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Peptide-based Inhibitors Of The Hepatitis C Virus NS3 Protease: Structure-activity Relationship At The C-terminal Position.

J. Rancourt, D. Cameron, V. Gorys, D. Lamarre, M. Poirier, D. Thibeault, M. Llinàs-Brunet
Published 2004 · Chemistry, Medicine

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The structure-activity relationship at the C-terminal position of peptide-based inhibitors of the hepatitis C virus NS3 protease is presented. The observation that the N-terminal cleavage product (DDIVPC-OH) of a substrate derived from the NS5A/5B cleavage site was a competitive inhibitor of the NS3 protease was previously described. The chemically unstable cysteine residue found at the P1 position of these peptide-based inhibitors could be replaced with a norvaline residue, at the expense of a substantial drop in the enzymatic activity. The fact that an aminocyclopropane carboxylic acid (ACCA) residue at the P1 position of a tetrapeptide such as 1 led to a significant gain in the inhibitory enzymatic activity, as compared to the corresponding norvaline derivative 2, prompted a systematic study of substituent effects on the three-membered ring. We report herein that the incorporation of a vinyl group with the proper configuration onto this small cycle produced inhibitors of the protease with much improved in vitro potency. The vinyl-ACCA is the first reported carboxylic acid containing a P1 residue that produced NS3 protease inhibitors that are significantly more active than inhibitors containing a cysteine at the same position.

This paper is referenced by
Blunting the Swiss army knife of hepatitis C virus: inhibitors of NS3/4A protease.
P. W. White (2006)
Peptide drug discovery and development : translational research in academia and industry
M. Castanho (2011)
Evolution of HCV NS3/4a Protease Inhibitors
Nigel J. Liverton (2019)
The effect of the P1 side chain on the binding of optimized carboxylate and activated carbonyl inhibitors of the hepatitis C virus NS3 protease.
S. H. Kawai (2010)
HCV NS3/4A Protease Inhibitors and the Road to Effective Direct-Acting Antiviral Therapies
Nicolas Tremblay (2016)
Ligand bioactive conformation plays a critical role in the design of drugs that target the hepatitis C virus NS3 protease.
S. LaPlante (2014)
A Practical Asymmetric Synthesis of Isopropyl (1R,2S)-Dehydrocoronamate
Wenjun Tang (2011)
The Growing Impact of Catalysis in the Pharmaceutical Industry
C. Busacca (2011)
Ribonucleic Acid Viruses: Antivirals for Influenza A and B, Hepatitis C Virus, and Respiratory Syncytial Virus
Uli Schmitz (2007)
Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery.
É. Marsault (2011)
Discovery and Development of BILN 2061 and Follow‐Up BI 201335
Montse Llinàs-Brunet (2011)
Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors : Targeting Different Genotypes and Drug-Resistant Variants
A. Belfrage (2015)
Synthesis of BILN 2061, an HCV NS3 protease inhibitor with proven antiviral effect in humans.
A. Faucher (2004)
HCV NS3-4A Serine Protease
C. Lin (2006)
Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease: use of cyclopentane and cyclopentene P2-motifs.
Marcus Bäck (2007)
Peptidomimetic therapeutic agents targeting the protease enzyme of the human immunodeficiency virus and hepatitis C virus.
Y. Tsantrizos (2008)
Structure-based design of a novel series of azetidine inhibitors of the hepatitis C virus NS3/4A serine protease.
Christophe Claude Parsy (2014)
High-Throughput Screening of Low Molecular Weight NS3-NS4A Protease Inhibitors Using a Fluorescence Resonance Energy Transfer Substrate
K. Sudo (2005)
Catalytic asymmetric synthesis of ethyl (1R,2S)-dehydrocoronamate
M. E. Fox (2007)
Toward the Synthesis of Fluorinated Analogues of HCV NS3/4A Serine Protease Inhibitors Using Methyl α-Amino-β-fluoro-β-vinylcyclopropanecarboxylate as Key Intermediate.
Gaëlle Milanole (2015)
Characterization of a novel class of anti-HCV agents targeting protein-protein interactions
Alex Park (2017)
Potent inhibitors of the hepatitis C virus NS3 protease: use of a novel P2 cyclopentane-derived template.
P. Johansson (2006)
Structure-Based Design and Synthesis of Protease Inhibitors Using Cycloalkenes as Proline Bioisosteres and Combinatorial Syntheses of a Targeted Library
F. Thorstensson (2005)
Chapter 18 Recent Progress on Novel HCV Inhibitors
C. W. Zapf (2007)
Synthesis and resolution of diethyl (1S,2S)-1-amino-2-vinylcyclopropane-1-phosphonate for HCV NS3 protease inhibitors
Hyung-Jung Pyun (2009)
Synthetic Challenges in the Assembly of Macrocyclic HCV NS3/NS4A Protease Inhibitors: The Case of BILN 2061 and Its Analogs
Youla S Tsantrizos (2015)
J. Reddy (2007)
1-Aminoxymethylcyclopropanecarboxylic acid as building block of β N–O turn and helix: synthesis and conformational analysis in solution and in the solid state
Xiao-wei Chang (2010)
Enhanced taxonomy annotation of antiviral activity data from ChEMBL
A. Nikitina (2019)
Phenylglycine as a novel P2 scaffold in hepatitis C virus NS3 protease inhibitors.
Pernilla Ortqvist (2007)
Chapter 13 – Substituent Groups
Patrick Bazzini (2008)
1 Peptides as Leads for Drug Discovery
P. J. Edwards (2011)
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