The active human immunodeficiency virus type 1 (HIV-1) protease has a homodimeric structure, the subunits are connected by an 'interface' beta-sheet formed by the NH2- and COOH-terminal amino acid segments. Short peptides derived from these segments are able to inhibit the protease activity in the range of micromolar IC50 values. We have further improved the inhibitory power of such peptides by computer modelling. The best inhibitor, the palmitoyl-blocked peptide Pam-Thr-Val-Ser-Tyr-Glu-Leu, has an IC50 value of less than 1 microM. Some of the peptides also showed very good inhibition of the HIV-2 protease. The C-terminal segment 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 structure and ionic strength, both dimerization inhibition and competitive inhibition were observed, as well as synergistic effects between competitive inhibitors and interface peptides.