
    Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
    Cusumano, Corinne K
    Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.
    Hung, Chia S
    Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Åberg, Veronica
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Walker, Jennifer N
    Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.
    Seed, Patrick C
    Departments of Pediatrics and Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chapman, Matthew R
    Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
    Hultgren, Scott J
    Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.
    Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation2009Inngår i: Nature Chemical Biology, ISSN 1552-4450, EISSN 1552-4469, Vol. 5, nr 12, s. 913-919Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Curli are functional extracellular amyloid fibers produced by uropathogenic Escherichia coli (UPEC) and other Enterobacteriaceae. Ring-fused 2-pyridones, such as FN075 and BibC6, inhibited curli biogenesis in UPEC and prevented the in vitro polymerization of the major curli subunit protein CsgA. The curlicides FN075 and BibC6 share a common chemical lineage with other ring-fused 2-pyridones termed pilicides. Pilicides inhibit the assembly of type

    1pili, which are required for pathogenesis during urinary tract infection. Notably, the curlicides retained pilicide activities and inhibited both curli-dependent and type 1–dependent biofilms. Furthermore, pretreatment of UPEC with FN075 significantly attenuated virulence in a mouse model of urinary tract infection. Curli and type 1pili exhibited exclusive and independent roles in promoting UPEC biofilms, and curli provided a fitness advantage in vivo. Thus, the ability of FN075 to block the biogenesis of both curli and type 1pili endows unique anti-biofilm and anti-virulence activities on these compounds.

  • 16.
    Chermenina, Maria
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Histologi med cellbiologi.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Henrik, Antti
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Wittung-Stafshede, Pernilla
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Strömberg, Ingrid
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Histologi med cellbiologi.
    A novel animal model for Parkinson's disease based on in vivo effects of small-molecule of alpha-synucleinManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Amyloid fibrils of alpha-synuclein are major constituents of Lewy bodies, the pathological hallmark of Parkinson’s disease. Monomeric α-synuclein is involved in synaptic vesicle trafficking and long-term maintenance of neurons. The underlying mechanisms of Parkinson’s disease are not known but it has been proposed that oligomers of α-synuclein, formed during the aggregation process, are toxic to neurons. To search for a new animal model of Parkinson’s disease, here we capitalized on the in vitro discovery of a small-molecule templator of α-synuclein fibrillization, the 2-pyridone, FN075. FN075 and MS382, another 2-pyridone variant that act as an inhibitor of amyloids in vitro, were injected into the striatum or substantia nigra of normal C57Bl/6 mice. No acute toxicity of the compounds was detected, as there was 100 % survival of the injected mice. At 6 months after the striatal injection, sensorimotor functions were impaired with no reduction in TH-positive neurons in the substantia nigra in mice injected with FN075, whereas mice injected with MS382 or vehicle had no dysfunctions. Injection of FN075 into the substantia nigra revealed a significant loss of TH-positive neurons already at 3 months and TH-negative inclusion-like structures were detected in substantia nigra neurons of these mice. Thus, the results suggest that injection of a templator of α-synuclein aggregation into the brain of normal mice can serve as a novel experimental design for an animal model of Parkinson’s disease.

  • 17.
    Chermenina, Maria
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Pokrzywa, Malgorzata
    Antti, Henrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Strömberg, Ingrid
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Wittung-Stafshede, Pernilla
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Single injection of small-molecule amyloid accelerator results in cell death of nigral dopamine neurons in mice2015Inngår i: Parkinson's Disease, ISSN 2090-8083, E-ISSN 2042-0080, Vol. 1, artikkel-id 15024Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The assembly process of a-synuclein toward amyloid fibers is linked to neurodegeneration in Parkinson´s disease. In the present study, we capitalized on the in vitro discovery of a small-molecule accelerator of a-synuclein amyloid formation and assessed its effects when injected in brains of normal mice. An accelerator and an inhibitor of a-synuclein amyloid formation, as well as vehicle only, were injected into the striatum of normal mice and follwed by behavioral evaluation, immunohistochemistry, and metabolomics up to six months later. The effects of molecules injected into the substansia nigra of normal and a-synuclein knockout mice were also analyzed. When accelerator or inhibitor was injected into the brain of normal mice no acute compound toxicity was found. However, 6 months after single striatal injection of accelerator, mice sensorimotor functions were impaired, whereas mice injected with inhibitor had no dysfunctions. Injection of accelerator (but not inhibitor or vehicle) into the substantia nigra revealed singificant loss of tyrosine hydroxylase (TH)-positive neurons after 3 months. No loss of TH-positive neurons was found in a-synuclein knock-out mice injected with accelerator intor the substantia nigra. Metabolic serum profiles from accelerator-injected normal mice matched those of newly diagnosed Parkinson´s disease patients, whereas the profiles from inhibitor-injected normal mice matched controls. Single inoculation of a small-molecule amyloid accelerator may be a new approach for studies of early events during dopamine neurodegeneration in mice.

    Fulltekst (pdf)
    fulltext
  • 18.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Pilicides and Curlicides: Design, synthesis, and evaluation of novel antibacterial agents targeting bacterial virulence2010Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    New strategies are needed to counter the growing problem of bacterial resistance to antibiotics. One such strategy is to design compounds that target bacterial virulence, which could work separately or in concert with conventional bacteriostatic or bactericidal antibiotics. Pilicides are a class of compounds based on a ring-fused 2-pyridone scaffold that target bacterial virulence by blocking the chaperone/usher pathway in E. coli and thereby inhibit the assembly of pili. This thesis describes the design, synthesis, and biological evaluation of compounds based on the pilicide scaffold with the goal of improving the pilicides and expanding their utility. Synthetic pathways have been developed to enable the introduction of substituents at the C-2 position of the pilicide scaffold. Biological evaluation of these compounds demonstrated that some C-2 substituents give rise to significant increases in potency. X-ray crystallography was used to elucidate the structural basis of this improved biological activity. Furthermore, improved methods for the preparation of oxygen-analogues and C-7 substituted derivatives of the pilicide scaffold have been developed. These new methods were used in combination with existing strategies to decorate the pilicide scaffold as part of a multivariate design approach to improve the pilicides and generate structure activity relationships (SARs).

    Fluorescent pilicides were prepared using a strategy where selected substituents were replaced with fluorophores having similar physicochemical properties as the original substituents. Many of the synthesized fluorescent compounds displayed potent pilicide activities and can thus be used to study the complex interactions between pilicide and bacteria. For example, when E. coli was treated with fluorescent pilicides, it was found that the compounds were not uniformly distributed throughout the bacterial population, suggesting that the compounds are primarily associated to bacteria with specific properties.

