Model peptides to study the effects of P2 and P3 substitutions in statine-containing HIV proteinase inhibitors.

Abstract Through a series of synthetic model peptides, we have examined the structural requirements of the P 2 and P 3 residues in statine-based HIV protease (PR) inhibitors. Results agree with the general observations that, the more bulky the P 3 aromatic hydrophobic side chain, the more potent is the inhibitor. At P 2 , an isopropyl side chain is critical in maintaining potency. Three-dimensional modeling demonstrates that the steric bulk of a leucyl residue or the unfavorable energy transfer, from water to enzyme, for a basic amino acid residue at P 2 markedly compromises activity. A naphthylalaninyl-valyl P 3 -P 2 substituted analogue inhibits PR with an IC 50 value of 6 nM, and was also effective as an antiviral agent.