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  • 1.
    Andersson, C David
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Karlberg, Tobias
    Ekblad, Torun
    Lindgren, Anders E G
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Thorsell, Ann-Gerd
    Spjut, Sara
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Uciechowska, Urszula
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Niemiec, Moritz S
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wittung-Stafshede, Pernilla
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Weigelt, Johan
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Schüler, Herwig
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Discovery of Ligands for ADP-Ribosyltransferases via Docking-Based Virtual Screening2012In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, no 17, p. 7706-7718Article in journal (Refereed)
    Abstract [en]

    The diphtheria toxin-like ADP-ribosyltransferases (ARTDs) are an enzyme family that catalyses the transfer of ADP-ribose units onto substrate proteins, using nicotinamide adenine dinucleotide (NAD(+)) as a co-substrate. They have a documented role in chromatin remodelling and DNA repair; and inhibitors of ARTD1 and 2 (PARP1 and 2) are currently in clinical trials for the treatment of cancer. The detailed function of most other ARTDs is still unknown. Using virtual screening we identified small ligands of ARTD7 (PARP15/BAL3) and ARTD8 (PARP14/BAL2). Thermal-shift assays confirmed that 16 compounds, belonging to eight structural classes, bound to ARTD7/ARTD8. Affinity measurements with isothermal titration calorimetry for two isomers of the most promising hit compound confirmed binding in the low micromolar range to ARTD8. Crystal structures showed anchoring of the hits in the nicotinamide pocket. These results form a starting point in the development of chemical tools for the study of the role and function of ARTD7 and ARTD8.

  • 2.
    Andersson, Emma K
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Strand, Mårten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Edlund, Karin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lindman, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Enquist, Per-Anders
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Spjut, Sara
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Allard, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Mei, Ya-Fang
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Small molecule screening using a whole cell viral replication reporter gene assay identifies 2-{[2-(benzoylamino)benzoyl]amino}-benzoic acid as a novel anti-adenoviral compound2010In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 54, no 9, p. 3871-3877Article in journal (Refereed)
    Abstract [en]

    Adenovirus infections are widespread in society and are occasionally associated with severe, but rarely with life-threatening, disease in otherwise healthy individuals. In contrast, adenovirus infections present a real threat to immunocompromised individuals and can result in disseminated and fatal disease. The number of patients undergoing immunosuppressive therapy for solid organ or hematopoietic stem cell transplantation is steadily increasing, as is the number of AIDS patients, and this makes the problem of adenovirus infections even more urgent to solve. There is no formally approved treatment of adenovirus infections today, and existing antiviral agents evaluated for their anti-adenoviral effect give inconsistent results. We have developed a whole cell-based assay for high-throughput screening of potential anti-adenoviral compounds. The assay is unique in that it is based on a replication competent adenovirus type 11p GFP-expressing vector (RCAd11pGFP). This allows measurement of fluorescence changes as a direct result of RCAd11pGFP genome expression. Using this assay, we have screened 9,800 commercially available small organic compounds. Initially, we observed approximately 400 compounds that inhibited adenovirus expression in vitro by >/= 80% but only 24 were later confirmed as dose-dependent inhibitors of adenovirus. One compound in particular, 2-[[2-(benzoylamino)benzoyl]amino]-benzoic acid, turned out to be a potent inhibitor of adenovirus replication.

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  • 3.
    Bailey, Leslie
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Gylfe, Åsa
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Sundin, Charlotta
    Muschiol, Sandra
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Henriques-Normark, Birgitta
    Lugert, Raimond
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wolf-Watz, Hans
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Small molecule inhibitors of type III secretion in Yersinia block the Chlamydia pneumoniae infection cycle2007In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 581, no 4, p. 587-595Article in journal (Refereed)
    Abstract [en]

    Intracellular parasitism by Chlamydiales is a complex process involving transmission of metabolically inactive particles that differentiate, replicate, and re-differentiate within the host cell. A type three secretion system (T3SS) has been implicated in this process. We have here identified small molecules of a chemical class of acylated hydrazones of salicylaldehydes that specifically blocks the T3SS of Chlamydia. These compounds also affect the developmental cycle showing that the T3SS has a pivotal role in the pathogenesis of Chlamydia. Our results suggest a previously unexplored avenue for development of novel anti-chlamydial drugs.

  • 4. Bao, Xiaofeng
    et al.
    Gylfe, Åsa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Sturdevant, Gail L.
    Gong, Zheng
    Xu, Shuang
    Caldwell, Harlan D.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Fan, Huizhou
    Benzylidene acylhydrazides inhibit chlamydial growth in a type III secretion- and iron chelation-independent manner2014In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 196, no 16, p. 2989-3001Article in journal (Refereed)
    Abstract [en]

    Chlamydiae are widespread Gram-negative pathogens of humans and animals. Salicylidene acylhydrazides, developed as inhibitors of type III secretion system (T3SS) in Yersinia spp., have an inhibitory effect on chlamydial infection. However, these inhibitors also have the capacity to chelate iron, and it is possible that their antichlamydial effects are caused by iron starvation. Therefore, we have explored the modification of salicylidene acylhydrazides with the goal to uncouple the antichlamydial effect from iron starvation. We discovered that benzylidene acylhydrazides, which cannot chelate iron, inhibit chlamydial growth. Biochemical and genetic analyses suggest that the derivative compounds inhibit chlamydiae through a T3SS-independent mechanism. Four single nucleotide polymorphisms were identified in a Chlamydia muridarum variant resistant to benzylidene acylhydrazides, but it may be necessary to segregate the mutations to differentiate their roles in the resistance phenotype. Benzylidene acylhydrazides are well tolerated by host cells and probiotic vaginal Lactobacillus species and are therefore of potential therapeutic value.

  • 5. Beck, Carole
    et al.
    Rodriguez-Vargas, José Manuel
    Boehler, Christian
    Robert, Isabelle
    Heyer, Vincent
    Hanini, Najat
    Gauthier, Laurent R.
    Tissier, Agnès
    Schreiber, Valérie
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    San Martin, Bernardo Reina
    Dantzer, Françoise
    PARP3, a new therapeutic target to alter Rictor/mTORC2 signaling and tumor progression in BRCA1-associated cancers2019In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 26, no 9, p. 1615-1630Article in journal (Refereed)
    Abstract [en]

    PARP3 has been shown to be a key driver of TGF beta-induced epithelial-to-mesenchymal transition (EMT) and sternness in breast cancer cells, emerging as an attractive therapeutic target. Nevertheless, the therapeutic value of PARP3 inhibition has not yet been assessed. Here we investigated the impact of the absence of PARP3 or its inhibition on the tumorigenicity of BRCA1-proficient versus BRCA1-deficient breast cancer cell lines, focusing on the triple-negative breast cancer subtype (TNBC). We show that PARP3 knockdown exacerbates centrosome amplification and genome instability and reduces survival of BRCA1-deficient TNBC cells. Furthermore, we engineered PARP3(-/- )BRCA1-deficient or BRCA1-proficient TNBC cell lines using the CRISPR/nCas9(D10A) gene editing technology and demonstrate that the absence of PARP3 selectively suppresses the growth, survival and in vivo tumorigenicity of BRCA1-deficient TNBC cells, mechanistically via effects associated with an altered Rictor/mTORC2 signaling complex resulting from enhanced ubiquitination of Rictor. Accordingly, PARP3 interacts with and ADP-ribosylates GSK3 beta, a positive regulator of Rictor ubiquitination and degradation. Importantly, these phenotypes were rescued by re-expression of a wild-type PARP3 but not by a catalytic mutant, demonstrating the importance of PARP3's catalytic activity. Accordingly, reduced survival and compromised Rictor/mTORC2 signaling were also observed using a cell-permeable PARP3-specific inhibitor. We conclude that PARP3 and BRCA1 are synthetic lethal and that targeting PARP3's catalytic activity is a promising therapeutic strategy for BRCA1-associated cancers via the Rictor/mTORC2 signaling pathway.