    Finally, by studying compounds designed to inhibit the aggregation of Aβ, it was found that some compounds based on the pilicide scaffold inhibit the formation of the functional bacterial amyloid fibers known as curli; these compounds are referred to as 'curlicides'. Some of the curlicides also prevent the formation of pili and thus exhibit dual pilicide-curlicide activity. The potential utility of such 'dual-action' compounds was highlighted by a study of one of the more potent dual pilicide-curlicides in a murine UTI model were the compound was found to significantly attenuate virulence in vivo.

    Fulltekst (pdf)
    FULLTEXT01
  • 19.
    Chorell, Erik
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Andersson, Emma
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Evans, Margery L.
    Jain, Neha
    Götheson, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Åden, Jörgen
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chapman, Matthew R.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Wittung-Stafshede, Pernilla
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bacterial Chaperones CsgE and CsgC Differentially Modulate Human α-Synuclein Amyloid Formation via Transient Contacts2015Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 10, nr 10, s. 1-11, artikkel-id e0140194Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Amyloid formation is historically associated with cytotoxicity, but many organisms produce functional amyloid fibers (e.g., curli) as a normal part of cell biology. Two E. coli genes in the curli operon encode the chaperone-like proteins CsgC and CsgE that both can reduce in vitro amyloid formation by CsgA. CsgC was also found to arrest amyloid formation of the human amyloidogenic protein α-synuclein, which is involved in Parkinson’s disease. Here, we report that the inhibitory effects of CsgC arise due to transient interactions that promote the formation of spherical α-synuclein oligomers. We find that CsgE also modulates α-synuclein amyloid formation through transient contacts but, in contrast to CsgC, CsgE accelerates α-synuclein amyloid formation. Our results demonstrate the significance of transient protein interactions in amyloid regulation and emphasize that the same protein may inhibit one type of amyloid while accelerating another.

    Fulltekst (pdf)
    fulltext
  • 20.
    Chorell, Erik
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bengtsson, Christoffer
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sainte-Luce Banchelin, Thomas
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Das, Pralay
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Uvell, Hanna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sinha, Arun K
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Pinkner, Jerome S
    Department of Molecular Microbiology, Washington University, School of Medicine, St. Louis, Missouri 63110, USA.
    Hultgren, Scott J
    Department of Molecular Microbiology, Washington University, School of Medicine, St. Louis, Missouri 63110, USA.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Synthesis and application of a bromomethyl substituted scaffold to be used for efficient optimization of anti-virulence activity2011Inngår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 46, nr 4, s. 1103-1116Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Pilicides are a class of compounds that attenuate virulence in Gram negative bacteria by blocking the chaperone/usher pathway in Escherichia coli. It has also been shown that compounds derived from the peptidomimetic scaffold that the pilicides are based on can prevent both Aβ aggregation and curli formation. To facilitate optimizations towards the different targets, a new synthetic platform has been developed that enables fast and simple introduction of various substituents in position C-7 on the peptidomimetic scaffold. Importantly, this strategy also enables introduction of previously unattainable heteroatoms in this position. Pivotal to the synthetic strategy is the synthesis of a C-7 bromomethyl substituted derivative of the ring-fused dihydrothiazolo 2-pyridone pilicide scaffold. From this versatile and reactive intermediate various heteroatom-linked substituents could be introduced on the scaffold including amines, ethers, amides and sulfonamides. In addition, carbon-carbon bonds could be introduced to the sp(3)-hybridized bromomethyl substituted scaffold by Suzuki-Miyaura cross couplings. Evaluation of the 24 C-7 substituted compounds in whole-bacterial assays provided important structure-activity data and resulted in the identification of a number of new pilicides with activity as good or better than those developed previously.

  • 21.
    Chorell, Erik
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chorell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Efficient Synthesis of 2-Substituted Phthalimides from Phthalic Acids in One Step2013Inngår i: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, Vol. 2013, nr 33, s. 7512-7516Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Efficient procedures for synthesizing 2-substituted phthalimide (isoindole-1,3-dione) analogues starting from phthalic acids have been developed by using experimental design. The phthalimide central fragment frequently appears in biologically active compounds, materials, catalysts, and fluorescent probes, and therefore the development of general, fast, and convenient synthetic methods to this scaffold under neutral, acidic, and basic conditions would be attractive. After an initial screening, the use of acetonitrile, acetic acid, or pyridine in combination with microwave heating proved most promising. Experimental design was applied to these conditions to optimize the time, temperature, and concentration. This strategy has successfully generated synthetic methods that have been used to synthesize a series of phthalimides from phthalic acids and various amines or anilines in excellent yields. The developed methods have proven to be general, fast, convenient, and economic, and thus are expected to have broad utility to efficiently construct novel compounds for future biological and chemical applications.

  • 22.
    Chorell, Erik
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Das, Pralay
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Diverse functionalization of Thiazolo ring-fused 2-Pyridones2007Inngår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 72, nr 13, s. 4917-4924Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Thiazolo ring-fused 2-pyridones have proven to be highly interesting scaffolds for the development of biologically active compounds. Many methods are today available to introduce a variety of substituents in the 2-pyridone part of the heterocycle. Herein we disclose how a diverse set of substituents can be introduced in the thiazolo ring, with possibilities to vary also the spatial arrangement of the substituents. A key intermediate is the oxidized framework 9 for which an effective synthesis is described. The thiazolo part of this system can be substituted either via conjugate additions, resulting in trans selectivity, or via microwave-assisted Heck couplings that result in unsaturated aryl-substituted analogues. The scaffold can also be lithiated followed by the addition of various electrophiles, which increases the diversification potential substantially, as exemplified with the introduction of halogens, alkyl, acyl, and amide substituents.

  • 23.
    Chorell, Erik
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Edvinsson, Sofie
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Improved procedure for the enantioselective synthesis of dihydrooxazolo and dihydrothiazolo ring-fused 2-pyridones2010Inngår i: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 51, nr 18, s. 2461-2463Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Improved procedures to synthesize enantioselectively analogues of a peptidomimetic scaffold with high biological relevance have been developed. Experimental design led to a general method for the preparation of dihydrooxazolo ring-fused 2-pyridones in good yields and high enantiomeric purity. The knowledge gained from this was also used to improve the microwave-accelerated synthesis of dihydrothiazolo ring-fused 2-pyridones to give complete stereo retention and high yields.

