Towards understanding ligand specificity of retroviral proteases. Implications for the design of human immunodeficiency virus type 1 and 2 protease inhibitors

Abstract

Despite sharing roughly 50% sequence identity to HIV-1 protease, the HIV-2 and SIV proteases can display differences in ligand specificity. The tripeptide analog inhibitor SB203386, containing a C-terminal imidazole substituent as an amide bond isostere, shows potent inhibition of HIV-1 protease ( Ki=18 nM) but shows decreased inhibition of an HIV-1 protease (Val32Ile, Ile47Val, Val82Ile) triple mutant ( Ki=112 nM) and SIV protease ( Ki=960 nM). Comparison of the x-ray structures of these three complexes shows that ligand specificity for this inhibitor is imparted by residues outside of the catalytic pocket. Inhibitor structure may also cause disparity in inhibition constants between the HIV-1, HIV-2 and SIV proteases. In designing inhibitors that are equally effective against the HIV-1 and HIV-2 proteases, it is important to balance the size of the side chains at P2, P1, P1′, and P2′ subsites.