Structure-activity studies of FIV and HIV protease inhibitors containing allophenylnorstatine

The interaction of P1 and P3 side chains with the combining S1 and S3 hydro phobic subsites of HIV and FIV proteases has been explored using asymmetric competitive inhibitors. The inhibitors evaluated contained (2S,3S)-3-amino -2-hydroxy-4-phenylbutyric acid (allophenylnorstatine) as the hydroxymethyl carbonyl isostere, (R)-5,5-dimethyl-1, 3-thiazolidine-4-carbonyl as P1 ', V al as P2 and P2 ' residues, and a variety of amino acids at the P3 and P3 ' positions. All inhibitors showed competitive inhibition of both enzymes wi th higher potency against the HIV protease in vitro. Within this series, 31 (VLE776) is the most effective inhibitor against FIV protease, and it cont ains Phe at P3, but no P3 ' residue. VLE776 also exhibited potent antiviral activities against the drug-resistant HIV mutants (G48V and V82F) and the TL3-resistant HIV mutants. Explanation of the inhibition activities was des cribed. In addition, a new strategy was described for development of bifunc tional inhibitors, which combine the protease inhibitor and another enzyme inhibitor in one molecule. (C) 2001 Elsevier Science Ltd. All rights reserv ed.