The Design and Synthesis of Potent Inhibitors of Hepatitis C Virus NS3–4A Proteinase

Hepatitis C virus (HCV) is the cause of the majority of transfusion-associated hepatitis and a significant proportion of community-acquired hepatitis worldwide. Infection by HCV frequently leads to persistent infections that result in a range of clinical conditions including an asymptomatic carrier...

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Bibliographic Details
Published in:	Antiviral chemistry & chemotherapy Vol. 10; no. 5; pp. 259 - 273
Main Authors:	Attwood, MR, Bennett, JM, Campbell, AD, Canning, GGM, Carr, MG, Conway, E, Dunsdon, RM, Greening, JR, Jones, PS, Kay, PB, Handa, BK, Hurst, DN, Jennings, NS, Jordan, S, Keech, E, O'Brien, MA, Overton, HA, King-Underwood, J, Raynham, TM, Stenson, KP, Wilkinson, CS, Wilkinson, TCI, Wilson, FX
Format:	Journal Article
Language:	English
Published:	London, England SAGE Publications 01-09-1999 International Medical Press Sage Publications Ltd
Subjects:	Amino Acid Sequence Amino acids Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Antiviral Agents - chemical synthesis Antiviral Agents - chemistry Antiviral Agents - pharmacology Binding Sites Biological and medical sciences Chronic active hepatitis Cirrhosis Drug Design Endopeptidases - chemistry Endopeptidases - genetics Endopeptidases - metabolism Enzymatic activity Enzymes Escherichia coli - enzymology Escherichia coli - genetics Fusion protein Genomes Hepacivirus - enzymology Hepacivirus - genetics Hepatitis Hepatitis C Hepatitis C virus Liver cirrhosis Medical sciences Molecular Sequence Data NS3 protein NS4A protein Nucleotides Peptides - chemical synthesis Peptides - metabolism Pharmacology. Drug treatments Proteinase Proteins Proteolysis Recombinant Fusion Proteins - biosynthesis Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - metabolism Ribonucleic acid RNA RNA Helicases Serine Serine Endopeptidases Serine proteinase Serine Proteinase Inhibitors - chemical synthesis Serine Proteinase Inhibitors - chemistry Serine Proteinase Inhibitors - pharmacology Substrate Specificity Viral Nonstructural Proteins - antagonists & inhibitors Viral Nonstructural Proteins - chemistry Viral Nonstructural Proteins - genetics inhibitors aldehydes NS4A synthetic substrates Hepatitis C virus NS3 boronic acids Enzyme Escherichia coli Enzyme inhibitor In vitro Research and development Virus Peptidases Structure activity relation Bacteria Hydrolases Antiviral Flaviviridae Fusion protein Hepacivirus Enterobacteriaceae
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Summary:	Hepatitis C virus (HCV) is the cause of the majority of transfusion-associated hepatitis and a significant proportion of community-acquired hepatitis worldwide. Infection by HCV frequently leads to persistent infections that result in a range of clinical conditions including an asymptomatic carrier state, severe chronic active hepatitis, cirrhosis and, in some cases, hepatocel-lular carcinoma. The HCV genome consists of a single-stranded, positive sense RNA containing an open reading frame of approximately 9060 nucleotides. This is translated into a single polyprotein of approximately 3020 amino acids (C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B), which in turn is processed by a series of host and viral proteinases into at least 10 cleavage products. The N-terminal portion of the NS3 protein encodes a serine proteinase that is responsible for the cleavage at the NS3–4A, NS4A-4B, NS4B-5A and NS5A-5B junctions. The 54 amino acid NS4A protein is a cofactor that binds to the NS3 protein and enhances its proteolytic activity. This report describes the expression of a recombinant NS3–4A proteinase fusion protein in Escherichia coli and the in vitro characterization of the enzyme activity using synthetic peptide substrates. It then demonstrates how these results were employed to guide the design of potent inhibitors of this enzyme.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	2040-2066 0956-3202 2040-2066
DOI:	10.1177/095632029901000505