  • 6.
    Beyer, Sarah
    et al.
    Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden.
    Kimani, Martha
    Chemical and Optical Sensing Division, Bundesanstalt für Materialforschung und-prüfung (BAM), Richard-Willstätter Straße 11, Berlin, Germany.
    Zhang, Yuecheng
    Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden; Biofilms-Research Center for Biointerfaces, Malmö University, Malmö, Sweden.
    Verhassel, Alejandra
    Institute of Biomedicine, University of Turku, Turku, Finland; FICAN West Cancer Centre, Turku University Hospital, Turku, Finland.
    Sternbæk, Louise
    Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden; Biofilms-Research Center for Biointerfaces, Malmö University, Malmö, Sweden; Phase Holographic Imaging AB, Lund, Sweden.
    Wang, Tianyan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Persson, Jenny L.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden; Biofilms-Research Center for Biointerfaces, Malmö University, Malmö, Sweden.
    Härkönen, Pirkko
    Institute of Biomedicine, University of Turku, Turku, Finland; FICAN West Cancer Centre, Turku University Hospital, Turku, Finland.
    Johansson, Emil
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Caraballo, Remi
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Gawlitza, Kornelia
    Chemical and Optical Sensing Division, Bundesanstalt für Materialforschung und-prüfung (BAM), Richard-Willstätter Straße 11, Berlin, Germany.
    Rurack, Knut
    Chemical and Optical Sensing Division, Bundesanstalt für Materialforschung und-prüfung (BAM), Richard-Willstätter Straße 11, Berlin, Germany.
    Ohlsson, Lars
    Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden; Biofilms-Research Center for Biointerfaces, Malmö University, Malmö, Sweden.
    El-Schich, Zahra
    Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden; Biofilms-Research Center for Biointerfaces, Malmö University, Malmö, Sweden.
    Wingren, Anette Gjörloff
    Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden; Biofilms-Research Center for Biointerfaces, Malmö University, Malmö, Sweden.
    Stollenwerk, Maria M.
    Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden; Biofilms-Research Center for Biointerfaces, Malmö University, Malmö, Sweden.
    Fluorescent Molecularly Imprinted Polymer Layers against Sialic Acid on Silica-Coated Polystyrene Cores — Assessment of the Binding Behavior to Cancer Cells2022In: Cancers, ISSN 2072-6694, Vol. 14, no 8, article id 1875Article in journal (Refereed)
    Abstract [en]

    Sialic acid (SA) is a monosaccharide usually linked to the terminus of glycan chains on the cell surface. It plays a crucial role in many biological processes, and hypersialylation is a common feature in cancer. Lectins are widely used to analyze the cell surface expression of SA. However, these protein molecules are usually expensive and easily denatured, which calls for the development of alternative glycan-specific receptors and cell imaging technologies. In this study, SA-imprinted fluorescent core-shell molecularly imprinted polymer particles (SA-MIPs) were employed to recognize SA on the cell surface of cancer cell lines. The SA-MIPs improved suspensibility and scattering properties compared with previously used core-shell SA-MIPs. Although SA-imprinting was performed using SA without preference for the α2,3-and α2,6-SA forms, we screened the cancer cell lines analyzed using the lectins Maackia Amurensis Lectin I (MAL I, α2,3-SA) and Sambucus Nigra Lectin (SNA, α2,6-SA). Our results show that the selected cancer cell lines in this study presented a varied binding behavior with the SA-MIPs. The binding pattern of the lectins was also demonstrated. Moreover, two different pentavalent SA conjugates were used to inhibit the binding of the SA-MIPs to breast, skin, and lung cancer cell lines, demonstrating the specificity of the SA-MIPs in both flow cytometry and confocal fluorescence microscopy. We concluded that the synthesized SA-MIPs might be a powerful future tool in the diagnostic analysis of various cancer cells.

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  • 7.
    Caraballo, Remi
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Larsson, Mikael
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Nilsson, Stefan K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Ericsson, Madelene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Tran, Nam Phuong Nguyen
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Kindahl, Tomas
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Svensson, Richard
    Uppsala, Sweden.
    Saar, Valeria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Artursson, Per
    Uppsala, Sweden.
    Olivecrona, Gunilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Enquist, Per-Anders
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Structure-activity relationships for lipoprotein lipase agonists that lower plasma triglycerides in vivo2015In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 103, p. 191-209Article in journal (Refereed)
    Abstract [en]

    The risk of cardiovascular events increases in individuals with elevated plasma triglyceride (TG) levels, therefore advocating the need for efficient TG-lowering drugs. In the blood circulation, TG levels are regulated by lipoprotein lipase (LPL), an unstable enzyme that is only active as a non-covalently associated homodimer. We recently reported on a N-phenylphthalimide derivative (1) that stabilizes LPL in vitro, and moderately lowers triglycerides in vivo (Biochem. Biophys. Res. Common. 2014, 450, 1063). Herein, we establish structure activity relationships of 51 N-phenylphthalimide analogs of the screening hit 1. In vitro evaluation highlighted that modifications on the phthalimide moiety were not tolerated and that lipophilic substituents on the central phenyl ring were functionally essential. The substitution pattern on the central phenyl ring also proved important to stabilize LPL However, in vitro testing demonstrated rapid degradation of the phthalimide fragment in plasma which was addressed by replacing the phthalimide scaffold with other heterocyclic fragments. The in vitro potency was retained or improved and substance 80 proved stable in plasma and efficiently lowered plasma TGs in vivo. 2015 The Authors. Published by Elsevier Masson SAS.

  • 8.
    Caraballo, Rémi
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Saleeb, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Bauer, Johannes
    Interfaculty Institute of Biochemistry, University of Tübingen, Germany.
    Liaci, Antonio-Manuel
    Interfaculty Institute of Biochemistry, University of Tübingen, Germany.
    Chandra, Naresh
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Storm, Rickard J
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Frängsmyr, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Stehle, Thilo
    Interfaculty Institute of Biochemistry, University of Tübingen, Germany ; Department of Pediatrics, Vanderbilt University School of Medicine, USA.
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Triazole linker-based trivalent sialic acid inhibitors of adenovirus type 37 infection of human corneal epithelial cells2015In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 13, no 35, p. 9194-9205Article in journal (Refereed)
    Abstract [en]

    Adenovirus type 37 (Ad37) is one of the principal agents responsible for epidemic keratoconjunctivitis (EKC), a severe ocular infection that remains without any available treatment. Recently, a trivalent sialic acid derivative (ME0322, Angew. Chem. Int. Ed., 2011, 50, 6519) was shown to function as a highly potent inhibitor of Ad37, efficiently preventing the attachment of the virion to the host cells and subsequent infection. Here, new trivalent sialic acid derivatives were designed, synthesized and their inhibitory properties against Ad37 infection of the human corneal epithelial cells were investigated. In comparison to ME0322, the best compound (17a) was found to be over three orders of magnitude more potent in a cell-attachment assay (IC50 = 1.4 nM) and about 140 times more potent in a cell-infection assay (IC50 = 2.9nM). X-ray crystallographic analysis demonstrated a trivalent binding mode of all compounds to the Ad37 fiber knob. For the most potent compound ophthalmic toxicity in rabbits was investigated and it was concluded that repeated eye administration did not cause any adverse effects.

  • 9.
    Chandra, Naresh
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Frängsmyr, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Imhof, Sophie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Caraballo, Rémi
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Sialic Acid-Containing Glycans as Cellular Receptors for Ocular Human Adenoviruses: Implications for Tropism and Treatment2019In: Viruses, E-ISSN 1999-4915, Vol. 11, no 5, article id 395Article in journal (Refereed)
    Abstract [en]

    Human adenoviruses (HAdV) are the most common cause of ocular infections. Species B human adenovirus type 3 (HAdV-B3) causes pharyngoconjunctival fever (PCF), whereas HAdV-D8, -D37, and -D64 cause epidemic keratoconjunctivitis (EKC). Recently, HAdV-D53, -D54, and -D56 emerged as new EKC-causing agents. HAdV-E4 is associated with both PCF and EKC. We have previously demonstrated that HAdV-D37 uses sialic acid (SA)-containing glycans as cellular receptors on human corneal epithelial (HCE) cells, and the virus interaction with SA is mediated by the knob domain of the viral fiber protein. Here, by means of cell-based assays and using neuraminidase (a SA-cleaving enzyme), we investigated whether ocular HAdVs other than HAdV-D37 also use SA-containing glycans as receptors on HCE cells. We found that HAdV-E4 and -D56 infect HCE cells independent of SAs, whereas HAdV-D53 and -D64 use SAs as cellular receptors. HAdV-D8 and -D54 fiber knobs also bound to cell-surface SAs. Surprisingly, HCE cells were found resistant to HAdV-B3 infection. We also demonstrated that the SA-based molecule i.e., ME0462, designed to bind to SA-binding sites on the HAdV-D37 fiber knob, efficiently prevents binding and infection of several EKC-causing HAdVs. Surface plasmon resonance analysis confirmed a direct interaction between ME0462 and fiber knobs. Altogether, we demonstrate that SA-containing glycans serve as receptors for multiple EKC-causing HAdVs, and, that SA-based compound function as a broad-spectrum antiviral against known and emerging EKC-causing HAdVs.

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  • 10. Chu, Hencelyn
    et al.
    Slepenkin, Anatoly
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Keyser, Pia
    de la Maza, Luis M
    Peterson, Ellena M
    Candidate vaginal microbicides with activity against Chlamydia trachomatis and Neisseria gonorrhoeae2010In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 36, no 2, p. 145-150Article in journal (Refereed)
    Abstract [en]

    Vaginal microbicides with activity towards organisms that cause sexually transmitted infections have been proposed as a strategy to reduce transmission. Small-molecule inhibitors of Chlamydia trachomatis serovar D belonging to the class of salicylidene acylhydrazides (INPs) have been shown to work through a mechanism that involves iron restriction. Expanding on this work, ten INPs were tested against a lymphogranuloma venereum strain of C. trachomatis (serovar L2), Neisseria gonorrhoeae, and hydrogen peroxide-producing Lactobacillus crispatus and Lactobacillus jensenii. Seven INPs had minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations of <50 microM towards C. trachomatis L2. Three INPs had a MIC <12.5 microM against N. gonorrhoeae. Inhibition was reversed by iron, holo-transferrin and holo-lactoferrin but not by the iron-poor forms of these compounds. The compounds exhibited no bactericidal activity toward Lactobacillus. The INPs were not cytotoxic to HeLa 229 cells. When INP 0341 was tested in a mouse model of a Chlamydia vaginal infection there was a significant reduction in the number of mice shedding C. trachomatis up to 4 days after infection (P<0.01). In summary, select INPs are promising vaginal microbicide candidates as they inhibit the growth of two common sexually transmitted organisms in vitro, are active in a mouse model against C. trachomatis, are not cytotoxic and do not inhibit organisms that compose the normal vaginal flora.

