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

Research output: Contribution to journalArticlepeer-review

10 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 languageEnglish
Pages (from-to)9032-9039
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number19
DOIs
StatePublished - 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.

Keywords

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

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