title: Smac-derived Aza-peptide As an Aminopeptidase-resistant XIAP BIR3 Antagonist.
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 Smac-derived 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.
authors.affiliation: Manchester Institute of Biotechnology, University of Manchester, 131 Princess Street, Manchester M1 7DN, UK. melsawy01@qub.ac.uk.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Elsawy
authors.forename: Irina G
authors.initials: IG
authors.lastname: Tikhonova
authors.forename: S Lorraine
authors.initials: SL
authors.lastname: Martin
authors.forename: Brian
authors.initials: B
authors.lastname: Walker