University of Massachusetts Medical School Faculty Publications

Title

Molecular and Structural Mechanism of Pan-Genotypic HCV NS3/4A Protease Inhibition by Glecaprevir

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Graduate School of Biomedical Sciences; Schiffer Lab

Publication Date

2020-02-21

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Molecular Biology | Structural Biology | Virus Diseases | Viruses

Abstract

Hepatitis C virus, 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 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 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

Peptides and proteins, Monomers, Crystal structure, Chemical structure, Inhibitors

DOI of Published Version

10.1021/acschembio.9b00675

Source

Timm J, Kosovrasti K, Henes M, Leidner F, Hou S, Ali A, Kurt Yilmaz N, Schiffer CA. Molecular and Structural Mechanism of Pan-Genotypic HCV NS3/4A Protease Inhibition by Glecaprevir. ACS Chem Biol. 2020 Feb 21;15(2):342-352. doi: 10.1021/acschembio.9b00675. Epub 2020 Jan 8. PMID: 31868341. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

ACS chemical biology

PubMed ID

31868341

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