Peptidyl epoxides extended in the P′ direction as cysteine protease inhibitors: Effect on affinity and mechanism of inhibition

Nurit Perlman; Maya Hazan; Michael Shokhen; Amnon Albeck

doi:10.1016/j.bmc.2008.08.031

Peptidyl epoxides extended in the P′ direction as cysteine protease inhibitors: Effect on affinity and mechanism of inhibition

Nurit Perlman, Maya Hazan, Michael Shokhen, Amnon Albeck

Department of Chemistry

Bar-Ilan University

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

Endo peptidyl epoxides, in which the central epoxidic moiety replaces the scissile amide bond of a P₃-P₃′ peptide, were designed as cysteine proteases inhibitors. The additional P′-S′ interactions, relative to those of an exo peptidyl epoxide of the same P₃-P₁ sequence, significantly improved affinity to the enzymes papain and cathepsin B, but also changed the mode of inhibition from active-site directed inactivation to reversible competitive inhibition. Computational models rationalize the binding affinity and the inhibition mechanism.

Original language	English
Pages (from-to)	9032-9039
Number of pages	8
Journal	Bioorganic and Medicinal Chemistry
Volume	16
Issue number	19
DOIs	https://doi.org/10.1016/j.bmc.2008.08.031
State	Published - 1 Oct 2008

Bibliographical note

Funding Information:
This work was supported by The Israel Science Foundation (Grant No. 1115/04) and by the ‘Marcus Center for Pharmaceutical and Medicinal Chemistry’ at Bar Ilan University.

Funding

This work was supported by The Israel Science Foundation (Grant No. 1115/04) and by the ‘Marcus Center for Pharmaceutical and Medicinal Chemistry’ at Bar Ilan University.

Funders	Funder number
Bar-Ilan University
Israel Science Foundation	1115/04

Keywords

Cathepsin B
Endo peptidyl epoxides
Enzyme inhibitors
Papain
Peptidomimetics
Structure-activity relationships

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10.1016/j.bmc.2008.08.031

Cite this

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abstract = "Endo peptidyl epoxides, in which the central epoxidic moiety replaces the scissile amide bond of a P3-P3′ peptide, were designed as cysteine proteases inhibitors. The additional P′-S′ interactions, relative to those of an exo peptidyl epoxide of the same P3-P1 sequence, significantly improved affinity to the enzymes papain and cathepsin B, but also changed the mode of inhibition from active-site directed inactivation to reversible competitive inhibition. Computational models rationalize the binding affinity and the inhibition mechanism.",

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AU - Albeck, Amnon

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AB - Endo peptidyl epoxides, in which the central epoxidic moiety replaces the scissile amide bond of a P3-P3′ peptide, were designed as cysteine proteases inhibitors. The additional P′-S′ interactions, relative to those of an exo peptidyl epoxide of the same P3-P1 sequence, significantly improved affinity to the enzymes papain and cathepsin B, but also changed the mode of inhibition from active-site directed inactivation to reversible competitive inhibition. Computational models rationalize the binding affinity and the inhibition mechanism.

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KW - Papain

KW - Peptidomimetics

KW - Structure-activity relationships

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Peptidyl epoxides extended in the P′ direction as cysteine protease inhibitors: Effect on affinity and mechanism of inhibition

Abstract

Bibliographical note

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Keywords

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