  • 11.
    Dahlgren, Markus K
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Zetterström, Caroline E
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gylfe, Åsa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Statistical molecular design of a focused salicylidene acylhydrazide library and multivariate QSAR of inhibition of type III secretion in the Gram-negative bacterium Yersinia2010In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 18, no 7, p. 2686-2703Article in journal (Refereed)
    Abstract [en]

    A combined application of statistical molecular design (SMD), quantitative structure-activity relationship (QSAR) modeling and prediction of new active compounds was effectively used to develop salicylidene acylhydrazides as inhibitors of type III secretion (T3S) in the Gram-negative pathogen Yersinia pseudotuberculosis. SMD and subsequent synthesis furnished 50 salicylidene acylhydrazides in high purity. Based on data from biological evaluation in T3S linked assays 18 compounds were classified as active and 25 compounds showed a dose-dependent inhibition. The 25 compounds were used to compute two multivariate QSAR models and two multivariate discriminant analysis models were computed from both active and inactive compounds. Three of the models were used to predict 4416 virtual compounds in consensus and eight new compounds were selected as an external test set. Synthesis and biological evaluation of the test set in Y. pseudotuberculosis and the intracellular pathogen Chlamydia trachomatis validated the models. Y. pseudotuberculosis and C. trachomatis cell-based infection models showed that compounds identified in this study are selective and non-toxic inhibitors of T3S dependent virulence.

  • 12.
    Dahlgren, Markus K
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Öberg, Christopher T
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wallin, Erika A
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Janson, Pär G
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Synthesis of 2-(2-Aminopyrimidine)-2,2-difluoroethanols as Potential Bioisosters of Salicylidene Acylhydrazides2010In: Molecules, ISSN 1431-5157, E-ISSN 1420-3049, Vol. 15, no 6, p. 4207-12Article in journal (Refereed)
    Abstract [en]

    Salicylidene acylhydrazides are inhibitors of type III secretion in several Gramnegative pathogens. To further develop the salicylidene acylhydrazides, scaffold hopping was applied to replace the core fragment of the compounds. The novel 2-(2-aminopyrimidine)-2,2-difluoroethanol scaffold was identified as a possible analog to thesalicylidene acylhydrazide core structure. The synthesis of a library of 2-(2-aminopyrimidine)-2,2-difluoro-ethanols is described in this paper.

  • 13.
    Dahlgren, Markus
    et al.
    Umeå University, Faculty of Science and Technology, Chemistry.
    Kauppi, Anna
    Umeå University, Faculty of Science and Technology, Chemistry.
    Olsson, Ing-Marie
    Umeå University, Faculty of Science and Technology, Chemistry.
    Linusson Jonsson, Anna
    Umeå University, Faculty of Science and Technology, Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Chemistry.
    Design, Synthesis, and Multivariate Quantitative Structure-Activity Relationship of Salicylanilides-Potent Inhibitors of Type III Secretion in Yersinia2007In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 50, no 24, p. 6177-6188Article in journal (Refereed)
    Abstract [en]

    Analogues to the salicylanilide N-(4-Chlorophenyl)-2-acetoxy-3,5-diiodobenzamide, 1a, an inhibitor of type III secretion (T3S) in Yersinia, were selected, synthesized, and biologically evaluated in three cycles. First, a set of analogues with variations in the salicylic acid ring moiety was synthesized to probe possible structural variation. A basic structure-activity relationship was established and then used to cherry-pick compounds from a principal component analysis score plot of salicylanilides to generate a second set. A third set with increased likelihood of biological activity was designed using D-optimal onion design. A quantitative structure-activity relationship model using hierarchical partial least-square regression to latent structures (Hi-PLS) was computed using PLS score vectors of building blocks correlated to the % inhibition of T3S as a response. A PLS discriminant analysis (PLS-DA) model was derived using the same descriptor set as that for the Hi-PLS model. Both models were validated with an external test set.

  • 14. Davis, Rohan A.
    et al.
    Beattie, Karren D.
    Xu, Min
    Yang, Xinzhou
    Yin, Sheng
    Holla, Harish
    Healy, Peter C.
    Sykes, Melissa
    Shelper, Todd
    Avery, Vicky M.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sundin, Charlotta
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Creative Antibiotics Sweden AB, Umeå, Sweden.
    Quinn, Ronald J.
    Solving the supply of resveratrol tetramers from Papua New Guinean rainforest anisoptera species that inhibit bacterial type Ill secretion systems2014In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 77, no 12, p. 2633-2640Article in journal (Refereed)
    Abstract [en]

    ABSTRACT: The supply of (−)-hopeaphenol (1) was achieved via enzymatic biotransformation in order to provide material for preclinical investigation. High-throughput screen- ing of a prefractionated natural product library aimed to identify compounds that inhibit the bacterial virulence type III secretion system (T3SS) identified several fractions derived from two Papua New Guinean Anisoptera species, showing activity against Yersinia pseudotuberculosis outer proteins E and H (YopE and YopH). Bioassay-directed isolation from the leaves of A. thurifera, and similarly A. polyandra, resulted in three known resveratrol tetramers, (−)-hopeaphenol (1), vatalbinoside A (2), and vaticanol B (3). Compounds 1−3 displayed IC50 values of 8.8, 12.5, and 9.9 μM in a luminescent reporter-gene assay (YopE) and IC50 values of 2.9, 4.5, and 3.3 μM in an enzyme-based YopH assay, respectively, which suggested that they could potentially act against the T3SS in Yersinia. The structures of 1−3 were confirmed through a combination of spectrometric, chemical methods, and single-crystal X-ray structure determinations of the natural product 1 and the permethyl ether analogue of 3. The enzymatic hydrolysis of the β-glycoside 2 to the aglycone 1 was achieved through biotransformation using the endogenous leaf enzymes. This significantly enhanced the yield of the target bioactive natural product from 0.08% to 1.3% and facilitates ADMET studies of (−)-hopeaphenol (1).

  • 15. Ekblad, Torun
    et al.
    Lindgren, Anders E. G.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Caraballo, Remi
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Thorsell, Ann-Gerd
    Karlberg, Tobias
    Spjut, Sara
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Schuler, Herwig
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Towards small molecule inhibitors of mono-ADP-ribosyltransferases2015In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 95, p. 546-551Article in journal (Refereed)
    Abstract [en]

    Protein ADP-ribosylation is a post-translational modification involved in DNA repair, protein degradation, transcription regulation, and epigenetic events. Intracellular ADP-ribosylation is catalyzed predominantly by ADP-ribosyltransferases with diphtheria toxin homology (ARTDs). The most prominent member of the ARTD family, poly(ADP-ribose) polymerase-1 (ARTD1/PARP1) has been a target for cancer drug development for decades. Current PARP inhibitors are generally non-selective, and inhibit the mono-ADP-ribosyltransferases with low potency. Here we describe the synthesis of acylated amino benzamides and screening against the mono-ADP-ribosyltransferases ARTD7/PARP15, ARTD8/PARP14, ARTD10/PARP10, and the poly-ADP-ribosyltransferase ARTD1/PARP1. The most potent compound inhibits ARTD10 with sub-micromolar IC50.

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  • 16. Ekblad, Torun
    et al.
    Verheugd, Patricia
    Lindgren, Anders E.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Nyman, Tomas
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Schüler, Herwig
    Identification of Poly(ADP-Ribose) Polymerase Macrodomain Inhibitors Using an AlphaScreen Protocol2018In: SLAS Discovery, ISSN 2472-5560, E-ISSN 2472-5552, Vol. 23, no 4, p. 353-362Article in journal (Refereed)
    Abstract [en]

    Macrodomains recognize intracellular adenosine diphosphate (ADP)-ribosylation resulting in either removal of the modification or a protein interaction event. Research into compounds that modulate macrodomain functions could make important contributions. We investigated the interactions of all seven individual macrodomains of the human poly(ADP-ribose) polymerase (PARP) family members PARP9, PARP14, and PARP15 with five mono-ADP-ribosylated (automodified) ADP-ribosyltransferase domains using an AlphaScreen assay. Several mono-ADP-ribosylation-dependent interactions were identified, and they were found to be in the micromolar affinity range using surface plasmon resonance (SPR). We then focused on the interaction between PARP14 macrodomain-2 and the mono-ADP-ribosylated PARP10 catalytic domain, and probed a similar to 1500-compound diverse library for inhibitors of this interaction using AlphaScreen. Initial hit compounds were verified by concentration-response experiments using AlphaScreen and SPR, and they were tested against PARP14 macrodomain-2 and -3. Two initial hit compounds and one chemical analog each were further characterized using SPR and microscale thermophoresis. In conclusion, our results reveal novel macrodomain interactions and establish protocols for identification of inhibitors of such interactions.

