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

Abstract

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 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-ProPhe-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.

The Multiple Roles of the IAP Super-family in cancer

“…Furthermore, in vivo studies demonstrated that SMAC mimetic peptides could enhance TRAIL-induced apoptosis in xenograft models (Simone Fulda, Wick, Weller, & Debatin, 2002). These studies were the first to prove that mimicking the N-terminus of SMAC could be an effective way to target IAPs and paved the way for the development of complex fusion and other synthetic peptides (A Elsawy, G Tikhonova, Martin, & Walker, 2015;Elsawy, Martin, Tikhonova, & Walker, 2013).…”

In Search of NPY Y4R Antagonists: Incorporation of Carbamoylated Arginine, Aza-Amino Acids, or d-Amino Acids into Oligopeptides Derived from the C-Termini of the Endogenous Agonists

“…Aza-peptides contain at least one amino acid in which the α-carbon atom is replaced by nitrogen . The semicarbazide substructure reduces conformational flexibility. , Several studies have revealed that the incorporation of aza-amino acids into bioactive peptides may result in a longer duration of action or higher potencies compared to the parent peptide. − Aza-peptides can be prepared by the reaction of an N-protected, N′-substituted hydrazine with an isocyanate . However, the synthesis of aza-peptides on a solid phase is compromised by an intramolecular side-reaction of resin-bound isocyanates that results in the formation of hydantoins (Figure A), lowering the yields of the target compounds and requiring time-consuming purification .…”

“…Without purification, the isocyanates were treated with hydrazines 10 and 12 affording the benzyl-protected N-Fmoc-aza 1 -dipeptides in yields >70%. Subsequent ester cleavage by hydrogenation gave access to the N-Fmoc-aza 1dipeptides Fmoc-aza-Leu-Arg(Pbf)-OH (17), Fmoc-aza-Orn-(Boc)-Tyr(tBu)-OH (18), and Fmoc-aza-Orn(Boc)-Leu-OH (19). The dipeptides 17−19 were employed in solid phase synthesis under the same conditions as those for the standard Fmoc-protected amino acids, resulting in quantitative coupling efficiencies.…”

“…1 H NMR (300 MHz, DMSO-d 6 ): δ (ppm) 1.26 (s, 9H), 1.80 (br s, 2H), 2.71−2.89 (m, 2H), 3.60 (t, 2H, J 6.9 Hz), 5.05 (s, 2H), 6.84 (d, 2H, J 8.5 Hz), 7.06 (d, 2H, J 8.4 Hz), 7.25−7.39 (m, 5H). 13 (17). Triphosgene (152 mg, 0.4 equiv) was dissolved in CH 2 Cl 2 (5 mL).…”

Negative correlation between X‑linked inhibitors of apoptosis and second mitochondria‑derived activator of caspase expression levels in cervical carcinoma and cervical intraepithelial neoplasia

“…Smac was first reported as a pro-apoptotic protein in July 2000 and is widely expressed in human normal tissues and primarily located in the cell mitochondria ( 29 ). Smac has been observed to act conversely to XIAP ( 37 , 38 ). Previous studies investigating Smac in numerous tumor tissues suggested that the low expression of Smac may inhibit the apoptosis of tumor cells ( 39 – 42 ).…”