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Model peptides to study the effects of P 2 and P 3 substitutions in statine‐containing HIV proteinase inhibitors
Author(s) -
Hui Kwan Y.,
Hermann Robert B.,
Manetta Joseph V.,
Gygi Theresa,
Angleton Eddie L.
Publication year - 1993
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/0014-5793(93)81020-z
Subject(s) - steric effects , chemistry , side chain , residue (chemistry) , stereochemistry , hiv 1 protease , potency , protease , enzyme inhibitor , enzyme , amino acid , ic50 , isopropyl , amino acid residue , biochemistry , in vitro , peptide sequence , organic chemistry , gene , polymer
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.