  • 17.
    El-Schich, Zahra
    et al.
    Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden; Biofilms-Research Center for Biointerfaces, Malmö University, Malmö, Sweden.
    Zhang, Yuecheng
    Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden; Biofilms-Research Center for Biointerfaces, Malmö University, Malmö, Sweden.
    Göransson, Tommy
    Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden.
    Dizeyi, Nishtman
    Department of Translational Medicine, Lund University, Malmö, Sweden.
    Persson, Jenny L.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö; Biofilms-Research Center for Biointerfaces, Malmö University.
    Johansson, Emil
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Caraballo, Remi
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Shinde, Sudhirkumar
    School of Consciousness, Vishwanath Karad Maharashtra Institute of Technology—World Peace University, Kothrud, Pune, India.
    Sellergren, Börje
    Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden; Biofilms-Research Center for Biointerfaces, Malmö University, Malmö, Sweden.
    Wingren, Anette Gjörloff
    Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden; Biofilms-Research Center for Biointerfaces, Malmö University, Malmö, Sweden.
    Sialic acid as a biomarker studied in breast cancer cell lines in vitro using fluorescent molecularly imprinted polymers2021In: Applied Sciences, E-ISSN 2076-3417, Vol. 11, no 7, article id 3256Article in journal (Refereed)
    Abstract [en]

    Sialylations are post-translational modifications of proteins and lipids that play important roles in many cellular events, including cell-cell interactions, proliferation, and migration. Tumor cells express high levels of sialic acid (SA), which are often associated with the increased invasive potential in clinical tumors, correlating with poor prognosis. To overcome the lack of natural SA-receptors, such as antibodies and lectins with high enough specificity and sensitivity, we have used molecularly imprinted polymers (MIPs), or “plastic antibodies”, as nanoprobes. Because high expression of epithelial cell adhesion molecule (EpCAM) in primary tumors is often associated with proliferation and a more aggressive phenotype, the expression of EpCAM and CD44 was initially analyzed. The SA-MIPs were used for the detection of SA on the cell surface of breast cancer cells. Lectins that specifically bind to the a-2,3 SA and a-2,6 SA variants were used for analysis of SA expression, with both flow cytometry and confocal microscopy. Here we show a correlation of EpCAM and SA expression when using the SA-MIPs for detection of SA. We also demonstrate the binding pattern of the SA-MIPs on the breast cancer cell lines using confocal microscopy. Pre-incubation of the SA-MIPs with SA-derivatives as inhibitors could reduce the binding of the SA-MIPs to the tumor cells, indicating the specificity of the SA-MIPs. In conclusion, the SA-MIPs may be a new powerful tool in the diagnostic analysis of breast cancer cells.

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  • 18.
    Engström, Patrik
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nguyen, Bidong D.
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Nilsson, Ingela
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Bastidas, Robert J.
    Gylfe, Åsa
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Elofsson, Mikael
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Fields, Kenneth A.
    Valdivia, Raphael H.
    Wolf-Watz, Hans
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Mutations in hemG Mediate Resistance to Salicylidene Acylhydrazides, Demonstrating a Novel Link between Protoporphyrinogen Oxidase (HemG) and Chlamydia trachomatis Infectivity2013In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 195, no 18, p. 4221-4230Article in journal (Refereed)
    Abstract [en]

    Salicylidene acylhydrazides (SAHs) inhibit the type III secretion system (T3S) of Yersinia and other Gram-negative bacteria. In addition, SAHs restrict the growth and development of Chlamydia species. However, since the inhibition of Chlamydia growth by SAH is suppressed by the addition of excess iron and since SAHs have an iron-chelating capacity, their role as specific T3S inhibitors is unclear. We investigated here whether SAHs exhibit a function on C. trachomatis that goes beyond iron chelation. We found that the iron-saturated SAH INP0341 (IS-INP0341) specifically affects C. trachomatis infectivity with reduced generation of infectious elementary body (EB) progeny. Selection and isolation of spontaneous SAH-resistant mutant strains revealed that mutations in hemG suppressed the reduced infectivity caused by IS-INP0341 treatment. Structural modeling of C. trachomatis HemG predicts that the acquired mutations are located in the active site of the enzyme, suggesting that IS-INP0341 inhibits this domain of HemG and that protoporphyrinogen oxidase (HemG) and heme metabolism are important for C. trachomatis infectivity.

  • 19.
    Enquist, Per-Anders
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gylfe, Åsa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Hägglund, Ulrik
    Creative Antibiotics, Tvistevägen 48, SE90719 Umeå, Sweden.
    Lindström, Pia
    Creative Antibiotics, Tvistevägen 48, SE90719 Umeå, Sweden.
    Norberg-Scherman, Henrik
    Creative Antibiotics, Tvistevägen 48, SE90719 Umeå, Sweden.
    Sundin, Charlotta
    Creative Antibiotics, Tvistevägen 48, SE90719 Umeå, Sweden.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Derivatives of 8-hydroxyquinoline-antibacterial agents that target intra- and extracellular Gram-negative pathogens2012In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1464-3405, Vol. 22, no 10, p. 3550-3553Article in journal (Refereed)
    Abstract [en]

    Small molecule screening identified 5-nitro-7-((4-phenylpiperazine-1-yl-)methyl)quinolin-8-ol INP1750 as a putative inhibitor of type III secretion (T3S) in the Gram-negative pathogen Yersinia pseudotuberculosis. In this study we report structure-activity relationships for inhibition of T3S and show that the most potent compounds target both the extracellular bacterium Y. pseudotuberculosis and the intracellular pathogen Chlamydia trachomatis in cell-based infection models.

  • 20.
    Eriksson, Jonas
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Grundström, Christin
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Sauer-Eriksson, A Elisabeth
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Sauer, Uwe H
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Wolf-Watz, Hans
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Small Molecule Screening for Inhibitors of the YopH Phosphatase of Yersinia pseudotuberculosis2012In: Advances in Yersinia Research, New York: Springer, 2012, Vol. 954, p. 357-363Chapter in book (Refereed)
    Abstract [en]

    Bacterial virulence systems are attractive targets for development of new antibacterial agents. Yersinia spp. utilize the type III secretion (T3S) system to secrete and translocate Yersinia outer proteins (Yop effectors) into the cytosol of the target cell and thereby overcome host defenses to successfully establish an infection. Thus, the Yop effectors constitute attractive targets for drug development. In the present study we apply small molecule screening to identify inhibitors of one of the secreted proteins YopH, a tyrosine phosphatase required for virulence. Characterization of seven inhibitors indicated that both competitive and noncompetitive inhibitors were identified with IC50 values of 6–20 μM.

  • 21. Forthal, Donald N
    et al.
    Phan, Tran B
    Slepenkin, Anatoly V
    Landucci, Gary
    Chu, Hencelyn
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Peterson, Ellena
    In vitro anti-HIV-1 activity of salicylidene acylhydrazide compounds2012In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 40, no 4, p. 354-360Article in journal (Refereed)
    Abstract [en]

    Salicylidene acylhydrazide compounds have been shown to inhibit bacterial pathogens, including Chlamydia and Neisseria gonorrhoeae. If such compounds could also target HIV-1, their potential use as topical microbicides to prevent sexually transmitted infections would be considerable. In this study, the in vitro anti-HIV-1 activity, cytotoxicity and mechanism of action of several salicylidene acylhydrazides were determined. Inhibitory activity was assessed using TZM-bl cells and primary peripheral blood mononuclear cells (PBMCs) as targets for HIV-1 infection. Antiviral activity was measured against cell-free and cell-associated virus and in vaginal fluid and semen simulants. Since the antibacterial activity of salicylidene acylhydrazides is reversible by Fe(2+), the ability of Fe(2+) and other cations to reverse the anti-HIV-1 activity of the compounds was determined. Real-time PCR was also employed to determine the stage affected in the HIV-1 replication cycle. Four compounds with 50% inhibitory concentrations against HIV-1 of 1-7μM were identified. In vitro toxicity varied but was generally limited. Activity was similar against three R5 clade B primary isolates and whether the target for virus replication was TZM-bl cells or PBMCs. Compounds inhibited cell-free and cell-associated virus and were active in vaginal fluid and semen simulants. Fe(2+), but not other cations, reversed the anti-HIV-1 effect. Finally, the inhibitory effect of the compounds occurred at a post-integration step. In conclusion, salicylidene acylhydrazides were identified with in vitro anti-HIV-1 activity in the micromolar range. The activity of these compounds against other sexually transmitted pathogens makes them potential candidates to formulate for use as a broad-spectrum topical genital microbicide.

  • 22. Gabrielsen, Mads
    et al.
    Beckham, Katherine S H
    Feher, Victoria A
    Zetterström, Caroline E
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Wang, Dai
    Müller, Sylke
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Amaro, Rommie E
    Byron, Olwyn
    Roe, Andrew J
    Structural Characterisation of Tpx from Yersinia pseudotuberculosis Reveals Insights into the Binding of Salicylidene Acylhydrazide Compounds2012In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 2, p. e32217-Article in journal (Refereed)
    Abstract [en]

    Thiol peroxidase, Tpx, has been shown to be a target protein of the salicylidene acylhydrazide class of antivirulence compounds. In this study we present the crystal structures of Tpx from Y. pseudotuberculosis (ypTpx) in the oxidised and reduced states, together with the structure of the C61S mutant. The structures solved are consistent with previously solved atypical 2-Cys thiol peroxidases, including that for “forced” reduced states using the C61S mutant. In addition, by investigating the solution structure of ypTpx using small angle X-ray scattering (SAXS), we have confirmed that reduced state ypTpx in solution is a homodimer. The solution structure also reveals flexibility around the dimer interface. Notably, the conformational changes observed between the redox states at the catalytic triad and at the dimer interface have implications for substrate and inhibitor binding. The structural data were used to model the binding of two salicylidene acylhydrazide compounds to the oxidised structure of ypTpx. Overall, the study provides insights into the binding of the salicylidene acylhydrazides to ypTpx, aiding our long-term strategy to understand the mode of action of this class of compounds.

