The p2gag peptide, AEAMSQVTNTATIM, processed from HIV-1 Pr55gag was found to be a suicide inhibitor of HIV-1 protease

The p2(gag) peptide (AEAMSQVTNTATIM) processed from HIV-1 Pr55(gag) by HIV-1 protease was identified as a suicide inhibitor of the enzyme (Ki = 30 mu M and IC50 = 10 mu M for the synthetic peptide substrate, succinyl-SQNYPIVQ), and potently inhibited the proteolytic cleavage of the viral precursor protein (Pr55(gag)) into functional structural units (p17(gag) and p24(gag)) in vitro. The nonapeptide (AEAMSQVTN) derived from N-terminus of the p2(gag) peptide exhibits a potent inhibitory action on HIV-1 protease, but the other peptides (AEAMSQ, AEAMSQV, AEAMSQVT, VTN and VTNTATIM) do not. It was determined by exclusion gel chromatography that HIV-1 protease after treatment of the synthetic p2(gag) peptide dissociated from the active dimeric form to an inactive monomeric form. The p2(gag) peptide and HIV-1 protease were also detected in HIV-1 viral particles using both matrix-assisted laser desorption/ionization time-of-flight mass spectrometric (MALDI TOF MS) and western immunoblot analyses. Taken together, these results suggest that the p2(gag) peptide is the inhibitor of preventing dimerization of HIV-1 protease and that the enzyme activity is completely suicide inhibited with the accumulated p2(gag) peptide producing by the processing of Pr55(gag) during viral maturation. (C) 1997 Academic Press.