Umeå University's logo

umu.sePublications
Change search
Link to record
Permanent link

Direct link
Alternative names
Publications (10 of 36) Show all publications
Johansson, E., Caraballo, R., Hurdiss, D. L., Mistry, N., Andersson, C. D., Thompson, R. F., . . . Elofsson, M. (2021). Exploring the effect of structure-based scaffold hopping on the inhibition of coxsackievirus a24v transduction by pentavalent n-acetylneuraminic acid conjugates. International Journal of Molecular Sciences, 22(16), Article ID 8418.
Open this publication in new window or tab >>Exploring the effect of structure-based scaffold hopping on the inhibition of coxsackievirus a24v transduction by pentavalent n-acetylneuraminic acid conjugates
Show others...
2021 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 22, no 16, article id 8418Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
5-N-acetylneuraminic acid, Antivirals, Conjunctivitis, Coxsackievirus A24v, Cryo-EM, Multivalency, Sialic acid conjugates
National Category
Microbiology in the medical area Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-186555 (URN)10.3390/ijms22168418 (DOI)000689130700001 ()2-s2.0-85111762142 (Scopus ID)
Available from: 2021-08-11 Created: 2021-08-11 Last updated: 2023-09-05Bibliographically approved
Johansson, E., Caraballo, R., Mistry, N., Zocher, G., Qian, W., Andersson, C. D., . . . Elofsson, M. (2020). Pentavalent Sialic Acid Conjugates Block Coxsackievirus A24 Variant and Human Adenovirus Type 37-Viruses That Cause Highly Contagious Eye Infections. ACS Chemical Biology, 15(10), 2683-2691
Open this publication in new window or tab >>Pentavalent Sialic Acid Conjugates Block Coxsackievirus A24 Variant and Human Adenovirus Type 37-Viruses That Cause Highly Contagious Eye Infections
Show others...
2020 (English)In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 15, no 10, p. 2683-2691Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2020
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-176796 (URN)10.1021/acschembio.0c00446 (DOI)000582580100008 ()32845119 (PubMedID)2-s2.0-85093538705 (Scopus ID)
Available from: 2020-11-24 Created: 2020-11-24 Last updated: 2023-03-24Bibliographically approved
Andersson, C. D., Mishra, B. K., Forsgren, N., Ekström, F. & Linusson, A. (2020). Physical Mechanisms Governing Substituent Effects on Arene-Arene Interactions in a Protein Milieu. Journal of Physical Chemistry B, 124(30), 6529-6539
Open this publication in new window or tab >>Physical Mechanisms Governing Substituent Effects on Arene-Arene Interactions in a Protein Milieu
Show others...
2020 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 124, no 30, p. 6529-6539Article in journal (Refereed) Published
Abstract [en]

Arene-arene interactions play important roles in protein-ligand complex formation. Here, we investigate the characteristics of arene-arene interactions between small organic molecules and aromatic amino acids in protein interiors. The study is based on X-ray crystallographic data and quantum mechanical calculations using the enzyme acetylcholinesterase and selected inhibitory ligands as a model system. It is shown that the arene substituents of the inhibitors dictate the strength of the interaction and the geometry of the resulting complexes. Importantly, the calculated interaction energies correlate well with the measured inhibitor potency. Non-hydrogen substituents strengthened all interaction types in the protein milieu, in keeping with results for benzene dimer model systems. The interaction energies were dispersion-dominated, but substituents that induced local dipole moments increased the electrostatic contribution and thus yielded more strongly bound complexes. These findings provide fundamental insights into the physical mechanisms governing arene-arene interactions in the protein milieu and thus into molecular recognition between proteins and small molecules.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2020
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-174580 (URN)10.1021/acs.jpcb.0c03778 (DOI)000558655900006 ()32610016 (PubMedID)2-s2.0-85089615974 (Scopus ID)
Funder
Swedish Research Council, 2018-05176
Available from: 2020-08-28 Created: 2020-08-28 Last updated: 2023-03-24Bibliographically approved
Rogne, P., Andersson, D., Grundström, C., Sauer-Eriksson, E., Linusson, A. & Wolf-Watz, M. (2019). Nucleation of an Activating Conformational Change by a Cation−Π Interaction. Biochemistry, 58(32), 3408-3412
Open this publication in new window or tab >>Nucleation of an Activating Conformational Change by a Cation−Π Interaction
Show others...
2019 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 58, no 32, p. 3408-3412Article in journal (Refereed) Published
Abstract [en]

