Molecular and structural mechanism of pan-genotypic HCV NS3/4A protease inhibition by glecaprevir [preprint]
Authors
Timm, JenniferKosovrasti, Klajdi
Henes, Mina
Leidner, Florian
Hou, Shurong
Ali, Akbar
Yilmaz, Nese Kurt
Schiffer, Celia A.
UMass Chan Affiliations
Graduate School of Biomedical SciencesSchiffer Lab
Department of Biochemistry and Molecular Pharmacology
Document Type
PreprintPublication Date
2019-07-03Keywords
biochemistryHepatitis C virus
NS3/4A
grazoprevir
glecaprevir
NS3/4A protease inhibition
Biochemistry
Enzymes and Coenzymes
Medicinal-Pharmaceutical Chemistry
Molecular Biology
Structural Biology
Viruses
Metadata
Show full item recordAbstract
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.Source
bioRxiv 692392; doi: https://doi.org/10.1101/692392. Link to preprint on bioRxiv service.
DOI
10.1101/692392Permanent Link to this Item
http://hdl.handle.net/20.500.14038/29391Rights
The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.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.Distribution License
http://creativecommons.org/licenses/by-nc-nd/4.0/ae974a485f413a2113503eed53cd6c53
10.1101/692392
Scopus Count
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.