  • 24.
    Chorell, Erik
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Pinkner, Jerome S
    Bengtsson, Christoffer
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Banchelin, Thomas Sainte-Luce
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Edvinsson, Sofie
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Linusson, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Hultgren, Scott J
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Mapping pilicide anti-virulence effect in Escherichia coli, a comprehensive structure-activity study2012Inngår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 20, nr 9, s. 3128-3142Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Pilicides prevent pili formation and thereby the development of bacterial biofilms in Escherichia coli. We have performed a comprehensive structure activity relationship (SAR) study of the dihydrothiazolo ring-fused 2-pyridone pilicide central fragment by varying all open positions. Orthogonal projections to latent structures discriminant analysis (OPLS-DA) was used to distinguish active from inactive compounds in which polarity proved to be the most important factor for discrimination. A quantitative SAR (QSAR) partial least squares (PLS) model was calculated on the active compounds for prediction of biofilm inhibition activity. In this model, compounds with high inhibitory activity were generally larger, more lipophilic, more flexible and had a lower HOMO. Overall, this resulted in both highly valuable SAR information and potent inhibitors of type 1 pili dependent biofilm formation. The most potent biofilm inhibitor had an EC(50) of 400nM.

  • 25.
    Chorell, Erik
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Pinkner, Jerome S
    Bengtsson, Christoffer
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Edvinsson, Sofie
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Cusumano, Corinne K
    Rosenbaum, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Johansson, Lennart B-Å
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Hultgren, Scott J
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Design and Synthesis of Fluorescent Pilicides and Curlicides: Bioactive Tools to Study Bacterial Virulence Mechanisms2012Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 18, nr 15, s. 4522-4532Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Pilicides and curlicides are compounds that block the formation of the virulence factors pili and curli, respectively. To facilitate studies of the interaction between these compounds and the pili and curli assembly systems, fluorescent pilicides and curlicides have been synthesized. This was achieved by using a strategy based on structure-activity knowledge, in which key pilicide and curlicide substituents on the ring-fused dihydrothiazolo 2-pyridone central fragment were replaced by fluorophores. Several of the resulting fluorescent compounds had improved activities as measured in pili- and curli-dependent biofilm assays. We created fluorescent pilicides and curlicides by introducing coumarin and 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophores at two positions on the peptidomimetic pilicide and curlicide central fragment. Fluorescence images of the uropathogenic Escherichia coli (UPEC) strain UTI89 grown in the presence of these compounds shows that the compounds are strongly associated with the bacteria with a heterogeneous distribution.

  • 26.
    Chorell, Erik
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Pinkner, Jerome S.
    Department of Molecular Microbiology, Washington University, School of Medicine, St. Louis, Missouri 63110, USA.
    Bengtsson, Christoffer
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Edvinsson, Sofie
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Cusumano, Corinne K.
    Rosenbaum, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Johansson, Lennart B-Å
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Hultgren, Scott J.
    Department of Molecular Microbiology, Washington University, School of Medicine, St. Louis, Missouri 63110, USA.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Design and synthesis of fluorescently labeled pilicides and curlicides: bioactive tools to study bacterial virulence mechanismsManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Pilicides and curlicides block formation of the E. coli virulence factors pili and curli. To facilitate studies of the interaction between these compounds and the pili and curli assembly systems, fluorescent pilicides and curlicides have been synthesized. This was achieved using a strategy where key pilicide and curlicide substituents were replaced by fluorophores having similar physicochemical properties. The resulting fluorescent compounds had improved anti-virulence activities as measured in pili- and curli-dependent biofilm assays. We created fluorescent pilicides and curlicides by introducing both coumarin and 4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophores at two positions on the peptidomimetic pilicide and curlicide scaffold. Fluorescence images of the uropathogenic Escherichia coli (UPEC) strain UTI89 grown in the presence of these compounds shows that the compounds are strongly associated to the bacteria and seem to discriminate between different bacteria in a population.

  • 27.
    Chorell, Erik
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Pinkner, Jerome S
    Department of Molecular Microbiology, Washington University, School of Medicine, St. Louis, Missouri 63110, USA.
    Phan, Gilles
    Institute of Structural and Molecular Biology, University College London/Birkbeck, Malet Street, London WC1E 7HX, U.K..
    Edvinsson, Sofie
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Buelens, Floris
    Institute of Structural and Molecular Biology, University College London/Birkbeck, Malet Street, London WC1E 7HX, U.K..
    Remaut, Han
    Institute of Structural and Molecular Biology, University College London/Birkbeck, Malet Street, London WC1E 7HX, U.K..
    Waksman, Gabriel
    Institute of Structural and Molecular Biology, University College London/Birkbeck, Malet Street, London WC1E 7HX, U.K..
    Hultgren, Scott J
    Department of Molecular Microbiology, Washington University, School of Medicine, St. Louis, Missouri 63110, USA.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Design and synthesis of C-2 substituted Thiazolo and Dihydrothiazolo ring-fused 2-Pyridones: pilicides with increased antivirulence activity2010Inngår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, nr 15, s. 5690-5695Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Pilicides block pili formation by binding to pilus chaperones and blocking their function in the chaperone/usher pathway in E. coli. Various C-2 substituents were introduced on the pilicide scaffold by design and synthetic method developments. Experimental evaluation showed that proper substitution of this position affected the biological activity of the compound. Aryl substituents resulted in pilicides with significantly increased potencies as measured in pili-dependent biofilm and hemagglutination assays. The structural basis of the PapD chaperone-pilicide interactions was determined by X-ray crystallography.

  • 28.
    Dang, Hung The
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, USA.
    Uvell, Hanna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Pinkner, Jerome S.
    Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, USA.
    Hultgren, Scott J.
    Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, USA.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Syntheses and biological evaluation of 2-amino-3-acyl-tetrahydrobenzothiophene derivatives: antibacterial agents with antivirulence activity2014Inngår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 12, nr 12, s. 1942-1956Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Developing new compounds targeting virulence factors (e.g., inhibition of pilus assembly by pilicides) is a promising approach to combating bacterial infection. A high-throughput screening campaign of a library of 17 500 small molecules identified 2-amino-3-acyl-tetrahydrobenzothiophene derivatives (hits 2 and 3) as novel inhibitors of pili-dependent biofilm formation in a uropathogenic Escherichia coli strain UTI89. Based on compounds 2 and 3 as the starting point, we designed and synthesized a series of structurally related analogs and investigated their activity against biofilm formation of E. coli UTI89. Systematic structural modification of the initial hits provided valuable information on their SARs for further optimization. In addition, small structural changes to the parent molecules resulted in low micromolar inhibitors (20-23) of E. coli biofilm development without an effect on bacterial growth. The hit compound 3 and its analog 20 were confirmed to prevent pili formation in a hemagglutination (HA) titer assay and electron microscopy (EM) measurements. These findings suggest that 2-amino-3-acyl-tetrahydrobenzothiophenes may serve as a new class of compounds for further elaboration as antibacterial agents with antivirulence activity.

