Hepatitis C virus NS3/4a protease inhibitors

McCauley, John A; Rudd, Michael T

doi:10.1016/j.coph.2016.07.015

Cited by 120Hepatitis C virus researchComputational Drug Discovery MethodsProtease and Inhibitor Mechanisms

Hepatitis C virus NS3/4a protease inhibitors

McCauley, John A, Rudd, Michael T·2016·Current Opinion in Pharmacology

DOI 10.1016/j.coph.2016.07.015

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Abstract

Hepatitis C virus (HCV) infection is a major health issue around the world and HCV NS3/4a protease inhibitors have been the focus of intensive research for the past 20 years. From the first identification of substrate-derived peptide inhibitors to the complex, macrocyclic compounds, including paritaprevir and grazoprevir, that are currently available, the field has used structure-based design to confront the issues of potency, resistance and pharmacokinetics. Numerous breakthrough structures from a multitude of companies have led to compounds that are now key components of combination therapies with cure rates of >90%. Herein, we detail the compounds that have advanced to clinical trials including their design and their impact on the NS3/4a protease field.

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The covalent interaction between ketoamide inhibitors and NS3/4a is relatively reversible because the serine alcohol group is eliminated from the protein-inhibitor adduct.
“This covalent interaction is relatively reversible owing to elimination of the serine alcohol group from the protein–inhibitor adduct114.”
From Advances in covalent drug discovery (2022) · cites this paper as [114]

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Authors: McCauley, J. A., & Rudd, M. T.
Affiliations: Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Corresponding author: McCauley, John A
ORCID: McCauley, John A
Rudd, Michael T
Venue: Current Opinion in Pharmacology
Publisher: Elsevier BV
Published: 2016-10
Volume: 30
Pages: 84-92
ISSN: 1471-4892 (ISSN-L)
DOI: 10.1016/j.coph.2016.07.015
OpenAlex: W2976752549
Cited by: 120
References: 52
Citations by year: 2026: 7 · 2025: 11 · 2024: 13 · 2023: 10 · 2022: 9 · 2021: 14 · 2020: 21 · 2019: 10 · 2018: 15 · 2017: 8 · 2016: 1 · 2015: 1
FWCI: 1.41
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Current Opinion in Pharmacology (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Hepatology › Hepatitis C virus research
Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Keywords: hepatitis C virus, NS3/4A protease, protease inhibitors, structure-based drug design, paritaprevir, grazoprevir, macrocycles, antiviral resistance, pharmacokinetics, combination antiviral therapy, clinical trial candidates
MeSH terms: Viral Proteases, Animals, Antiviral Agents, Hepatitis C, Humans, Protease Inhibitors, Serine Endopeptidases, Structure-Activity Relationship, Drug Design, Hepacivirus, Viral Nonstructural Proteins, Nucleoside-Triphosphatase, DEAD-box RNA Helicases

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Hepatitis C virus NS3/4a protease inhibitors

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