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  • 23. Gabrielsen, Mads
    et al.
    Zetterström, Caroline E
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wang, Dai
    Beckham, Katherine S H
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Isaacs, Neil W
    Roe, Andrew J
    Expression, purification, crystallization and initial X-ray diffraction analysis of thiol peroxidase from Yersinia pseudotuberculosis2010In: Acta Crystallographica. Section F: Structural Biology and Crystallization Communications, ISSN 1744-3091, E-ISSN 1744-3091, Vol. 66, no Pt 12, p. 1606-1609Article in journal (Refereed)
    Abstract [en]

    Thiol peroxidase is an atypical 2-Cys peroxiredoxin that reduces alkyl hydroperoxides. Wild-type and C61S mutant protein have been recombinantly expressed in Escherichia coli and purified using nickel-affinity chromatography. Initial crystallization trials yielded three crystal forms in three different space groups (P2(1), P6(4) and P2(1)2(1)2(1)) both in the presence and the absence of DTT.

  • 24.
    Gwon, Yong-Dae
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Strand, Mårten
    Lindquist, Richard
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Nilsson, Emma
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Saleeb, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Antiviral Activity of Benzavir-2 against Emerging Flaviviruses2020In: Viruses, E-ISSN 1999-4915, Vol. 12, no 3, article id 351Article in journal (Refereed)
    Abstract [en]

    Most flaviviruses are arthropod-borne viruses, transmitted by either ticks or mosquitoes, and cause morbidity and mortality worldwide. They are endemic in many countries and have recently emerged in new regions, such as the Zika virus (ZIKV) in South-and Central America, the West Nile virus (WNV) in North America, and the Yellow fever virus (YFV) in Brazil and many African countries, highlighting the need for preparedness. Currently, there are no antiviral drugs available to treat flavivirus infections. We have previously discovered a broad-spectrum antiviral compound, benzavir-2, with potent antiviral activity against both DNA- and RNA-viruses. Our purpose was to investigate the inhibitory activity of benzavir-2 against flaviviruses. We used a ZIKV ZsGreen-expressing vector, two lineages of wild-type ZIKV, and other medically important flaviviruses. Benzavir-2 inhibited ZIKV derived reporter gene expression with an EC50 value of 0.8 +/- 0.1 µM. Furthermore, ZIKV plaque formation, progeny virus production, and viral RNA expression were strongly inhibited. In addition, 2.5 µM of benzavir-2 reduced infection in vitro in three to five orders of magnitude for five other flaviviruses: WNV, YFV, the tick-borne encephalitis virus, Japanese encephalitis virus, and dengue virus. In conclusion, benzavir-2 was a potent inhibitor of flavivirus infection, which supported the broad-spectrum antiviral activity of benzavir-2.

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  • 25. Hakala, Elina F.
    et al.
    Hanski, Leena
    Uvell, Hanna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Yrjonen, Teijo
    Vuorela, Heikki
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Vuorela, Pia Maarit
    Dibenzocyclooctadiene lignans from Schisandra spp. selectively inhibit the growth of the intracellular bacteria Chlamydia pneumoniae and Chlamydia trachomatis2015In: Journal of antibiotics (Tokyo. 1968), ISSN 0021-8820, E-ISSN 1881-1469, Vol. 68, no 10, p. 609-614Article in journal (Refereed)
    Abstract [en]

    Lignans from Schisandra chinensis berries show various pharmacological activities, of which their antioxidative and cytoprotective properties are among the most studied ones. Here, the first report on antibacterial properties of six dibenzocyclooctadiene lignans found in Schisandra spp. is presented. The activity was shown on two related intracellular Gram-negative bacteria Chlamydia pneumoniae and Chlamydia trachomatis upon their infection in human epithelial cells. All six lignans inhibited C. pneumoniae inclusion formation and infectious progeny production. Schisandrin B inhibited C. pneumoniae inclusion formation even when administered 8 h post infection, indicating a target that occurs relatively late within the infection cycle. Upon infection, lignan-pretreated C. pneumoniae elementary bodies had impaired inclusion formation capacity. The presence and substitution pattern of methylenedioxy, methoxy and hydroxyl groups of the lignans had a profound impact on the antichlamydial activity. In addition our data suggest that the antichlamydial activity is not caused only by the antioxidative properties of the lignans. None of the compounds showed inhibition on seven other bacteria, suggesting a degree of selectivity of the antibacterial effect. Taken together, the data presented support a role of the studied lignans as interesting antichlamydial lead compounds.

  • 26. Hanski, Leena
    et al.
    Genina, Natalja
    Uvell, Hanna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Malinovskaja, Kristina
    Gylfe, Asa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Laaksonen, Timo
    Kolakovic, Ruzica
    Makila, Ermei
    Salonen, Jarno
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hirvonen, Jouni
    Sandler, Niklas
    Vuorela, Pia M.
    Inhibitory Activity of the Isoflavone Biochanin A on Intracellular Bacteria of Genus Chlamydia and Initial Development of a Buccal Formulation2014In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 12, article id e115115Article in journal (Refereed)
    Abstract [en]

    Given the established role of Chlamydia spp. as causative agents of both acute and chronic diseases, search for new antimicrobial agents against these intracellular bacteria is required to promote human health. Isoflavones are naturally occurring phytoestrogens, antioxidants and efflux pump inhibitors, but their therapeutic use is limited by poor water-solubility and intense first-pass metabolism. Here, we report on effects of isoflavones against C. pneumoniae and C. trachomatis and describe buccal permeability and initial formulation development for biochanin A. Biochanin A was the most potent Chlamydia growth inhibitor among the studied isoflavones, ;with an IC50=12 mu M on C. pneumoniae inclusion counts and 6.5 mu M on infectious progeny production, both determined by immunofluorescent staining of infected epithelial cell cultures. Encouraged by the permeation of biochanin A across porcine buccal mucosa without detectable metabolism, oromucosal film formulations were designed and prepared by a solvent casting method. The film formulations showed improved dissolution rate of biochanin A compared to powder or a physical mixture, presumably due to the solubilizing effect of hydrophilic additives and presence of biochanin A in amorphous state. In summary, biochanin A is a potent inhibitor of Chlamydia spp., and the in vitro dissolution results support the use of a buccal formulation to potentially improve its bioavailability in antichlamydial or other pharmaceutical applications.

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  • 27.
    Hillgren, J. Mikael
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Öberg, Christopher T
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Syntheses of pseudoceramines A-D and a new synthesis of spermatinamine, bromotyrosine natural products from marine sponges2012In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 10, no 6, p. 1246-1254Article in journal (Refereed)
    Abstract [en]

    Herein we report the total syntheses of pseudoceramine A-D (2-5) and spermatinamine (1) isolated from the marine sponge Pseudoceratina sp. Direct acyl substitution of α-hydroxyiminoesters with amine nucleophiles was developed as a key transformation. The synthetic compounds confirm the reported structures and importantly gives access to non-symmetrical spermine based natural products carrying two different bromotyrosine building blocks. Our new synthesis of spermatinamine is two steps shorter and more efficient than the previously reported sequence.

  • 28.
    Hillgren, Mikael J
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Dahlgren, Markus K
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    To, Tam M
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Synthesis of [4-(2-Hydroxyphenyl)thiazol-2-yl]methanones as Potential Bioisosteres of Salicylidene Acylhydrazides2010In: Molecules, ISSN 1431-5157, E-ISSN 1420-3049, Vol. 15, no 9, p. 6019-34Article in journal (Refereed)
    Abstract [en]

    A focused library of [4-(2-hydroxyphenyl)thiazol-2-yl]methanones was prepared in a four-step synthesis with the aim to obtain potent inhibitors of type III secretion in Gram-negative bacteria. The compounds are potential bioisosteres of salicylidene acylhydrazides that are a known class of type III secretion inhibitors.