  • 29.
    Das, Rabindra Nath
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Andréasson, Måns
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Kumar, Rajendra
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Macrocyclization of bis-indole quinolines for selective stabilization of G-quadruplex DNA structures2020Inngår i: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 11, nr 38, s. 10529-10537Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The recognition of G-quadruplex (G4) DNA structures as important regulatory elements in biological mechanisms, and the connection between G4s and the evolvement of different diseases, has sparked interest in developing small organic molecules targeting G4s. However, such compounds often lack drug-like properties and selectivity. Here, we describe the design and synthesis of a novel class of macrocyclic bis-indole quinolines based on their non-macrocyclic lead compounds. The effects of the macrocyclization on the ability to interact with G4 DNA structures were investigated using biophysical assays and molecular dynamic simulations. Overall, this revealed compounds with potent abilities to interact with and stabilize G4 structures and a clear selectivity for both G4 DNA over dsDNA and for parallel/hybrid G4 topologies, which could be attributed to the macrocyclic structure. Moreover, we obtained knowledge about the structure-activity relationship of importance for the macrocyclic design and how structural modifications could be made to construct improved macrocyclic compounds. Thus, the macrocyclization of G4 ligands can serve as a basis for the optimization of research tools to study G4 biology and potential therapeutics targeting G4-related diseases.

    Fulltekst (pdf)
    fulltext
  • 30.
    Das, Rabindra Nath
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Berner, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Bhuma, Naresh
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Golebiewska, Justyna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Abrahamsson, Alva
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Andréasson, Måns
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chaudhari, Namrata
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Doimo, Mara
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Development of a G4 Ligand-Conjugated Oligonucleotide Modality that Selectively Targets Individual G4 DNA StructuresManuskript (preprint) (Annet vitenskapelig)
  • 31.
    Deiana, Marco
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chand, Karam
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sabouri, Nasim
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Parallel G-quadruplex DNA structures from nuclear and mitochondrial genomes trigger emission enhancement in a nonfluorescent nano-aggregated fluorine-boron-based dye2023Inngår i: Journal of Physical Chemistry Letters, ISSN 1948-7185, E-ISSN 1948-7185, Vol. 14, nr 7, s. 1862-1869Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Molecular self-assembly is a powerful tool for the development of functional nanostructures with adaptive optical properties. However, in aqueous solution, the hydrophobic effects in the monomeric units often afford supramolecular architectures with typical side-by-side π-stacking arrangement with compromised emissive properties. Here, we report on the role of parallel DNA guanine quadruplexes (G4s) as supramolecular disaggregating-capture systems capable of coordinating a zwitterionic fluorine-boron-based dye and promoting activation of its fluorescence signal. The dye's high binding affinity for parallel G4s compared to nonparallel topologies leads to a selective disassembly of the dye's supramolecular state upon contact with parallel G4s. This results in a strong and selective disaggregation-induced emission that signals the presence of parallel G4s observable by the naked eye and inside cells. The molecular recognition strategy reported here will be useful for a multitude of affinity-based applications with potential in sensing and imaging systems.

    Fulltekst (pdf)
    fulltext
  • 32.
    Deiana, Marco
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chand, Karam
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Jamroskovic, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Das, Rabindra Nath
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Obi, Ikenna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sabouri, Nasim
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    A Site-Specific Self-Assembled Light-up Rotor Probe for Selective Recognition and Stabilization of c-MYC G-Quadruplex DNA2020Inngår i: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 12, nr 24, s. 12950-12957Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Direct and unambiguous evidence of the formation of G-quadruplexes (G4s) in human cells have shown their implication in several key biological events and has emphasized their role as important targets for small-molecule cancer therapeutics. Here, we report on the first example of a self-assembled multitasking molecular-rotor G4-binder able to discriminate between an extensive panel of G4 and non-G4 structures and to selectively light-up (up to 105-fold), bind (nanomolar range), and stabilize the c-MYC promoter G4 DNA. In particular, association with the c-MYC G4 triggers the disassembly of its supramolecular state (disaggregation-induced emission, DIE) and induces geometrical restrictions (motion-induced change in emission, MICE) leading to a significant enhancement of its emission yield. Moreover, this optical reporter is able to selectively stabilize the c-MYC G4 and inhibit DNA synthesis. Finally, by using confocal laser-scanning microscopy (CLSM) we show the ability of this compound to localize primarily in the subnuclear G4-rich compartments of cancer cells. This work provides a benchmark for the future design and development of a new generation of smart sequence-selective supramolecular G4-binders that combine outstanding sensing and stability properties, to be utilized in anti-cancer therapy.

    Fulltekst (pdf)
    fulltext
  • 33.
    Deiana, Marco
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chand, Karam
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Jamroskovic, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Obi, Ikenna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sabouri, Nasim
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    A Light‐up Logic Platform for Selective Recognition of Parallel G‐Quadruplex Structures via Disaggregation‐Induced Emission2020Inngår i: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 59, nr 2, s. 896-902Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The design of turn‐on dyes with optical signals sensitive to the formation of supramolecular structures provides fascinating and underexplored opportunities for G‐quadruplex (G4) DNA detection and characterization. Here, we show a new switching mechanism that relies on the recognition‐driven disaggregation (on‐signal) of an ultrabright coumarin‐quinazoline conjugate. The synthesized probe selectively lights‐up parallel G4 DNA structures via the disassembly of its supramolecular state, demonstrating outputs that are easily integrable into a label free molecular logic system. Finally, our molecule preferentially stains the G4‐rich nucleoli of cancer cells.

