MODEL PEPTIDES TO STUDY THE EFFECTS OF P-2 AND P-3 SUBSTITUTIONS IN STATINE-CONTAINING HIV PROTEINASE-INHIBITORS

Through a series of synthetic model peptides, we have examined the str uctural requirements of the P2 and P3 residues in statine-based HIV pr otease (PR) inhibitors. Results agree with the general observations th at, the more bulky the P3 aromatic hydrophobic side chain, the more po tent is the inhibitor. At P2, an isopropyl side chain is critical in m aintaining potency. Three-dimensional modeling demonstrates that the s teric bulk of a leucyl residue or the unfavorable energy transfer, fro m water to enzyme, for a basic amino acid residue at P2 markedly compr omises activity. A naphthylalaninyl-valyl P3-P2 substituted analogue i nhibits PR with an IC50 value of 6 nM, and was also effective as an an tiviral agent.