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dc.contributor.authorZephyr, Jacqueto
dc.contributor.authorDesaboini, Nageswara Rao
dc.contributor.authorVo, Sang V.
dc.contributor.authorHenes, Mina
dc.contributor.authorKosovrasti, Klajdi
dc.contributor.authorMatthew, Ashley N.
dc.contributor.authorHedger, Adam K.
dc.contributor.authorTimm, Jennifer
dc.contributor.authorChan, Elise T.
dc.contributor.authorAli, Akbar
dc.contributor.authorYilmaz, Nese Kurt
dc.contributor.authorSchiffer, Celia A.
dc.date2022-08-11T08:08:34.000
dc.date.accessioned2022-08-23T15:59:45Z
dc.date.available2022-08-23T15:59:45Z
dc.date.issued2021-11-30
dc.date.submitted2022-06-02
dc.identifier.citation<p>bioRxiv 2021.11.30.470632; doi: https://doi.org/10.1101/2021.11.30.470632. <a href="https://doi.org/10.1101/2021.11.30.470632" target="_blank" title="view preprint in bioRxiv">Link to preprint on bioRxiv.</a></p>
dc.identifier.doi10.1101/2021.11.30.470632
dc.identifier.urihttp://hdl.handle.net/20.500.14038/30740
dc.description<p>This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.</p>
dc.description.abstractThird generation Hepatitis C virus (HCV) NS3/4A protease inhibitors (PIs), glecaprevir and voxilaprevir, are highly effective across genotypes and against many resistant variants. Unlike earlier PIs, these compounds have fluorine substitutions on the P2-P4 macrocycle and P1 moieties. Fluorination has long been used in medicinal chemistry as a strategy to improve physicochemical properties and potency. However, the molecular basis by which fluorination improves potency and resistance profile of HCV NS3/4A PIs is not well understood. To systematically analyze the contribution of fluorine substitutions to inhibitor potency and resistance profile, we used a multi-disciplinary approach involving inhibitor design and synthesis, enzyme inhibition assays, co-crystallography, and structural analysis. A panel of inhibitors in matched pairs were designed with and without P4 cap fluorination, tested against WT protease and the D168A resistant variant, and a total of 22 high-resolution co-crystal structures were determined. While fluorination did not significantly improve potency against the WT protease, PIs with fluorinated P4 caps retained much better potency against the D168A protease variant. Detailed analysis of the co-crystal structures revealed that PIs with fluorinated P4 caps can sample alternate binding conformations that enable adapting to structural changes induced by the D168A substitution. Our results elucidate molecular mechanisms of fluorine-specific inhibitor interactions that can be leveraged in avoiding drug resistance.
dc.language.isoen_US
dc.relation<p>Now published in <em>Journal of Molecular Biology</em> doi: <a href="http://dx.doi.org/10.1016/j.jmb.2022.167503" target="_blank">10.1016/j.jmb.2022.167503</a></p>
dc.rightsThe copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectX-ray crystallography
dc.subjectProtease inhibitors
dc.subjectStructure-based drug design
dc.subjectStructural biology
dc.subjectMedicinal chemistry
dc.subjectBiochemistry
dc.subjectEnzymes and Coenzymes
dc.subjectMedicinal-Pharmaceutical Chemistry
dc.subjectMolecular Biology
dc.subjectStructural Biology
dc.titleDeciphering the Molecular Mechanism of HCV Protease Inhibitor Fluorination as a General Approach to Avoid Drug Resistance [preprint]
dc.typePreprint
dc.source.journaltitlebioRxiv
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=3245&amp;context=faculty_pubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/2211
dc.identifier.contextkey29506876
refterms.dateFOA2022-08-23T15:59:45Z
html.description.abstract<p>Third generation Hepatitis C virus (HCV) NS3/4A protease inhibitors (PIs), glecaprevir and voxilaprevir, are highly effective across genotypes and against many resistant variants. Unlike earlier PIs, these compounds have fluorine substitutions on the P2-P4 macrocycle and P1 moieties. Fluorination has long been used in medicinal chemistry as a strategy to improve physicochemical properties and potency. However, the molecular basis by which fluorination improves potency and resistance profile of HCV NS3/4A PIs is not well understood. To systematically analyze the contribution of fluorine substitutions to inhibitor potency and resistance profile, we used a multi-disciplinary approach involving inhibitor design and synthesis, enzyme inhibition assays, co-crystallography, and structural analysis. A panel of inhibitors in matched pairs were designed with and without P4 cap fluorination, tested against WT protease and the D168A resistant variant, and a total of 22 high-resolution co-crystal structures were determined. While fluorination did not significantly improve potency against the WT protease, PIs with fluorinated P4 caps retained much better potency against the D168A protease variant. Detailed analysis of the co-crystal structures revealed that PIs with fluorinated P4 caps can sample alternate binding conformations that enable adapting to structural changes induced by the D168A substitution. Our results elucidate molecular mechanisms of fluorine-specific inhibitor interactions that can be leveraged in avoiding drug resistance.</p>
dc.identifier.submissionpathfaculty_pubs/2211
dc.contributor.departmentGraduate School of Biomedical Sciences
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology


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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Except where otherwise noted, this item's license is described as The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.