  • 34.
    Deiana, Marco
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Obi, Ikenna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Andréasson, Måns
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Tamilselvi, Shanmugam
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chand, Karam
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sabouri, Nasim
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    A Minimalistic Coumarin Turn-On Probe for Selective Recognition of Parallel G-Quadruplex DNA Structures2021Inngår i: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 16, nr 8, s. 1365-1376Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    G-quadruplex (G4) DNA structures are widespread in the human genome and are implicated in biologically important processes such as telomere maintenance, gene regulation, and DNA replication. Guanine-rich sequences with potential to form G4 structures are prevalent in the promoter regions of oncogenes, and G4 sites are now considered as attractive targets for anticancer therapies. However, there are very few reports of small “druglike” optical G4 reporters that are easily accessible through one-step synthesis and that are capable of discriminating between different G4 topologies. Here, we present a small water-soluble light-up fluorescent probe that features a minimalistic amidinocoumarin-based molecular scaffold that selectively targets parallel G4 structures over antiparallel and non-G4 structures. We showed that this biocompatible ligand is able to selectively stabilize the G4 template resulting in slower DNA synthesis. By tracking individual DNA molecules, we demonstrated that the G4-stabilizing ligand perturbs DNA replication in cancer cells, resulting in decreased cell viability. Moreover, the fast-cellular entry of the probe enabled detection of nucleolar G4 structures in living cells. Finally, insights gained from the structure–activity relationships of the probe suggest the basis for the recognition of parallel G4s, opening up new avenues for the design of new biocompatible G4-specific small molecules for G4-driven theranostic applications.

    Fulltekst (pdf)
    fulltext
  • 35.
    Doimo, Mara
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Department of Women and Children Health, University of Padova, Padova, Italy.
    Chaudhari, Namrata
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Abrahamsson, Sanna
    Bioinformatics and Data Centre, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    L'Hôte, Valentin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Nguyen, Tran V. H.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Berner, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ndi, Mama
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Abrahamsson, Alva
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Das, Rabindra Nath
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Aasumets, Koit
    Department of Environmental and Biological Sciences, University of Eastern Finland, Joensuu, Finland.
    Goffart, Steffi
    Department of Environmental and Biological Sciences, University of Eastern Finland, Joensuu, Finland.
    Pohjoismäki, Jaakko L. O.
    Department of Environmental and Biological Sciences, University of Eastern Finland, Joensuu, Finland.
    López, Marcela Dávila
    Bioinformatics and Data Centre, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Enhanced mitochondrial G-quadruplex formation impedes replication fork progression leading to mtDNA loss in human cells2023Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 51, nr 14, s. 7392-7408Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mitochondrial DNA (mtDNA) replication stalling is considered an initial step in the formation of mtDNA deletions that associate with genetic inherited disorders and aging. However, the molecular details of how stalled replication forks lead to mtDNA deletions accumulation are still unclear. Mitochondrial DNA deletion breakpoints preferentially occur at sequence motifs predicted to form G-quadruplexes (G4s), four-stranded nucleic acid structures that can fold in guanine-rich regions. Whether mtDNA G4s form in vivo and their potential implication for mtDNA instability is still under debate. In here, we developed new tools to map G4s in the mtDNA of living cells. We engineered a G4-binding protein targeted to the mitochondrial matrix of a human cell line and established the mtG4-ChIP method, enabling the determination of mtDNA G4s under different cellular conditions. Our results are indicative of transient mtDNA G4 formation in human cells. We demonstrate that mtDNA-specific replication stalling increases formation of G4s, particularly in the major arc. Moreover, elevated levels of G4 block the progression of the mtDNA replication fork and cause mtDNA loss. We conclude that stalling of the mtDNA replisome enhances mtDNA G4 occurrence, and that G4s not resolved in a timely manner can have a negative impact on mtDNA integrity.

    Fulltekst (pdf)
    fulltext
  • 36.
    Engström, Patrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Krishnan, K. Syam
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Ngyuen, Bidong D.
    Chorell, Erik
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Normark, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Silver, Jim
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Bastidas, Robert J.
    Welch, Matthew D.
    Hultgren, Scott J.
    Wolf-Watz, Hans
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Valdivia, Raphael H.
    Almqvist, Fredrik
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bergström, Sven
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    A 2-Pyridone-Amide Inhibitor Targets the Glucose Metabolism Pathway of Chlamydia trachomatis2015Inngår i: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 6, nr 1, artikkel-id e02304-14Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In a screen for compounds that inhibit infectivity of the obligate intracellular pathogen Chlamydia trachomatis, we identified the 2-pyridone amide KSK120. A fluorescent KSK120 analogue was synthesized and observed to be associated with the C. trachomatis surface, suggesting that its target is bacterial. We isolated KSK120-resistant strains and determined that several resistance mutations are in genes that affect the uptake and use of glucose-6-phosphate (G-6P). Consistent with an effect on G-6P metabolism, treatment with KSK120 blocked glycogen accumulation. Interestingly, KSK120 did not affect Escherichia coli or the host cell. Thus, 2-pyridone amides may represent a class of drugs that can specifically inhibit C. trachomatis infection. IMPORTANCE Chlamydia trachomatis is a bacterial pathogen of humans that causes a common sexually transmitted disease as well as eye infections. It grows only inside cells of its host organism, within a parasitophorous vacuole termed the inclusion. Little is known, however, about what bacterial components and processes are important for C. trachomatis cellular infectivity. Here, by using a visual screen for compounds that affect bacterial distribution within the chlamydial inclusion, we identified the inhibitor KSK120. As hypothesized, the altered bacterial distribution induced by KSK120 correlated with a block in C. trachomatis infectivity. Our data suggest that the compound targets the glucose-6-phosphate (G-6P) metabolism pathway of C. trachomatis, supporting previous indications that G-6P metabolism is critical for C. trachomatis infectivity. Thus, KSK120 may be a useful tool to study chlamydial glucose metabolism and has the potential to be used in the treatment of C. trachomatis infections.

    Fulltekst (pdf)
    fulltext
  • 37. Evans, Margery L.
    et al.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Taylor, Jonathan D.
    Ådén, Jörgen
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Götheson, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Li, Fei
    Koch, Marion
    Sefer, Lea
    Matthews, Steve J.
    Wittung-Stafshede, Pernilla
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chapman, Matthew R.
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    The Bacterial Curli System Possesses a Potent and Selective Inhibitor of Amyloid Formation2015Inngår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 57, nr 3, s. 445-455Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Summary Curli are extracellular functional amyloids that are assembled by enteric bacteria during biofilm formation and host colonization. An efficient secretion system and chaperone network ensures that the major curli fiber subunit, CsgA, does not form intracellular amyloid aggregates. We discovered that the periplasmic protein CsgC was a highly effective inhibitor of CsgA amyloid formation. In the absence of CsgC, CsgA formed toxic intracellular aggregates. In vitro, CsgC inhibited CsgA amyloid formation at substoichiometric concentrations and maintained CsgA in a non-β-sheet-rich conformation. Interestingly, CsgC inhibited amyloid assembly of human α-synuclein, but not Aβ42, in vitro. We identified a common D-Q-Φ-X0,1-G-K-N-ζ-E motif in CsgC client proteins that is not found in Aβ42. CsgC is therefore both an efficient and selective amyloid inhibitor. Dedicated functional amyloid inhibitors may be a key feature that distinguishes functional amyloids from disease-associated amyloids.

