BIOMAT Database Logo BIOMAT Database Logo

Macrocyclic inhibitors of HCV NS3 protease. 2009

Srikanth Venkatraman, and F George Njoroge
MS 3545, K15, Schering Plough Research Institute, , Kenilworth NJ 07033, USA. Srikanth.Venkatraman@spcorp.com

BACKGROUND HCV NS3 is a serine protease that plays a pivotal role in catalyzing the cleavage of the single polyprotein encoded by HCV after infection of hepatocytes. Analysis of the X-ray crystal structure of the enzyme reveals a shallow catalytic site located on the surface of the protein, which has made development of inhibitors a formidable task. Attempts to discover leads by a traditional approach of screening of compound libraries have proved futile and, therefore, researchers have adopted a structure-based drug design. Analysis of the X-ray structure of NS3 protease reveals close proximity of S(1)-S(3) and S(2)-S(4) pockets. Various novel approaches have been used to design preorganized, depeptidized macrocyclic inhibitors linking the P(2)-P(4) groups and P(1)-P(3) residues. OBJECTIVE The article summarizes efforts by various groups to develop inhibitors that bind to the active site and inhibit viral replication. METHODS Review of recent patents and scientific literature. CONCLUSIONS Macrocyclization has proved to be an effective tool for depeptidization of peptidic inhibitors with improved binding and pharmacokinetic properties.

UI MeSH Term Description Entries
D010330 Patents as Topic Works about exclusive legal rights or privileges applied to inventions, plants, etc. Trademarks,Patents as Topics,Trademark
D011480 Protease Inhibitors Compounds which inhibit or antagonize biosynthesis or actions of proteases (ENDOPEPTIDASES). Antiprotease,Endopeptidase Inhibitor,Endopeptidase Inhibitors,Peptidase Inhibitor,Peptidase Inhibitors,Peptide Hydrolase Inhibitor,Peptide Hydrolase Inhibitors,Peptide Peptidohydrolase Inhibitor,Peptide Peptidohydrolase Inhibitors,Protease Antagonist,Protease Antagonists,Antiproteases,Protease Inhibitor,Antagonist, Protease,Antagonists, Protease,Hydrolase Inhibitor, Peptide,Hydrolase Inhibitors, Peptide,Inhibitor, Endopeptidase,Inhibitor, Peptidase,Inhibitor, Peptide Hydrolase,Inhibitor, Peptide Peptidohydrolase,Inhibitor, Protease,Inhibitors, Endopeptidase,Inhibitors, Peptidase,Inhibitors, Peptide Hydrolase,Inhibitors, Peptide Peptidohydrolase,Inhibitors, Protease,Peptidohydrolase Inhibitor, Peptide,Peptidohydrolase Inhibitors, Peptide
D011485 Protein Binding The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Plasma Protein Binding Capacity,Binding, Protein
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000998 Antiviral Agents Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly. Antiviral,Antiviral Agent,Antiviral Drug,Antivirals,Antiviral Drugs,Agent, Antiviral,Agents, Antiviral,Drug, Antiviral,Drugs, Antiviral
D001665 Binding Sites The parts of a macromolecule that directly participate in its specific combination with another molecule. Combining Site,Binding Site,Combining Sites,Site, Binding,Site, Combining,Sites, Binding,Sites, Combining
D014779 Virus Replication The process of intracellular viral multiplication, consisting of the synthesis of PROTEINS; NUCLEIC ACIDS; and sometimes LIPIDS, and their assembly into a new infectious particle. Viral Replication,Replication, Viral,Replication, Virus,Replications, Viral,Replications, Virus,Viral Replications,Virus Replications
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D016174 Hepacivirus A genus of FLAVIVIRIDAE causing parenterally-transmitted HEPATITIS C which is associated with transfusions and drug abuse. Hepatitis C virus is the type species. Hepatitis C virus,Hepatitis C-Like Viruses,Hepaciviruses,Hepatitis C Like Viruses,Hepatitis C viruses,Hepatitis C-Like Virus

Related Publications

Srikanth Venkatraman, and F George Njoroge
Development of potent macrocyclic inhibitors of genotype 3a HCV NS3/4A protease.
December 2012, Bioorganic & medicinal chemistry letters,
Srikanth Venkatraman, and F George Njoroge
Novel macrocyclic HCV NS3 protease inhibitors derived from α-amino cyclic boronates.
October 2010, Bioorganic & medicinal chemistry letters,
Srikanth Venkatraman, and F George Njoroge
Synthesis and biological activity of macrocyclic inhibitors of hepatitis C virus (HCV) NS3 protease.
October 2005, Bioorganic & medicinal chemistry letters,
Srikanth Venkatraman, and F George Njoroge
Synthesis and biological evaluations of P4-benzoxaborole-substituted macrocyclic inhibitors of HCV NS3 protease.
December 2010, Bioorganic & medicinal chemistry letters,
Srikanth Venkatraman, and F George Njoroge
Biochemical evaluation of HCV NS3 protease inhibitors.
September 2011, Current protocols in pharmacology,
Srikanth Venkatraman, and F George Njoroge
Development of macrocyclic inhibitors of HCV NS3/4A protease with cyclic constrained P2-P4 linkers.
December 2012, Bioorganic & medicinal chemistry letters,
Srikanth Venkatraman, and F George Njoroge
Discovery of novel, potent and bioavailable proline-urea based macrocyclic HCV NS3/4A protease inhibitors.
December 2008, Bioorganic & medicinal chemistry letters,
Srikanth Venkatraman, and F George Njoroge
Novel Quinoline-Based P2-P4 Macrocyclic Derivatives As Pan-Genotypic HCV NS3/4a Protease Inhibitors.
March 2014, ACS medicinal chemistry letters,
Srikanth Venkatraman, and F George Njoroge
Novel P2-P4 macrocyclic inhibitors of HCV NS3/4A protease by P3 succinamide fragment depeptidization strategy.
January 2010, Bioorganic & medicinal chemistry letters,
Srikanth Venkatraman, and F George Njoroge
Glycine alpha-ketoamides as HCV NS3 protease inhibitors.
March 2003, Bioorganic & medicinal chemistry letters,
Copied contents to your clipboard!