Highly potent and selective peptide-based inhibitors of the hepatitis C virus serine protease: Towards smaller inhibitors

Structure-activity studies on a hexapeptide N-terminal cleavage product of a dodecamer substrate led to the identification of very potent and highly s pecific inhibitors of the HCV NS3 protease/NS4A cofactor peptide complex. T he largest increase in potency was accomplished by the introduction of a (4 R)-naphthalen-1-yl-4-methoxy substituent to the P2 proline. N-Terminal trun cation resulted in tetrapeptides containing a C-terminal carboxylic acid, w hich exhibited low micromolar activity against the HCV serine protease. (C) 2000 Elsevier Science Ltd. All rights reserved.