Smac-derived aza-peptide as an aminopeptidase-resistant XIAP BIR3 antagonist

Date

2015

Advisors

Journal Title

Journal ISSN

ISSN

Volume Title

Publisher

Bentham Science

Type

Article

Peer reviewed

Yes

Abstract

The peptidic nature of anti-IAPs N-terminus Smac-derived peptides precludes their utilization as potential therapeutic anticancer agents. Recent advances in the development of novel Smacderived peptidomimetics and non-peptidic molecules with improved anti-IAPs activity and resistance to proteolytic cleavage have been reported and led to a number of candidates that are currently in clinical trials including LCL-161, SM-406/AT-406, GDC-0512/GDC-0917, and birinapant. As an attempt to improve the proteolytic stability of Smac peptides, we developed the Aza-peptide AzaAla- Val-Pro-Phe-Tyr-NH2 (2). Unlike unmodified peptide Ala-Val-Pro-Phe-Tyr-NH2 (1), analogue (2) exhibited resistance towards proteolytic cleavage by two aminopeptidases; LAP and DPP-IV, while retaining its IAP inhibitory activity. This was due to the altered planar geometry of the P1 residue side chain. Our findings showed that using aza-isosteres of bioactive peptide sequences imbue the residue with imperviousness to proteolysis; underscoring a potential approach for developing a new generation of Smac-derived Aza-peptidomimetics.

Description

The Publisher's final version can be found by following the DOI link.

Keywords

Smac-Derived Aza-Peptide, Caspase-9, IAPs, Smac

Citation

Elsawy, M., Martin, L., Tikhonova, I., Walker, B. (2015) Smac-derived aza-peptide as an aminopeptidase-resistant XIAP BIR3 antagonist. Protein & Peptide Letters, 22, pp. 836-843.

Rights

Research Institute

Leicester Institute for Pharmaceutical Innovation - From Molecules to Practice (LIPI)