  • 29. Horvath, Dragos
    et al.
    Lisurek, Michael
    Rupp, Bernd
    Kuehne, Ronald
    Specker, Edgar
    von Kries, Jens
    Rognan, Didier
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Enqvist, Per-Anders
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gustavsson, Anna-Lena
    Remez, Nikita
    Mestres, Jordi
    Marcou, Gilles
    Varnek, Alexander
    Hibert, Marcel
    Quintana, Jordi
    Frank, Ronald
    Design of a general-purpose European compound screening library for EU-OPENSCREEN2014In: ChemMedChem, ISSN 1860-7179, E-ISSN 1860-7187, Vol. 9, no 10, p. 2309-2326Article in journal (Refereed)
    Abstract [en]

    This work describes a collaborative effort to define and apply a protocol for the rational selection of a general-purpose screening library, to be used by the screening platforms affiliated with the EU-OPENSCREEN initiative. It is designed as a standard source of compounds for primary screening against novel biological targets, at the request of research partners. Given the general nature of the potential applications of this compound collection, the focus of the selection strategy lies on ensuring chemical stability, absence of reactive compounds, screening-compliant physicochemical properties, loose compliance to drug-likeness criteria (as drug design is a major, but not exclusive application), and maximal diversity/coverage of chemical space, aimed at providing hits for a wide spectrum of drugable targets. Finally, practical availability/cost issues cannot be avoided. The main goal of this publication is to inform potential future users of this library about its conception, sources, and characteristics. The outline of the selection procedure, notably of the filtering rules designed by a large committee of European medicinal chemists and chemoinformaticians, may be of general methodological interest for the screening/medicinal chemistry community. The selection task of 200K molecules out of a pre-filtered set of 1.4M candidates was shared by five independent European research groups, each picking a subset of 40K compounds according to their own in-house methodology and expertise. An in-depth analysis of chemical space coverage of the library serves not only to characterize the collection, but also to compare the various chemoinformatics-driven selection procedures of maximal diversity sets. Compound selections contributed by various participating groups were mapped onto general-purpose self-organizing maps (SOMs) built on the basis of marketed drugs and bioactive reference molecules. In this way, the occupancy of chemical space by the EU-OPENSCREEN library could be directly compared with distributions of known bioactives of various classes. This mapping highlights the relevance of the selection and shows how the consensus reached by merging the five different 40K selections contributes to achieve this relevance. The approach also allows one to readily identify subsets of target-or target-class-oriented compounds from the EU-OPENSCREEN library to suit the needs of the diverse range of potential users. The final EU-OPENSCREEN library, assembled by merging five independent selections of 40K compounds from various expert groups, represents an excellent example of a Europe-wide collaborative effort toward the common objective of building best-in-class European open screening platforms.

  • 30. Hudson, Debra L
    et al.
    Layton, Abigail N
    Field, Terry R
    Bowen, Alison J
    Wolf-Watz, Hans
    Umeå University, Faculty of Science and Technology, Molecular Biology (Faculty of Science and Technology).
    Elofsson, Mikael
    Chemistry.
    Stevens, Mark P
    Galyov, Edouard E
    Inhibition of Type III Secretion in Salmonella enterica Serovar Typhimurium by Small-Molecule Inhibitors2007In: Antimicrobial Agents and Chemotherapy, Vol. 51, no 7, p. 2631-5Article in journal (Refereed)
    Abstract [en]

    Type III secretion systems (T3SS) are conserved in many pathogenic gram-negative bacteria. Small molecules that specifically target T3SS in Yersinia and Chlamydia spp. have recently been identified. Here we show that two such compounds inhibit Salmonella T3SS-1, preventing secretion of T3SS-1 effectors, invasion of cultured epithelial cells, and enteritis in vivo.

  • 31. Huerta-Uribe, Alejandro
    et al.
    Marjenberg, Zoe R.
    Yamaguchi, Nao
    Fitzgerald, Stephen
    Connolly, James P. R.
    Carpena, Nuria
    Uvell, Hanna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Douce, Gillian
    Elofsson, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Byron, Olwyn
    Marquez, Rudi
    Gally, David L.
    Roe, Andrew J.
    Identification and Characterization of Novel Compounds Blocking Shiga Toxin Expression in Escherichia coli O157:H72016In: Frontiers in Microbiology, E-ISSN 1664-302X, Vol. 7, article id 1930Article in journal (Refereed)
    Abstract [en]

    Infections caused by Shiga toxin-producing E. coli strains constitute a health problem, as they are problematic to treat. Shiga toxin (Stx) production is a key virulence factor associated with the pathogenicity of enterohaemorrhagic E. coli (EHEC) and can result in the development of haemolytic uremic syndrome in infected patients. The genes encoding Stx are located on temperate lysogenic phages integrated into the bacterial chromosome and expression of the toxin is generally coupled to phage induction through the SOS response. We aimed to find new compounds capable of blocking expression of Stx type 2 (Stx2) as this subtype of Stx is more strongly associated with human disease. High-throughput screening of a small-molecule library identified a lead compound that reduced Stx2 expression in a dose-dependent manner. We show that the optimised compound interferes with the SOS response by directly affecting the activity and oligomerisation of RecA, thus limiting phage activation and Stx2 expression. Our work suggests that RecA is highly susceptible to inhibition and that targeting this protein is a viable approach to limiting production of Stx2 by EHEC. This type of approach has the potential to limit production and transfer of other phage induced and transduced determinants.

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  • 32.
    Islam, Md. Koushikul
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Strand, Mårten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Saleeb, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Svensson, Richard
    Baranczewski, Pawel
    Artursson, Per
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Anti-Rift Valley fever virus activity in vitro, pre-clinical pharmacokinetics and oral bioavailability of benzavir-2, a broad-acting antiviral compound2018In: Scientific Reports, E-ISSN 2045-2322, Vol. 8, article id 1925Article in journal (Refereed)
    Abstract [en]

    Rift Valley fever virus (RVFV) is a mosquito-borne hemorrhagic fever virus affecting both humans and animals with severe morbidity and mortality and is classified as a potential bioterror agent due to the possible aerosol transmission. At present there is no human vaccine or antiviral therapy available. Thus, there is a great need to develop new antivirals for treatment of RVFV infections. Benzavir-2 was previously identified as potent inhibitor of human adenovirus, herpes simplex virus type 1, and type 2. Here we assess the anti-RVFV activity of benzavir-2 together with four structural analogs and determine pre-clinical pharmacokinetic parameters of benzavir-2. In vitro, benzavir-2 efficiently inhibited RVFV infection, viral RNA production and production of progeny viruses. In vitro, benzavir-2 displayed satisfactory solubility, good permeability and metabolic stability. In mice, benzavir-2 displayed oral bioavailability with adequate maximum serum concentration. Oral administration of benzavir-2 formulated in peanut butter pellets gave high systemic exposure without any observed toxicity in mice. To summarize, our data demonstrated potent anti-RVFV activity of benzavir-2 in vitro together with a promising pre-clinical pharmacokinetic profile. This data support further exploration of the antiviral activity of benzavir-2 in in vivo efficacy models that may lead to further drug development for human use.

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  • 33.
    Johansson, Emil
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Caraballo, Remi
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Synthesis of 4-O-alkylated N-acetylneuraminic acid derivatives2021In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 86, no 13, p. 9145-9154Article in journal (Refereed)
    Abstract [en]

    The synthesis of 4-O-alkyl analogs of N-acetylneuraminic acid (Neu5Ac) and the scope of the reaction are described. Activated alkyl halides and sulfonates and primary alkyl iodides give products in useful yields. The utility of the methodology is exemplified using a thiophenyl Neu5Ac building block to synthesize a 4-O-alkyl DANA analog. These results expand the toolbox of Neu5Ac chemistry with value in drug discovery and for the design of novel tools to study the biology of Neu5Ac lectins. 

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  • 34.
    Johansson, Emil
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Caraballo, Remi
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hurdiss, Daniel L.
    Virology Section, Infectious Diseases and Immunology Division, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands.
    Mistry, Nitesh
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Thompson, Rebecca F.
    Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.
    Ranson, Neil A.
    Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.
    Zocher, Georg
    Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.
    Stehle, Thilo
    Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany; Department of Pediatrics, Vanderbilt University School of Medicine, TN, Nashville, United States.
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Exploring the effect of structure-based scaffold hopping on the inhibition of coxsackievirus a24v transduction by pentavalent n-acetylneuraminic acid conjugates2021In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 22, no 16, article id 8418Article in journal (Refereed)
    Abstract [en]

    Coxsackievirus A24 variant (CVA24v) is the primary causative agent of the highly contagious eye infection designated acute hemorrhagic conjunctivitis (AHC). It is solely responsible for two pandemics and several recurring outbreaks of the disease over the last decades, thus affecting millions of individuals throughout the world. To date, no antiviral agents or vaccines are available for combating this disease, and treatment is mainly supportive. CVA24v utilizes Neu5Ac-containing glycans as attachment receptors facilitating entry into host cells. We have previously reported that pentavalent Neu5Ac conjugates based on a glucose-scaffold inhibit CVA24v infection of human corneal epithelial cells. In this study, we report on the design and synthesis of scaffold-replaced pentavalent Neu5Ac conjugates and their effect on CVA24v cell transduction and the use of cryogenic electron microscopy (cryo-EM) to study the binding of these multivalent conjugates to CVA24v. The results presented here provide insights into the development of Neu5Ac-based inhibitors of CVA24v and, most significantly, the first application of cryo-EM to study the binding of a multivalent ligand to a lectin.

