Phenylglycine as a Novel P2 Scaffold in Hepatitis C Virus NS3 Protease Inhibitors
2007 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 15, no 3, 1448-1474 p.Article in journal (Refereed) Published
Molecular modeling and inhibitory potencies of tetrapeptide protease inhibitors of HCV NS3 proposed phenylglycine as a new promising P2 residue. The results suggest that phenylglycine might be capable of interacting with the NS3 (protease-helicase/NTPase) in ways not possible for the common P2 proline-based inhibitors. Thus, a series of tripeptides, both linear and macrocyclic, based on p-hydroxy-phenylglycine in the P2 position were prepared and their inhibitory effect determined. When the p-hydroxy group was replaced by methoxy, isoquinolin-, or quinolinyloxy functions, inhibitors with improved potencies were obtained. The P2 phenylglycine-based inhibitors were further optimized by C-terminal extension to acyl sulfonamides and by P1–P3 cyclization, which gave products with inhibition constants in the nanomolar range (75 nM).
Place, publisher, year, edition, pages
2007. Vol. 15, no 3, 1448-1474 p.
HCV, Phenylglycine, Protease inhibitor, Acyl sulfonamide
IdentifiersURN: urn:nbn:se:uu:diva-24860DOI: 10.1016/j.bmc.2006.11.003ISI: 000243959100025PubMedID: 17113777OAI: oai:DiVA.org:uu-24860DiVA: diva2:52634