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

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. © 2015 bentham science publishers.