As a key molecule in biology, adenosine triphosphate (ATP) has numerous crucial functions in, for instance, energetics, post-translational modifications, nucleotide biosynthesis, and cofactor metabolism. Here, we have discovered an intricate interplay between the enzyme adenylate kinase and its substrate ATP. The side chain of an arginine residue was found to be an efficient sensor of the aromatic moiety of ATP through the formation of a strong cation−π interaction. In addition to recognition, the interaction was found to have dual functionality. First, it nucleates the activating conformational transition of the ATP binding domain and also affects the specificity in the distant AMP binding domain. In light of the functional consequences resulting from the cation−π interaction, it is possible that the mode of ATP recognition may be a useful tool in enzyme design.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2019
National Category
Organic Chemistry Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-162099 (URN)10.1021/acs.biochem.9b00538 (DOI)000480827100002 ()31339702 (PubMedID)2-s2.0-85070652179 (Scopus ID)
Available from: 2019-08-14 Created: 2019-08-14 Last updated: 2023-03-23Bibliographically approved
Broman, K., Mårell-Olsson, E., Johnels, D., Andersson, C. D., Chorell, E., Westerlind, U., . . . Norrby, M. (2019). Spatial Ability in Organic Chemistry: Can Virtual and Augmented Reality be Valuable?. In: 7:e Utvecklingskonferensen för Sveriges ingenjörsutbildningar: . Paper presented at 7:e Utvecklingskonferensen för Sveriges ingenjörsutbildningar 2019, Luleå tekniska universitet, Luleå, 27–28 november, 2019. Luleå tekniska universitet
Open this publication in new window or tab >>Spatial Ability in Organic Chemistry: Can Virtual and Augmented Reality be Valuable?
Show others...
2019 (English)In: 7:e Utvecklingskonferensen för Sveriges ingenjörsutbildningar, Luleå tekniska universitet , 2019Conference paper, Published paper (Other academic)
Abstract [en]

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

Place, publisher, year, edition, pages
Luleå tekniska universitet, 2019
Keywords
Spatial ability, Visualisation, Virtual reality, Augmented reality, Organic chemistry, Lewis structures, Biotechnology engineering students
National Category
Didactics
Research subject
didactics of chemistry
Identifiers
urn:nbn:se:umu:diva-165507 (URN)
Conference
7:e Utvecklingskonferensen för Sveriges ingenjörsutbildningar 2019, Luleå tekniska universitet, Luleå, 27–28 november, 2019
Available from: 2019-11-28 Created: 2019-11-28 Last updated: 2022-12-02Bibliographically approved
Larsson, M., Fraccalvieri, D., Andersson, C. D., Bonati, L., Linusson, A. & Andersson, P. L. (2018). Identification of potential aryl hydrocarbon receptor ligands by virtual screening of industrial chemicals. Environmental Science and Pollution Research, 25(3), 2436-2449
Open this publication in new window or tab >>Identification of potential aryl hydrocarbon receptor ligands by virtual screening of industrial chemicals
Show others...
2018 (English)In: Environmental Science and Pollution Research, ISSN 0944-1344, E-ISSN 1614-7499, Vol. 25, no 3, p. 2436-2449Article in journal (Refereed) Published
Abstract [en]

We have developed a virtual screening procedure to identify potential ligands to the aryl hydrocarbon receptor (AhR) among a set of industrial chemicals. AhR is a key target for dioxin-like compounds, which is related to these compounds’ potential to induce cancer and a wide range of endocrine and immune system related effects. The virtual screening procedure included an initial filtration aiming at identifying chemicals with structural similarities to 66 known AhR binders, followed by three enrichment methods run in parallel. These include two ligand-based methods (structural fingerprints and nearest neighbor analysis) and one structure-based method using an AhR homology model. A set of 6,445 commonly used industrial chemicals was processed, and each step identified unique potential ligands. Seven compounds were identified by all three enrichment methods, and these compounds included known activators and suppressors of AhR. Only approximately 0.7% (41 compounds) of the studied industrial compounds was identified as potential AhR ligands and among these, 28 compounds have to our knowledge not been tested for AhR-mediated effects or have been screened with low purity. We suggest assessment of AhR-related activities of these compounds and in particular 2-chlorotrityl chloride, 3-p-hydroxyanilino-carbazole, and 3-(2-chloro-4-nitrophenyl)-5-(1,1-dimethylethyl)-1,3,4-oxadiazol-2(3H)-one.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
virtual screening, aryl hydrocarbon receptor, industrial chemicals, molecular descriptors, structural similarity, molecular docking
National Category
Chemical Sciences Environmental Sciences
Identifiers
urn:nbn:se:umu:diva-139486 (URN)10.1007/s11356-017-0437-9 (DOI)000422970600042 ()29127629 (PubMedID)2-s2.0-85033444555 (Scopus ID)
Note

