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Bioorg Med Chem. 2013 Sep 1;21(17):5004-11. doi: 10.1016/j.bmc.2013.06.055. Epub 2013 Jul 2.

Solid phase synthesis of Smac/DIABLO-derived peptides using a 'Safety-Catch' resin: identification of potent XIAP BIR3 antagonists.

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  • 1School of Pharmacy, Queen's University of Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.

Abstract

The N-terminal sequence of the Smac/DIABLO protein is known to be involved in binding to the BIR3 domain of the anti-apoptotic proteins IAPs, antagonizing their action. Short peptides and peptide mimetics based on the first 4-residues of Smac/DIABLO have been demonstrated to re-sensitize resistant cancer cells, over-expressing IAPs, to apoptosis. Based on the well-defined structural basis for this interaction, a small focused library of C-terminal capped Smac/DIABLO-derived peptides was designed in silico using docking to the XIAP BIR3 domain. The top-ranked computational hits were conveniently synthesized employing Solid Phase Synthesis (SPS) on an alkane sulfonamide 'Safety-Catch' resin. This novel approach afforded the rapid synthesis of the target peptide library with high flexibility for the introduction of various C-terminal amide-capping groups. The library members were obtained in high yield (>65%) and purity (>85%), upon nucleophilic release from the activated resin by treatment with various amine nucleophiles. In vitro caspase-9 activity reconstitution assays of the peptides in the presence of the recombinant BIR3-domain of human XIAP (500nM) revealed N-methylalanyl-tertiarybutylglycinyl-4-(R)-phenoxyprolyl-N-biphenylmethyl carboxamide (11a) to be the most potent XIAP BIR3 antagonist of the series synthesized inducing 93% recovery of caspase-9 activity, when used at 1μM concentration. Compound (11a) also demonstrated moderate cytotoxicity against the breast cancer cell lines MDA-MB-231 and MCF-7, compared to the Smac/DIABLO-derived wild-type peptide sequences that were totally inactive in the same cell lines.

KEYWORDS:

Apoptosis; Cancer resistance; Peptidomimetics; SPPS; Safety-Catch resin; Smac/DIABLO; XIAP BIR3

PMID:
23886811
DOI:
10.1016/j.bmc.2013.06.055
[PubMed - indexed for MEDLINE]

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