University of Massachusetts Medical School Faculty Publications
UMMS Affiliation
Department of Biochemistry and Molecular Pharmacology; Schiffer Lab; Graduate School of Biomedical Sciences
Publication Date
2019-07-03
Document Type
Article Preprint
Disciplines
Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Molecular Biology | Structural Biology | Viruses
Abstract
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.
Keywords
biochemistry, Hepatitis C virus, NS3/4A, grazoprevir, glecaprevir, NS3/4A protease inhibition
Rights and Permissions
The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.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.
DOI of Published Version
10.1101/692392
Source
bioRxiv 692392; doi: https://doi.org/10.1101/692392. Link to preprint on bioRxiv service.
Journal/Book/Conference Title
bioRxiv
Repository Citation
Timm J, Kosovrasti K, Henes M, Leidner F, Hou S, Ali A, Yilmaz NK, Schiffer CA. (2019). Molecular and structural mechanism of pan-genotypic HCV NS3/4A protease inhibition by glecaprevir [preprint]. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1101/692392. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1621
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Included in
Biochemistry Commons, Enzymes and Coenzymes Commons, Medicinal-Pharmaceutical Chemistry Commons, Molecular Biology Commons, Structural Biology Commons, Viruses Commons