Originally included in thesis in manuscript form

Available from: 2017-09-14 Created: 2017-09-14 Last updated: 2023-03-24Bibliographically approved
Andersson, C. D., Martinez, N., Zeller, D., Allgardsson, A., Koza, M. M., Frick, B., . . . Linusson, A. (2018). Influence of Enantiomeric Inhibitors on the Dynamics of Acetylcholinesterase Measured by Elastic Incoherent Neutron Scattering. Journal of Physical Chemistry B, 122(36), 8516-8525
Open this publication in new window or tab >>Influence of Enantiomeric Inhibitors on the Dynamics of Acetylcholinesterase Measured by Elastic Incoherent Neutron Scattering
Show others...
2018 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 122, no 36, p. 8516-8525Article in journal (Refereed) Published
Abstract [en]

The enzyme acetylcholinesterase (AChE) is essential in humans and animals because it catalyzes the breakdown of the nerve-signaling substance acetylcholine. Small molecules that inhibit the function of AChE are important for their use as drugs in the, for example, symptomatic treatment of Alzheimer's disease. New and improved inhibitors are warranted, mainly because of severe side effects of current drugs. In the present study, we have investigated if and how two enantiomeric inhibitors of AChE influence the overall dynamics of noncovalent complexes, using elastic incoherent neutron scattering. A fruitful combination of univariate models, including a newly developed non-Gaussian model for atomic fluctuations, and multivariate methods (principal component analysis and discriminant analysis) was crucial to analyze the fine details of the data. The study revealed a small but clear increase in the dynamics of the inhibited enzyme compared to that of the noninhibited enzyme and contributed to the fundamental knowledge of the mechanisms of AChE-inhibitor binding valuable for the future development of inhibitors.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-152405 (URN)10.1021/acs.jpcb.8b05485 (DOI)000444922800003 ()30110543 (PubMedID)2-s2.0-85052311395 (Scopus ID)
Funder
Swedish Research Council, 2014-4675
Available from: 2018-10-05 Created: 2018-10-05 Last updated: 2023-03-24Bibliographically approved
Saleeb, M., Mojica, S., Eriksson, A. U., Andersson, C. D., Gylfe, Å. & Elofsson, M. (2018). Natural product inspired library synthesis – Identification of 2,3-diarylbenzofuran and 2,3-dihydrobenzofuran based inhibitors of Chlamydia trachomatis. European Journal of Medicinal Chemistry, 143, 1077-1089
Open this publication in new window or tab >>Natural product inspired library synthesis – Identification of 2,3-diarylbenzofuran and 2,3-dihydrobenzofuran based inhibitors of Chlamydia trachomatis
Show others...
2018 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 143, p. 1077-1089Article in journal (Refereed) Published
Abstract [en]

A natural product inspired library was synthesized based on 2,3-diarylbenzofuran and 2,3-diaryl-2,3-dihydrobenzofuran scaffolds. The library of forty-eight compounds was prepared by utilizing Pd-catalyzed one-pot multicomponent reactions and ruthenium-catalyzed intramolecular carbenoid C-H insertions. The compounds were evaluated for antibacterial activity in a panel of test systems including phenotypic, biochemical and image-based screening assays. We identified several potent inhibitors that block intracellular replication of pathogenic Chlamydia trachomatis with IC50 ≤ 3 μM. These new C. trachomatis inhibitors can serve as starting points for the development of specific treatments that reduces the global burden of C. trachomatis infections.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
2, 3-diaryl-2, 3-dihydrobenzofuran, 2, 3-diaryl-benzofuran, Antibacterial, Benzofuran, Chlamydia
National Category
Organic Chemistry Biological Sciences
Identifiers
urn:nbn:se:umu:diva-143062 (URN)10.1016/j.ejmech.2017.11.099 (DOI)000428216700089 ()29232584 (PubMedID)2-s2.0-85037621393 (Scopus ID)
Funder
Swedish Foundation for Strategic Research , SB12-0022Swedish Research Council, 621-2014-4670
Available from: 2017-12-18 Created: 2017-12-18 Last updated: 2023-03-24Bibliographically approved
Allgardsson, A., Andersson, C. D., Akfur, C., Worek, F., Linusson, A. & Ekström, F. (2017). An unusual dimeric inhibitor of acetylcholinesterase: cooperative binding of crystal violet. Molecules, 22(9), Article ID 1433.
Open this publication in new window or tab >>An unusual dimeric inhibitor of acetylcholinesterase: cooperative binding of crystal violet
Show others...
2017 (English)In: Molecules, ISSN 1431-5157, E-ISSN 1420-3049, Vol. 22, no 9, article id 1433Article in journal (Refereed) Published
Abstract [en]

