THE INHIBITION OF HUMAN-IMMUNODEFICIENCY-VIRUS PROTEASES BY INTERFACEPEPTIDES

The active human immuondeficiency virus type 1 (HIV-1) protease has a homodimeric structure, the subunits are connected by an 'interface' be ta-sheet formed by the NH2- and COOH-terminal amino acid segments. Sho rt peptides derived from these segments are able to inhibit the protea se activity in the range of micromolar IC50 values. We have further im proved the inhibitory power of such peptides by computer modelling. Th e best inhibitor, the palmitoyl-blocked peptide Pam-Thr-Val-Ser-Tyr-Gl u-Leu, has an IC50 value of less than 1 mu M Some of the peptides also showed very good inhibition of the HIV-2 protease. The C-terminal seg ment of the HIV-1 matrix protein, Acetyl-Gln-Val-Ser-Gln-Asn-Tyr, also inhibits HIV-1 protease. Kinetic studies confirmed the 'dissociative' mechanism of inhibition by the peptides. Depending on the peptide str ucture and ionic strength, both dimerization inhibition and competitiv e inhibition were observed, as well as synergistic effects between com petitive inhibitors and interface peptides.