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 microM. Kinetic analysis reveals inhibition by warfarin occurs in a competitive manner, with Ki = 3.3 microM. 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.