Acetylcholinesterase (AChE) is an essential enzyme that terminates cholinergic transmission by a rapid hydrolysis of the neurotransmitter acetylcholine. AChE is an important target for treatment of various cholinergic deficiencies, including Alzheimer's disease and myasthenia gravis. In a previous high throughput screening campaign, we identified the dye crystal violet (CV) as an inhibitor of AChE. Herein, we show that CV displays a significant cooperativity for binding to AChE, and the molecular basis for this observation has been investigated by X-ray crystallography. Two monomers of CV bind to residues at the entrance of the active site gorge of the enzyme. Notably, the two CV molecules have extensive intermolecular contacts with each other and with AChE. Computational analyses show that the observed CV dimer is not stable in solution, suggesting the sequential binding of two monomers. Guided by the structural analysis, we designed a set of single site substitutions, and investigated their effect on the binding of CV. Only moderate effects on the binding and the cooperativity were observed, suggesting a robustness in the interaction between CV and AChE. Taken together, we propose that the dimeric cooperative binding is due to a rare combination of chemical and structural properties of both CV and the AChE molecule itself.

Place, publisher, year, edition, pages
MDPI AG, 2017
Keywords
cholinesterase, acetylcholinesterase, cooperativity, crystal violet, Hill coefficient, new modality, non-bonded bivalence
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-140654 (URN)10.3390/molecules22091433 (DOI)000411499400040 ()2-s2.0-85029609614 (Scopus ID)
Available from: 2017-10-17 Created: 2017-10-17 Last updated: 2023-08-28Bibliographically approved
Andersson, D. C., Martinez, N., Zeller, D., Rondahl, S. H., Koza, M. M., Frick, B., . . . Linusson, A. (2017). Changes in dynamics of alpha-chymotrypsin due to covalent inhibitors investigated by elastic incoherent neutron scattering. Physical Chemistry, Chemical Physics - PCCP, 19(37), 25369-25379
Open this publication in new window or tab >>Changes in dynamics of alpha-chymotrypsin due to covalent inhibitors investigated by elastic incoherent neutron scattering
Show others...
2017 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 19, no 37, p. 25369-25379Article in journal (Refereed) Published
Abstract [en]

An essential role of enzymes is to catalyze various chemical reactions in the human body and inhibition of the enzymatic activity by small molecules is the mechanism of action of many drugs or tool compounds used to study biological processes. Here, we investigate the effect on the dynamics of the serine protease alpha-chymotrypsin when in complex with two different covalently bound inhibitors using elastic incoherent neutron scattering. The results show that the inhibited enzyme displays enhanced dynamics compared to the free form. The difference was prominent at higher temperatures (240-310 K) and the type of motions that differ include both small amplitude motions, such as hydrogen atom rotations around a methyl group, and large amplitude motions, such as amino acid side chain movements. The measurements were analyzed with multivariate methods in addition to the standard univariate methods, allowing for a more in-depth analysis of the types of motions that differ between the two forms. The binding strength of an inhibitor is linked to the changes in dynamics occurring during the inhibitor-enzyme binding event and thus these results may aid in the deconvolution of this fundamental event and in the design of new inhibitors.

Place, publisher, year, edition, pages
ROYAL SOC CHEMISTRY, 2017
National Category
Biochemistry and Molecular Biology Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-140878 (URN)10.1039/c7cp04041e (DOI)000412271600015 ()28894859 (PubMedID)2-s2.0-85030718584 (Scopus ID)
Available from: 2017-11-20 Created: 2017-11-20 Last updated: 2023-03-23Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-8198-1688

Search in DiVA

Show all publications