COMPETITIVE-INHIBITION OF HIV-1 PROTEASE BY WARFARIN DERIVATIVES

The oral anticoagulant warfarin (4-hydroxy-3-(3-oxo-1-phenylbutyl)-benzopyran-2-one) is a structurally novel low micromolar competitive inhibitor of HIV-1 protease in vitro. It was recently reported that warfarin inhibits HIV-1 infection in U-1 monocytes and viral production in ACH-2 lymphocytes (Bourinbaiar, A. S. et al., (1993) AIDS 7, 129-130.). Our results demonstrate that warfarin and a series of structurally related analogs inhibit the viral protease, the most potent analog having an IC50 = 1.9 mu M. Kinetic analysis reveals inhibition by warfarin occurs in a competitive manner, with K-i = 3.3 mu M. While it is unclear whether the cellular inhibition previously reported is due to inhibition of HIV-1 protease, the warfarin analogs are a novel class of nonpeptide HIV-1 protease inhibitors. (C) 1994 Academic Press, Inc.