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  • 35.
    Johansson, Emil
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Caraballo, Remi
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Mistry, Nitesh
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Zocher, Georg
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hurdiss, Daniel L.
    Chandra, Naresh
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Thompson, Rebecca
    Frängsmyr, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Stehle, Thilo
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Pentavalent Sialic Acid Conjugates Block Coxsackievirus A24 Variant and Human Adenovirus Type 37-Viruses That Cause Highly Contagious Eye Infections2020In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 15, no 10, p. 2683-2691Article in journal (Refereed)
    Abstract [en]

    Coxsackievirus A24 variant (CVA24v) and human adenovirus 37 (HAdV-37) are leading causative agents of the severe and highly contagious ocular infections acute hemorrhagic conjunctivitis and epidemic keratoconjunctivitis, respectively. Currently, neither vaccines nor antiviral agents are available for treating these diseases, which affect millions of individuals worldwide. CVA24v and HAdV-37 utilize sialic acid as attachment receptors facilitating entry into host cells. Previously, we and others have shown that derivatives based on sialic acid are effective in preventing HAdV-37 binding and infection of cells. Here, we designed and synthesized novel pentavalent sialic acid conjugates and studied their inhibitory effect against CVA24v and HAdV-37 binding and infection of human corneal epithelial cells. The pentavalent conjugates are the first reported inhibitors of CVA24v infection and proved efficient in blocking HAdV-37 binding. Taken together, the pentavalent conjugates presented here form a basis for the development of general inhibitors of these highly contagious ocular pathogens.

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  • 36.
    Johansson, Emil
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Caraballo, Remi
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Zocher, Georg
    Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.
    Mistry, Nitesh
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Stehle, Thilo
    Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany; Vanderbilt University, School of Medicine, TN, Nashville, United States.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Exploring divalent conjugates of 5-N-acetyl-neuraminic acid as inhibitors of coxsackievirus A24 variant (CVA24v) transduction2022In: RSC Advances, E-ISSN 2046-2069, Vol. 12, no 4, p. 2319-2331Article in journal (Refereed)
    Abstract [en]

    Coxsackievirus A24 variant (CVA24v) is responsible for several outbreaks and two pandemics of the highly contagious eye infection acute hemorrhagic conjunctivitis (AHC). Currently, neither prevention (vaccines) nor treatments (antivirals) are available for combating this disease. CVA24v attaches to cells by binding Neu5Ac-containing glycans on the surface of cells which facilitates entry. Previously, we have demonstrated that pentavalent Neu5Ac conjugates attenuate CVA24v infection of human corneal epithelial (HCE) cells. In this study, we report on the structure-based design of three classes of divalent Neu5Ac conjugates, with varying spacer lengths, and their effect on CVA24v transduction in HCE cells. In relative terms, the most efficient class of divalent Neu5Ac conjugates are more efficient than the pentavalent Neu5Ac conjugates previously reported.

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  • 37.
    Johansson, Susanne M C
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kihlberg, Jan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Multivalent HSA conjugates of 3 '-siallyllactose are potent inhibitors of adenoviral cell attachment and infection2005In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 6, no 2, p. 358-364Article in journal (Refereed)
    Abstract [en]

    Adenoviruses of serotypes 8, 19 and 37 are the major cause of the severe eye infection EKC (epidemic keratoconjunctivitis). In general, all adenoviruses interact with their cellular receptors through the fibre proteins, which extend from the virus particle. Recently, adenovirus type 37 (Ad37) was found to bind and infect human corneal cells through attachment to carbohydrate structures that carry terminal alpha-(2-3)-linked sialic acids. Herein we present a synthetic route to a 3'-sialyllactose derivative and corresponding multivalent HSA conjugates with varying orders of valency. The potential of these compounds as inhibitors of EKC causing adenovirus of serotype Ad37, was studied with both binding assay and an infectivity assay. The results revealed that these compounds effectively prevent Ad37 from binding to and infecting human corneal epithelial (HCE) cells. Moreover, the inhibition is significantly increased with higher orders of multivalency.

  • 38.
    Johansson, Susanne M C
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Nilsson, Emma C
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ahlskog, Nina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kihlberg, Jan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Multivalent sialic acid conjugates inhibit adenovirus type 37 from binding to and infecting human corneal epithelial cells2007In: Antiviral Research, ISSN 0166-3542, E-ISSN 1872-9096, Vol. 73, no 2, p. 92-100Article in journal (Refereed)
    Abstract [en]

    Adenovirus type 37 is one of the main causative agents of epidemic keratoconjunctivitis. In a series of publications, we have reported that this virus uses sialic acid as a cellular receptor. Here we demonstrate in vitro that on a molar basis, multivalent sialic acid conjugated to human serum albumin prevents adenovirus type 37 from binding to and infecting human corneal epithelial cells 1000-fold more efficiently than monosaccharidic sialic acid. We also demonstrate that the extraordinary inhibitory effect of multivalent sialic acid is due to the ability of this compound to aggregate virions. We conclude that multivalent sialic acid may be a potential new antiviral drug, for use in the treatment of epidemic keratoconjunctivitis caused by the adenoviruses that use sialic acid as cellular receptor.

  • 39.
    Johansson, Susanne
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Nilsson, Emma
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Kihlberg, Jan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Design, synthesis and evaluation of N-acyl modified sialic acids as inhibitors of EKC-causing adenovirusesManuscript (preprint) (Other academic)
  • 40.
    Johansson, Susanne
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Nilsson, Emma
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Guilligay, Delphine
    Crepin, Thibaut
    Cusack, Stephen
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Design, synthesis, and evaluation of N-acyl modified sialic acids as inhibitors of adenoviruses causing epidemic keratoconjunctivitis2009In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 52, no 12, p. 3666-3678Article in journal (Refereed)
    Abstract [en]

    The adenovirus serotype Ad37 binds to and infects human corneal epithelial (HCE) cells through attachment to cellular glycoproteins carrying terminal sialic acids. By use of the crystallographic structure of the sialic acid-interacting domain of the Ad37 fiber protein in complex with sialyllactose, a set of N-acyl modified sialic acids were designed to improve binding affinity through increased hydrophobic interactions. These N-acyl modified sialic acids and their corresponding multivalent human serum albumin (HSA) conjugates were synthesized and tested in Ad37 cell binding and cell infectivity assays. Compounds bearing small substituents were as effective inhibitors as sialic acid. X-ray crystallography and overlays with the Ad37-sialyllactose complex showed that the N-acyl modified sialic acids were positioned in the same orientation as sialic acid. Their multivalent counterparts achieved a strong multivalency effect and were more effective to prevent infection than the monomers. Unfortunately, they were less active as inhibitors than multivalent sialic acid.

  • 41. Karlberg, Tobias
    et al.
    Hornyak, Peter
    Pinto, Ana Filipa
    Milanova, Stefina
    Ebrahimi, Mahsa
    Lindberg, Mikael J.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Püllen, Nikolai
    Nordström, Axel
    Löverli, Elinor
    Caraballo, Remi
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wong, Emily V.
    Näreoja, Katja
    Thorsell, Ann-Gerd
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    De la Cruz, Enrique M.
    Björkegren, Camilla
    Schüler, Herwig
    14-3-3 proteins activate Pseudomonas exotoxins-S and -T by chaperoning a hydrophobic surface2018In: Nature Communications, E-ISSN 2041-1723, Vol. 9, article id 3785Article in journal (Refereed)
    Abstract [en]

    Pseudomonas are a common cause of hospital-acquired infections that may be lethal. ADP-ribosyltransferase activities of Pseudomonas exotoxin-S and -T depend on 14-3-3 proteins inside the host cell. By binding in the 14-3-3 phosphopeptide binding groove, an amphipathic C-terminal helix of ExoS and ExoT has been thought to be crucial for their activation. However, crystal structures of the 14-3-3 beta: ExoS and -ExoT complexes presented here reveal an extensive hydrophobic interface that is sufficient for complex formation and toxin activation. We show that C-terminally truncated ExoS ADP-ribosyltransferase domain lacking the amphipathic binding motif is active when co-expressed with 14-3-3. Moreover, swapping the amphipathic C-terminus with a fragment from Vibrio Vis toxin creates a 14-3-3 independent toxin that ADP-ribosylates known ExoS targets. Finally, we show that 14-3-3 stabilizes ExoS against thermal aggregation. Together, this indicates that 14-3-3 proteins activate exotoxin ADP-ribosyltransferase domains by chaperoning their hydrophobic surfaces independently of the amphipathic C-terminal segment.

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  • 42.
    Kauppi, Anna M.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, David C.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Norberg, Henrik A.
    Innate Pharmaceuticals AB, Umestan Företagspark, SE-90347 Umeå, Sweden.
    Sundin, Charlotta
    Innate Pharmaceuticals AB, Umestan Företagspark, SE-90347 Umeå, Sweden.
    Linusson Jonsson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Inhibitors of type III secretion in Yersinia: design, synthesis and multivariate QSAR of 2-sulfonamino-benzanilides2007In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 15, no 22, p. 6994-7011Article in journal (Other academic)
    Abstract [en]

    Compound 1, 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-N-(3,4-dichloro-phenyl)-benzamide, was identified as a putative type III secretion inhibitor in Yersinia, and the compound thus has a potential to be used to prevent or treat bacterial infections. A set of seven analogues was synthesized and evaluated in a type III secretion dependent reporter-gene assay with viable bacterial to give basic SAR. A second set of 19 compounds was obtained by statistical molecular design in the building block and product space and subsequent synthesis. Evaluation in the reporter-gene assay showed that the compounds ranged from non-active to compounds more potent than 1. Based on the data multivariate QSAR models were established and the final Hi-PLS model showed good correlation between experimentally determined % inhibition and the calculated % inhibition of the reporter-gene signal.

