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.
Manchester Institute of Biotechnology, University of Manchester, 131 Princess Street, Manchester M1 7DN, UK. melsawy01@qub.ac.uk.
Mohamed A
MA
Elsawy
Irina G
IG
Tikhonova
Lorraine
L
Martin
Brian
B
Walker
D000595:Amino Acid Sequence; D000626:Aminopeptidases / Q000378:metabolism*; D017209:Apoptosis; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism*; D055550:Protein Stability; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
D009842:Oligopeptides; C532637:SMAC peptide; D051636:X-Linked Inhibitor of Apoptosis Protein; D000626:Aminopeptidases; D053453:Caspase 9