  • 38. Flentie, Kelly
    et al.
    Harrison, Gregory A.
    Tükenmez, Hasan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Livny, Jonathan
    Good, James A. D.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Sarkar, Souvik
    Zhu, Dennis X.
    Kinsella, Rachel L.
    Weiss, Leslie A.
    Solomon, Samantha D.
    Schene, Miranda E.
    Hansen, Mette R.
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Cairns, Andrew G.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Kulén, Martina
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Wixe, Torbjörn
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Lindgren, Anders E. G.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110.
    Bengtsson, Christoffer
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Krishnan, K. Syam
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Hultgren, Scott J.
    Larsson, Christer
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Stallings, Christina L.
    Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis2019Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, nr 21, s. 10510-10517Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mycobacterium tuberculosis (Mtb) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of Mtb that are resistant to frontline antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are major obstacles to successful TB therapy. Using a chemical approach to identify compounds that block stress and drug tolerance, as opposed to traditional screens for compounds that kill Mtb, we identified a small molecule, C10, that blocks tolerance to oxidative stress, acid stress, and the frontline antibiotic isoniazid (INH). In addition, we found that C10 prevents the selection for INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb strains harboring mutations in the katG gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits Mtb respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect Mtb persistence, we discovered that INH resistance is not absolute and can be reversed.

  • 39.
    Good, James A. D.
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Andersson, Christopher
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Hansen, Sabine
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Wall, Jessica
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Krishnan, Syam
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Begum, Afshan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Grundström, Christin
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Niemiec, Moritz Sebastian
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Vaitkevicius, Karolis
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Wittung-Stafshede, Pernilla
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sauer, Uwe H.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Sauer–Eriksson, A. Elisabeth
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Johansson, Jörgen
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Attenuating Listeria monocytogenes virulence by targeting the regulatory protein PrfA2016Inngår i: Cell chemical biology, ISSN 2451-9448, Vol. 23, nr 3, s. 404-414Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The transcriptional activator PrfA, a member of the Crp/Fnr family, controls the expression of some key virulence factors necessary for infection by the human bacterial pathogen Listeria monocytogenes. Phenotypic screening identified ring-fused 2-pyridone molecules that at low micromolar concentrations attenuate L. monocytogenes infectivity by reducing the expression of virulence genes, without compromising bacterial growth. These inhibitors bind the transcriptional regulator PrfA and decrease its affinity for the consensus DNA binding site. Structural characterization of this interaction revealed that one of the ring-fused 2-pyridones, compound 1, binds within a hydrophobic pocket, located between the C- and N-terminal domains of PrfA, and interacts with residues important for PrfA activation. This indicates that these inhibitors maintain the DNA-binding helix-turn-helix motif of PrfA in a disordered state, thereby preventing a PrfA:DNA interaction. Ring-fused 2-pyridones represent a new class of chemical probes for studying virulence in L. monocytogenes.

    Fulltekst (pdf)
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  • 40. Greene, Sarah E.
    et al.
    Pinkner, Jerome S.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Dodson, Karen W.
    Shaffer, Carrie L.
    Conover, Matt S.
    Livny, Jonathan
    Hadjifrangiskou, Maria
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Hultgren, Scott J.
    Pilicide ec240 Disrupts Virulence Circuits in Uropathogenic Escherichia coli2014Inngår i: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 5, nr 6, s. UNSP e02038-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chaperone-usher pathway (CUP) pili are extracellular organelles produced by Gram-negative bacteria that mediate bacterial pathogenesis. Small-molecule inhibitors of CUP pili, termed pilicides, were rationally designed and shown to inhibit type 1 or P piliation. Here, we show that pilicide ec240 decreased the levels of type 1, P, and S piliation. Transcriptomic and proteomic analyses using the cystitis isolate UTI89 revealed that ec240 dysregulated CUP pili and decreased motility. Paradoxically, the transcript levels of P and S pilus genes were increased during growth in ec240, even though the level of P and S piliation decreased. In contrast, the most downregulated transcripts after growth in ec240 were from the type 1 pilus genes. Type 1 pilus expression is controlled by inversion of the fimS promoter element, which can oscillate between phase on and phase off orientations. ec240 induced the fimS phase off orientation, and this effect was necessary for the majority of ec240's inhibition of type 1 piliation. ec240 increased levels of the transcriptional regulators SfaB and PapB, which were shown to induce the fimS promoter phase off orientation. Furthermore, the effect of ec240 on motility was abolished in the absence of the SfaB, PapB, SfaX, and PapX regulators. In contrast to the effects of ec240, deletion of the type 1 pilus operon led to increased S and P piliation and motility. Thus, ec240 dysregulated several uropathogenic Escherichia coli (UPEC) virulence factors through different mechanisms and independent of its effects on type 1 pilus biogenesis and may have potential as an antivirulence compound. IMPORTANCE CUP pili and flagella play active roles in the pathogenesis of a variety of Gram-negative bacterial infections, including urinary tract infections mediated by UPEC. These are extremely common infections that are often recurrent and increasingly caused by antibiotic-resistant organisms. Preventing piliation and motility through altered regulation and assembly of these important virulence factors could aid in the development of novel therapeutics. This study increases our understanding of the regulation of these virulence factors, providing new avenues by which to target their expression.

