Smac-Derived Aza-Peptide As an Aminopeptidase-Resistant XIAP BIR3 Antagonist

Elsawy, Mohamed orcid iconORCID: 0000-0003-3964-2150, Tikhonova, Irina, Martin, Lorraine and Walker, Brian (2015) Smac-Derived Aza-Peptide As an Aminopeptidase-Resistant XIAP BIR3 Antagonist. Protein and Peptide Letters, 22 (9). pp. 836-843. ISSN 0929-8665

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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.

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