A novel bicyclic enzyme inhibitor as a consensus peptidomimetic for the receptor-bound conformations of 12 peptidic inhibitors of HIV-1 protease

Reid, Robert C., March, Darren R., Dooley, Michael J., Bergman, Doug A., Abbenante, Giovanni and Fairlie, David P. (1996) A novel bicyclic enzyme inhibitor as a consensus peptidomimetic for the receptor-bound conformations of 12 peptidic inhibitors of HIV-1 protease. Journal of The American Chemical Society, 118 36: 8511-8517. doi:10.1021/ja960433v


Author Reid, Robert C.
March, Darren R.
Dooley, Michael J.
Bergman, Doug A.
Abbenante, Giovanni
Fairlie, David P.
Title A novel bicyclic enzyme inhibitor as a consensus peptidomimetic for the receptor-bound conformations of 12 peptidic inhibitors of HIV-1 protease
Journal name Journal of The American Chemical Society   Check publisher's open access policy
ISSN 0002-7863
Publication date 1996-09-11
Sub-type Article (original research)
DOI 10.1021/ja960433v
Volume 118
Issue 36
Start page 8511
End page 8517
Total pages 7
Place of publication Washington, D.C. U.S.A.
Publisher American Chemical Society
Language eng
Abstract The X-ray crystal structures of 12 substrate-based peptidic inhibitors bound in the active site of the aspartyl protease, HIV-1 protease, have been compared. The inhibitor-binding modes of these inhibitors are remarkably similar despite their structural diversity and conformational flexibility. This prompted the design of a bicyclic peptidomimetic inhibitor 13 with macrocyclic components in constrained conformations that are preorganized for receptor-binding. This inhibitor is a consensus conformational mimic of the protease-bound inhibitor structures with superior properties to peptides, including stability to acid and peptidases as well as antiviral activity. Each of its 15- and 16-membered rings, formed through side-chain to backbone condensation, contains two proteolytically resistant amide bonds and either isoleucine or valine linked via a short aliphatic spacer to tyrosine. The two cycles are connected by a hydroxyethylamine transition state isostere. Molecular modeling and NMR studies indicate that each macrocycle is a highly constrained structural mimic of tripeptide components of linear peptide substrates/inhibitors of HIV-1 protease. Thus the bicyclic peptidomimetic superimposes upon and structurally mimics acyclic hexapeptide inhibitors and their analogues. This results in functional mimicry, as demonstrated by comparable inhibition of HIV-1 protease by acyclic and cyclic molecules at nanomolar concentrations. The rational design of cycles which fix receptor-bound conformations of these bioactive peptides has potential applications for the structural mimicry of other bioactive peptides and may facilitate rational drug design.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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Created: Mon, 22 Nov 2010, 20:24:15 EST by Dr Robert Reid on behalf of Institute for Molecular Bioscience