    Fulltekst (pdf)
    fulltext
  • 41.
    Horvath, Istvan
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Weise, Christoph F
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Andersson, Emma K
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sellstedt, Magnus
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bengtsson, Christoffer
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Olofsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Hultgren, Scott J
    Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
    Chapman, Matthew
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Wolf-Watz, Magnus
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Wittung-Stafshede, Pernilla
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Mechanisms of Protein Oligomerization: Inhibitor of Functional Amyloids Templates α-Synuclein Fibrillation2012Inngår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 134, nr 7, s. 3439-3444Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Small organic molecules that inhibit functional bacterial amyloid fibers, curli, are promising new antibiotics. Here we investigated the mechanism by which the ring-fused 2-pyridone FN075 inhibits fibrillation of the curli protein CsgA. Using a variety of biophysical techniques, we found that FN075 promotes CsgA to form off-pathway, non-amyloidogenic oligomeric species. In light of the generic properties of amyloids, we tested whether FN075 would also affect the fibrillation reaction of human α-synuclein, an amyloid-forming protein involved in Parkinson's disease. Surprisingly, FN075 stimulates α-synuclein amyloid fiber formation as measured by thioflavin T emission, electron microscopy (EM), and atomic force microscopy (AFM). NMR data on (15)N-labeled α-synuclein show that upon FN075 addition, α-synuclein oligomers with 7 nm radius form in which the C-terminal 40 residues remain disordered and solvent exposed. The polypeptides in these oligomers contain β-like secondary structure, and the oligomers are detectable by AFM, EM, and size-exclusion chromatography (SEC). Taken together, FN075 triggers oligomer formation of both proteins: in the case of CsgA, the oligomers do not proceed to fibers, whereas for α-synuclein, the oligomers are poised to rapidly form fibers. We conclude that there is a fine balance between small-molecule inhibition and templation that depends on protein chemistry.

  • 42.
    Jamroskovic, Jan
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Doimo, Mara
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chand, Karam
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Obi, Ikenna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Kumar, Rajendra
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Brännström, Kristoffer
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Hedenström, Mattias
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Das, Rabindra Nath
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Akhunzianov, Almaz
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia.
    Deiana, Marco
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Kasho, Kazutoshi
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Sulis Sato, Sebastian
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Pourbozorgi-Langroudi, Parham
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Mason, James E.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Medini, Paolo
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Öhlund, Daniel
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sabouri, Nasim
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Quinazoline Ligands Induce Cancer Cell Death through Selective STAT3 Inhibition and G-Quadruplex Stabilization2020Inngår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 142, nr 6, s. 2876-2888Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The signal transducer and activator of transcription 3 (STAT3) protein is a master regulator of most key hallmarks and enablers of cancer, including cell proliferation and the response to DNA damage. G-Quadruplex (G4) structures are four-stranded noncanonical DNA structures enriched at telomeres and oncogenes' promoters. In cancer cells, stabilization of G4 DNAs leads to replication stress and DNA damage accumulation and is therefore considered a promising target for oncotherapy. Here, we designed and synthesized novel quinazoline-based compounds that simultaneously and selectively affect these two well-recognized cancer targets, G4 DNA structures and the STAT3 protein. Using a combination of in vitro assays, NMR, and molecular dynamics simulations, we show that these small, uncharged compounds not only bind to the STAT3 protein but also stabilize G4 structures. In human cultured cells, the compounds inhibit phosphorylation-dependent activation of STAT3 without affecting the antiapoptotic factor STAT1 and cause increased formation of G4 structures, as revealed by the use of a G4 DNA-specific antibody. As a result, treated cells show slower DNA replication, DNA damage checkpoint activation, and an increased apoptotic rate. Importantly, cancer cells are more sensitive to these molecules compared to noncancerous cell lines. This is the first report of a promising class of compounds that not only targets the DNA damage cancer response machinery but also simultaneously inhibits the STAT3-induced cancer cell proliferation, demonstrating a novel approach in cancer therapy.

    Fulltekst (pdf)
    fulltext
  • 43.
    Jamroskovic, Jan
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Livendahl, Madeleine
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Eriksson, Jonas
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sabouri, Nasim
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Identification of Compounds that Selectively Stabilize Specific G-Quadruplex Structures by Using a Thioflavin T-Displacement Assay as a Tool2016Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 22, nr 52, s. 18932-18943Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Small molecules are used in the G-quadruplex (G4) research field in vivo and in vitro, and there are increasing demands for ligands that selectively stabilize different G4 structures. Thioflavin T (ThT) emits an enhanced fluorescence signal when binding to G4 structures. Herein, we show that ThT can be competitively displaced by the binding of small molecules to G4 structures and develop a ThT-displacement high-throughput screening assay to find novel and selective G4-binding compounds. We screened approximately 28 000 compounds by using three different G4 structures and identified eight novel G4 binders. Analysis of the structural conformation and stability of the G4 structures in presence of these compounds demonstrated that the four compounds enhance the thermal stabilization of the structures without affecting their structural conformation. In addition, all four compounds also increased the G4-structure block of DNA synthesis by Taq DNA polymerase. Also, two of these compounds showed selectivity between certain Schizosaccharomyces pombe G4 structures, thus suggesting that these compounds or their analogues can be used as selective tools for G4 DNA studies.

  • 44.
    Jamroskovic, Jan
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Obi, Ikenna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Movahedi, Anahita
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chand, Karam
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sabouri, Nasim
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Identification of putative G-quadruplex DNA structures in S. pombe genome by quantitative PCR stop assay2019Inngår i: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 82, artikkel-id 102678Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In order to understand in which biological processes the four-stranded G-quadruplex (G4) DNA structures play a role, it is important to determine which predicted regions can actually adopt a G4 structure. Here, to identify DNA regions in Schizosaccharomyces pombe that fold into G4 structures, we first optimized a quantitative PCR (qPCR) assay using the G4 stabilizer, PhenDC3. We call this method the qPCR stop assay, and used it to screen for G4 structures in genomic DNA. The presence of G4 stabilizers inhibited DNA amplification in 14/15 unexplored genomic regions in S. pombe that encompassed predicted G4 structures, suggesting that at these sites the stabilized G4 structure formed an obstacle for the DNA polymerase. Furthermore, the formation of G4 structures was confirmed by complementary in vitro assays. In vivo, the S. pombe G4 unwinder Pif1 helicase, Pfh1, was associated with tested G4 sites, suggesting that the G4 structures also formed in vivo. Thus, we propose that the confirmed G4 structures in S. pombe form an obstacle for replication in vivo, and that the qPCR stop assay is a method that can be used to identify G4 structures. Finally, we suggest that the qPCR stop assay can also be used for identifying G4 structures in other organisms, as well as being adapted to screen for novel G4 stabilizers.

