Phenylglycine as a novel P2 scaffold in hepatitis C virus NS3 protease inhibitors.
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 ( approximately 75nM).
Ortqvist
Pernilla
P
Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden.
Peterson
Shane D
SD
Kerblom
Eva
E
Gossas
Thomas
T
Sabnis
Yogesh A
YA
Fransson
Rebecca
R
Lindeberg
Gunnar
G
Helena Danielson
U
U
Karlén
Anders
A
Sandström
Anja
A
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding; D013329:Structure-Activity Relationship; 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; D005998:Glycine; 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; C027797:phenylglycine chloride; C008852:2-phenylglycine