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dc.contributor.authorTimm, Jennifer
dc.contributor.authorKosovrasti, Klajdi
dc.contributor.authorHenes, Mina
dc.contributor.authorLeidner, Florian
dc.contributor.authorHou, Shurong
dc.contributor.authorAli, Akbar
dc.contributor.authorYilmaz, Nese Kurt
dc.contributor.authorSchiffer, Celia A.
dc.date2022-08-11T08:08:24.000
dc.date.accessioned2022-08-23T15:53:37Z
dc.date.available2022-08-23T15:53:37Z
dc.date.issued2019-07-03
dc.date.submitted2019-07-18
dc.identifier.citation<p>bioRxiv 692392; doi: https://doi.org/10.1101/692392. <a href="https://doi.org/10.1101/692392" target="_blank" title="Link to preprint on bioRxiv">Link to preprint on bioRxiv service.</a></p>
dc.identifier.doi10.1101/692392
dc.identifier.urihttp://hdl.handle.net/20.500.14038/29391
dc.description.abstractHepatitis C virus (HCV), causative agent of chronic viral hepatitis, infects 71 million people worldwide and is divided into seven genotypes and multiple subtypes with sequence identities between 68 to 82%. While older generation direct-acting antivirals (DAAs) had varying effectiveness against different genotypes, the newest NS3/4A protease inhibitors including glecaprevir (GLE) have pan-genotypic activity. The structural basis for pan-genotypic inhibition and effects of polymorphisms on inhibitor potency were not well known due to lack of crystal structures of GLE-bound NS3/4A or genotypes other than 1. In this study, we determined the crystal structures of NS3/4A from genotypes 1a, 3a, 4a and 5a in complex with GLE. Comparison with the highly similar grazoprevir (GZR) indicated the mechanism of GLE’s drastic improvement in potency. We found that while GLE is highly potent against wild type NS3/4A of all genotypes, specific resistance-associated substitutions (RASs) confer orders of magnitude loss in inhibition. Our crystal structures reveal molecular mechanisms behind pan-genotypic activity of GLE, including potency loss due to RASs at D168. Our structures permit for the first time analysis of changes due to polymorphisms among genotypes, providing insights into design principles that can aid future drug development and potentially can be extended to other proteins.
dc.language.isoen_US
dc.relationNow published in ACS Chemical Biology doi: 10.1021/acschembio.9b00675
dc.rightsThe copyright holder for this preprint (which was not peer-reviewed) is the author/funder. 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.subjectbiochemistry
dc.subjectHepatitis C virus
dc.subjectNS3/4A
dc.subjectgrazoprevir
dc.subjectglecaprevir
dc.subjectNS3/4A protease inhibition
dc.subjectBiochemistry
dc.subjectEnzymes and Coenzymes
dc.subjectMedicinal-Pharmaceutical Chemistry
dc.subjectMolecular Biology
dc.subjectStructural Biology
dc.subjectViruses
dc.titleMolecular and structural mechanism of pan-genotypic HCV NS3/4A protease inhibition by glecaprevir [preprint]
dc.typePreprint
dc.source.journaltitlebioRxiv
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2631&amp;context=faculty_pubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/1621
dc.identifier.contextkey14951468
refterms.dateFOA2022-08-23T15:53:38Z
html.description.abstract<p>Hepatitis C virus (HCV), causative agent of chronic viral hepatitis, infects 71 million people worldwide and is divided into seven genotypes and multiple subtypes with sequence identities between 68 to 82%. While older generation direct-acting antivirals (DAAs) had varying effectiveness against different genotypes, the newest NS3/4A protease inhibitors including glecaprevir (GLE) have pan-genotypic activity. The structural basis for pan-genotypic inhibition and effects of polymorphisms on inhibitor potency were not well known due to lack of crystal structures of GLE-bound NS3/4A or genotypes other than 1. In this study, we determined the crystal structures of NS3/4A from genotypes 1a, 3a, 4a and 5a in complex with GLE. Comparison with the highly similar grazoprevir (GZR) indicated the mechanism of GLE’s drastic improvement in potency. We found that while GLE is highly potent against wild type NS3/4A of all genotypes, specific resistance-associated substitutions (RASs) confer orders of magnitude loss in inhibition. Our crystal structures reveal molecular mechanisms behind pan-genotypic activity of GLE, including potency loss due to RASs at D168. Our structures permit for the first time analysis of changes due to polymorphisms among genotypes, providing insights into design principles that can aid future drug development and potentially can be extended to other proteins.</p>
dc.identifier.submissionpathfaculty_pubs/1621
dc.contributor.departmentGraduate School of Biomedical Sciences
dc.contributor.departmentSchiffer Lab
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology


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The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. 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 (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.