G. Abbenante et al., REGIOSELECTIVE STRUCTURAL AND FUNCTIONAL MIMICRY OF PEPTIDES - DESIGNOF HYDROLYTICALLY-STABLE CYCLIC PEPTIDOMIMETIC INHIBITORS OF HIV-1 PROTEASE, Journal of the American Chemical Society, 117(41), 1995, pp. 10220-10226
Hydrolytically-stable cyclic mimetics of the tripeptides Leu-Asn-Phe a
nd Phe-Ile-Val were designed and incorporated into peptidic inhibitors
, Ac-{Leu-Asn-Phe}-CHOHCH2-Pro-Ile-Val-NH2 and Ac-Leu-Val-Phe-CHOHCH2-
{Phe-Ile-Val}-NH2, of HIV-1 protease. Structural mimicry has been esta
blished through molecular modeling and X-ray crystallographic studies
of inhibitors bound to HIV-1 protease. Cyclic and acyclic inhibitors h
ad similar conformations that were superimposable and formed similar i
nteractions with the enzyme. Functional mimicry was demonstrated by co
mparable inhibition of the protease by acyclic and cyclic molecules. F
urther substitution of the residual acyclic Pro-Ile-Val or Leu-Val-Phe
inhibitor components, with Pip-NHtBu or Boc-Phe, respectively, gave h
ydrolytically stable, water-soluble, lipophilic inhibitors of similar
potency. The use of cycles to fix the conformations of amino acid sequ
ences in peptides allows regioselective structural mimicry leading to
functional mimicry and also permits localized structure-activity optim
ization in inhibitors of HIV-1 protease. This approach might be useful
ly applied to inhibitors of other proteins.