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.
Keywords: Aminopeptidases, Apoptosis, Aza-peptides, Caspase 9, IAPs, Smac.
Rights & PermissionsPrintExport