    Fulltekst (pdf)
    fulltext
  • 45.
    Kindahl, Tomas
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chorell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Development and optimization of simple one-step methods for the synthesis of 4-amino-substituted 1,8-naphthalimides2014Inngår i: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, nr 28, s. 6175-6182Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The 1,8-naphthalimide central fragment can be found in a vast number of bioactive compounds and drugs in clinical trials, and can be recognized from their use as fluorescent probes. Of key importance for the fluorescent properties of the scaffold is the 4-amino substituent, which has also proven to be critical in several other chemical and biological applications. Because of the great interest in 1,8-naphthalimides in general, and 4-amino-substituted 1,8-naphthalimides in particular, we have developed and optimized one-step procedures with which to access these derivatives by using an experimental design approach. The multivariate studies of temperature, reaction time, and equivalents of substrates identified conditions with close to quantitative yields that could be applied to generate a range of 4-amino-substituted 1,8-naphthalimides in high yields.

  • 46.
    Kindahl, Tomas
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Efficient one-step synthesis of 4-amino substituted phthalimides and evaluation of their potential as fluorescent probes2014Inngår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 12, nr 25, s. 4461-4470Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The phthalimide scaffold is recognized from bioactive compounds and marketed drugs, but can also be used as fluorescent probes by introducing a 4-amino substituent. Unfortunately, a general and convenient method to synthesize various 4-amino substituted phthalimides has been lacking. To overcome this, an atom efficient one-step synthesis of 4-amino substituted phthalimides in good to excellent yields that tolerate a wide range of substituents has been developed. Several of the generated compounds display interesting solvatochromic properties with high quantum yield of fluorescence in non-polar solvents that are significantly reduced in polar protic solvents. Many of these compounds displayed non-toxic properties and non-detectable unspecific binding and can thus potentially be linked to a substrate and used as fluorescent probes. Furthermore, bioactive and fluorescent 4-amino substituted phthalimides with IC50-values in the low micromolar range in cell-based assays have been identified and could be used to study uptake and distribution. The developed convenient synthetic method is thus valuable not only to construct fluorescent probes and fluorescent bioactive compounds to gain information about target binding, but also from a structure activity point of view in the various areas where the phthalimides have displayed activity.

  • 47.
    Krishnan, K. Syam
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bengtsson, Christoffer
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Good, James A. D.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Mirkhanov, Shamil
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Johansson, Lennart B. -Å.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Synthesis of fluorescent ring-fused 2-pyridone peptidomimetics2013Inngår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 78, nr 23, s. 12207-12213Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Thiazolino fused 2-pyridones peptidomimetics are of significant biological importance due to their ability to interfere with adhesive fiber formation in uropathogenic Escherichia coli and oligomerization of amyloid fibres. We have developed an efficient synthetic route to fluorescent BODIPY analogues, with structural diversification from a key intermediate enabling introduction of C-2 substituents and late incorporation of the BODIPY moiety. A mild lithium halide mediated hydrolysis enabled preparation of peptidomimetic fluorophores with useful photophysical properties for further chemical biology applications.

  • 48.
    Kumar, Rajendra
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chand, Karam
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bhowmik, Sudipta
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Department of Biophysics, Molecular Biology & Bioinformatics, University of Calcutta, 92, APC Road, Kolkata 700009, India.
    Das, Rabindra Nath
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bhattacharjee, Snehasish
    Hedenström, Mattias
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Subtle structural alterations in G-quadruplex DNA regulate site specificity of fluorescence light-up probes2020Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 48, nr 3, s. 1108-1119Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    G-quadruplex (G4) DNA structures are linked to key biological processes and human diseases. Small molecules that target specific G4 DNA structures and signal their presence would therefore be of great value as chemical research tools with potential to further advance towards diagnostic and therapeutic developments. However, the development of these types of specific compounds remain as a great challenge. In here, we have developed a compound with ability to specifically signal a certain c-MYC G4 DNA structure through a fluorescence light-up mechanism. Despite the compound's two binding sites on the G4 DNA structure, only one of them result in the fluorescence light-up effect. This G-tetrad selectivity proved to originate from a difference in flexibility that affected the binding affinity and tilt the compound out of the planar conformation required for the fluorescence light-up mechanism. The intertwined relation between the presented factors is likely the reason for the lack of examples using rational design to develop compounds with turn-on emission that specifically target certain G4 DNA structures. However, this study shows that it is indeed possible to develop such compounds and present insights into the molecular details of specific G4 DNA recognition and signaling to advance future studies of G4 biology.

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    fulltext
  • 49.
    Kumar, Vipan
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chand, Karam
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Guru Nanak Dev Univ, Punjab, India.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Synthesis of Various N-Substituted 4-Aryloxy/Thiophenoxy/Thioisopropyloxy-Phthalimides2017Inngår i: ChemistrySelect, ISSN 2365-6549, Vol. 2, nr 11, s. 3293-3296Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    N-substituted phthalimides have been used to target many biological systems with examples that are clinically used as drugs. Furthermore, N-substituted phthalimides can also be used in other settings such as in the preparation of polymers, as catalysts, and as protective groups. Because of all these important fields of application, the synthesis of phthalimides is well reported. However, synthetic methods to phthalimides with different heteroatom substituents in position 4 are lacking. The present work describes the development of robust synthetic methods to N-substituted 4-aryloxy/thiophenoxy/thioisopropyloxy-phthalimides. The developed methods allow for the introduction of these substituents through an atom efficient one-step synthesis, which gives good to excellent yields and tolerate a wide range of substituents.

  • 50.
    Livendahl, Madeleine
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Jamroskovic, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Hedenström, Mattias
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Görlich, T.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sabouri, Nasim
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Synthesis of phenanthridine spiropyrans and studies of their effects on G-quadruplex DNA2017Inngår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 15, nr 15, s. 3265-3275Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    G-quadruplex (G4) DNA structures are involved in many important biological processes and can be linked to several human diseases. Drug-like low molecular weight compounds that target G4 structures are therefore interesting not only for their potential therapeutic properties but also for their potential use as chemical research tools. We report here on the development of methods to synthesize spiropyrans using a condensation-cyclisation reaction of quaternary salts of [small alpha]-methyl quinoline or phenanthridine with salicylaldehydes. Evaluation of the synthesized phenanthridine spiropyrans' interactions with G4 DNA was performed with a Thioflavin T displacement assay, circular dichroism, Taq DNA polymerase stop assay, and NMR. This revealed that the substitution pattern on the phenanthridine spiropyrans was very important for their ability to bind and stabilize G4 structures. Some of the synthesized low molecular weight spirocyclic compounds efficiently stabilized G4 structures without inducing structural changes by binding the first G-tetrad in the G4 structure.

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