  • 43. Kauppi, Anna
    et al.
    Nordfelth, Roland
    Umeå University, Faculty of Science and Technology, Molecular Biology (Faculty of Science and Technology).
    Hägglund, U
    Wolf-Watz, Hans
    Umeå University, Faculty of Science and Technology, Molecular Biology (Faculty of Science and Technology).
    Elofsson, Mikael
    Chemistry.
    Salicylanilides are potent inhibitors of type III secretion in Yersinia2003In: Advances in Experimental Medicine and Biology, Vol. 529, p. 97-100Article in journal (Refereed)
  • 44.
    Kauppi, Anna
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Nordfelth, Roland
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Uvell, Hanna
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Wolf-Watz, Hans
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Targeting bacterial Virulence:  Inhibitors of type III secretion in Yersinia2003In: Chemistry and Biology, ISSN 1074-5521, E-ISSN 1879-1301, Vol. 10, no 3, p. 241-249Article in journal (Refereed)
    Abstract [en]

    Agents that target bacterial virulence without detrimental effect on bacterial growth are useful chemical probes for studies of virulence and potential candidates for drug development. Several gram-negative pathogens employ type III secretion to evade the innate immune response of the host. Screening of a chemical library with a luciferase reporter gene assay in viable Yersinia pseudotuberculosis furnished several compounds that inhibit the reporter gene signal expressed from the yopE promoter and effector protein secretion at concentrations with no or modest effect on bacterial growth. The selectivity patterns observed for inhibition of various reporter gene strains indicate that the compounds target the type III secretion machinery at different levels. Identification of this set of inhibitors illustrates the approach of utilizing cell-based assays to identify compounds that affect complex bacterial virulence systems.

  • 45. Keyser, P.
    et al.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Rosell, S.
    Wolf-Watz, Hans
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Virulence blockers as alternatives to antibiotics: type III secretion inhibitors against Gram-negative bacteria2008In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 264, no 1, p. 17-29Article in journal (Refereed)
    Abstract [en]

    In recent years mounting problems related to antibiotic-resistant bacteria have resulted in the prediction that we are entering the preantibiotic era. A way of preventing such a development would be to introduce novel antibacterial medicines with modes of action distinct from conventional antibiotics. Recent studies of bacterial virulence factors and toxins have resulted in increased understanding of the way in which pathogenic bacteria manipulate host cellular processes. This knowledge may now be used to develop novel antibacterial medicines that disarm pathogenic bacteria. The type III secretion system (T3SS) is known to be a potent virulence mechanism shared by a broad spectrum of pathogenic Gram-negative bacteria that interact with human, animal and plant hosts by injecting effector proteins into the cytosol of host cells. Diseases, such as bubonic plague, shigellosis, salmonellosis, typhoid fever, pulmonary infections, sexually transmitted chlamydia and diarrhoea largely depend on the bacterial proteins injected by the T3SS machinery. Recently a number of T3SS inhibitors have been identified using screening-based approaches. One class of inhibitors, the salicylidene acylhydrazides, has been subjected to chemical optimization and evaluation in several in vitro and ex vivo assays in multiple bacterial species including Yersinia spp., Chlamydia spp., Salmonella spp. and Pseudotuberculosis aeruginosa. Reports published up to date indicate that T3SS inhibitors have the potential to be developed into novel antibacterial therapeutics.

  • 46.
    Krzyzanowski, Adrian
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Saleeb, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Synthesis of Indole-, Benzo[ b]thiophene-, and Benzo[ b]selenophene-Based Analogues of the Resveratrol Dimers Viniferifuran and (±)-Dehydroampelopsin B.2018In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 20, no 21, p. 6650-6654Article in journal (Refereed)
    Abstract [en]

    A convenient synthetic strategy to obtain viniferifuran and (±)-dehydroampelopsin B analogues based on the heterocyclic cores of indole, benzo[ b]thiophene, and benzo[ b]selenophene is presented. The key transformations utilized in the described syntheses include Sonogashira couplings, Cacchi and alkyne electrophilic cyclizations, Horner-Wadsworth-Emmons (HWE) reaction, chemoselective Suzuki-Miyaura couplings, and acid-promoted intramolecular cyclization to form the seven-membered ring of (±)-dehydroampelopsin B.

  • 47.
    Kumar, Arvind
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Saleeb, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Werz, Dominik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Cyclopropylmethyl Protection of Phenols: Total Synthesis of the Resveratrol Dimers Anigopreissin A and Resveratrol-Piceatannol Hybrid2018In: ChemistryOpen, ISSN 2191-1363, Vol. 7, no 12, p. 953-956Article in journal (Refereed)
    Abstract [en]

    We demonstrate the versatile use of the cyclopropylmethyl group to protect phenols through the total synthesis of two benzofuran-based natural products, that is, anigopreissin A and the resveratrol-piceatannol hybrid. This protecting group is a good alternative to the conventional methyl group, owing to the feasibility of introduction, stability under a variety of conditions, and its relative ease of removal under different acidic conditions.

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  • 48. Kwoka, Benjamin H B
    et al.
    Koh, Brian
    Ndubuisia, MacKevin I
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Chemistry.
    Crews, Craig M
    The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IkappaB kinase2001In: Chemistry & Biology, Vol. 8, no 8, p. 759-77Article in journal (Refereed)
    Abstract [en]

    Background: Biologically active natural products continue to be useful in the exploration and control of intracellular signaling processes. For example, the sesquiterpene lactone parthenolide from the anti-inflammatory medicinal herb Feverfew (Tanacetum parthenium) appears to inhibit the pro-inflammatory signaling pathway. Parthenolide’s direct molecular target, however, remains unknown. We set out to identify the molecular mechanisms of parthenolide’s anti-inflammatory activity.

    Results: A parthenolide affinity reagent was synthesized and shown to bind directly to and inhibit IκB kinase β (IKKβ), the kinase subunit known to play a critical role in cytokine-mediated signaling. Mutation of cysteine 179 in the activation loop of IKKβ abolished sensitivity towards parthenolide. Moreover, we showed that parthenolide’s in vitro and in vivo anti-inflammatory activity is mediated through the α-methylene γ-lactone moiety shared by other sesquiterpene lactones.

    Conclusions: In recent years, the multi-subunit IKK complex has been shown to be responsible for cytokine-mediated stimulation of genes involved in inflammation and as such represents an attractive target for pharmaceutical intervention. Our finding that parthenolide targets this kinase complex provides a possible molecular basis for the anti-inflammatory properties of parthenolide. In addition, these results may be useful in the development of additional anti-inflammatory agents.

  • 49.
    Larsson, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Caraballo, Rémi
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ericsson, Madelene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Lookene, Aivar
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. Tallinn University of Technology, Department of Chemistry, Tallinn, Estonia.
    Enquist, Per-Anders
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Nilsson, Stefan K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Olivecrona, Gunilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Identification of a small molecule that stabilizes lipoprotein lipase in vitro and lowers triglycerides in vivo2014In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 450, no 2, p. 1063-1069Article in journal (Refereed)
    Abstract [en]

    Patients at increased cardiovascular risk commonly display high levels of plasma triglycerides (TGs) levels, elevated LDL cholesterol, small dense LDL particles and low levels of HDL-cholesterol. Many remain at high risk even after successful statin therapy, presumably because TG levels remain high. Lipoprotein lipase (LPL) maintains TG homeostasis in blood by hydrolysis of TG-rich lipoproteins. Efficient clearance of TGs is accompanied by increased levels of HDL-cholesterol and decreased levels of small dense LDL. Given the central role of LPL in lipid metabolism we sought to find small molecules that could increase LPL activity and serve as starting points for drug development efforts against cardiovascular disease. Using a small molecule screening approach we have identified small molecules that can protect LPL from inactivation by the controller protein angiopoietin-like protein 4 during incubations in vitro. One of the selected compounds, 50F10, was directly shown to preserve the active homodimer structure of LPL, as demonstrated by heparin-Sepharose chromatography. This compound tended to reduce fasting TG levels in normal rats. On injection to hypertriglyceridemic apolipoprotein A-V deficient mice the compound ameliorated the postprandial response after an olive oil gavage. This compound is a potential lead compound for the development of drugs that could reduce the residual risk associated with elevated TGs in dyslipidemia.

  • 50.
    Lindgren, Anders E. G.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Karlberg, Tobias
    Ekblad, Torun
    Spjut, Sara
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Thorsell, Ann-Gerd
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Nhan, Ton Tong
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hellsten, Victor
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Weigelt, Johan
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Schuler, Herwig
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Chemical Probes to Study ADP-Ribosylation: Synthesis and Biochemical Evaluation of Inhibitors of the Human ADP-Ribosyltransferase ARTD3/PARP32013In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 56, no 23, p. 9556-9568Article in journal (Refereed)
    Abstract [en]

    The racemic 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-N-[1-(pyridin-2-yl)ethyl]propanamide, 1, has previously been identified as a potent but unselective inhibitor of diphtheria toxin-like ADP-ribosyltransferase 3 (ARTD3). Herein we describe synthesis and evaluation of SS compounds in this class. It was found that the stereochemistry is of great importance for both selectivity and potency and that substituents on the phenyl ring resulted in poor solubility. Certain variations at the meso position were tolerated and caused a large shift in the binding pose. Changes to the ethylene linker that connects the quinazolinone to the amide were also investigated but proved detrimental to binding. By combination of synthetic organic chemistry and structure-based design, two selective inhibitors of ARTD3 were discovered.

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