Macrocyclic inhibitors of HCV NS3 protease.
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.
Venkatraman
Srikanth
S
MS 3545, K15, Schering Plough Research Institute, , Kenilworth NJ 07033, USA. Srikanth.Venkatraman@spcorp.com
Njoroge
F George
FG
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D015195:Drug Design; D016174:Hepacivirus / Q000201:enzymology; D006801:Humans; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D010330:Patents as Topic; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases