Substrate-based cyclic peptidomimetics of Phe-Ile-Val that inhibit HIV-1 protease using a novel enzyme-binding mode

March, D. R., Abbenante, G., Bergman, D. A., Brinkworth, R. I., Wickramasinghe, W., Begun, J., Martin, J. L. and Fairlie, D. P. (1996) Substrate-based cyclic peptidomimetics of Phe-Ile-Val that inhibit HIV-1 protease using a novel enzyme-binding mode. Journal of The American Chemical Society, 118 14: 3375-3379. doi:10.1021/ja953790z


Author March, D. R.
Abbenante, G.
Bergman, D. A.
Brinkworth, R. I.
Wickramasinghe, W.
Begun, J.
Martin, J. L.
Fairlie, D. P.
Title Substrate-based cyclic peptidomimetics of Phe-Ile-Val that inhibit HIV-1 protease using a novel enzyme-binding mode
Journal name Journal of The American Chemical Society   Check publisher's open access policy
ISSN 0002-7863
Publication date 1996-04-01
Year available 1996
Sub-type Article (original research)
DOI 10.1021/ja953790z
Open Access Status Not yet assessed
Volume 118
Issue 14
Start page 3375
End page 3379
Total pages 5
Place of publication WASHINGTON
Publisher AMER CHEMICAL SOC
Language eng
Abstract Results are presented for inhibitors of HIV-1 protease that demonstrate a new strategy for developing peptidomimetics, involving the replacement of flexible segments of peptide substrates with conformationally constrained hydrolytically-stable macrocyclic structural mimics. A 15-membered macrocycle that imitates the tripeptide Phe-IIe-Val was designed and incorporated into the C-terminus of Ac-Leu-Val-Phe-CHOHCH2-{Phe-Ile-Val}-NH2 an inhibitor of HIV-I protease derived from a substrate sequence. Advantages of the macrocycle over the acyclic peptide include constraining its components into their bioactive conformation and protecting the amide bonds from enzymatic degradation, the cycle being stable to acid, gastric proteases, and plasma. Molecular modeling and X-ray structural studies reveal that the cyclic inhibitors have a unique enzyme-binding mode, the sterically unencumbered hydroxyethylamine isostere binds via both its hydroxyl and protonated nitrogen to the anionic Asp25 catalytic residues. The novel macrocycle superimposes well on the linear peptidic inhibitor for which it was designed as a structural mimic. Structural mimicry led to functional mimicry as shown by comparable inhibition of the protease by cyclic and acyclic molecules. Further modification of the acyclic N-terminus (Leu-Val-Phe) gave stable, water-soluble, potent inhibitors of HIV-1 protease. This approach may have general application to the development of mimetics of other bioactive peptides, including inhibitors of other enzymes.
Keyword Infectivity
Proteinase
Design
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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Created: Tue, 10 Nov 2009, 18:46:08 EST