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Stereoisomerism of stapled peptide inhibitors of the p53-Mdm2 interaction: an assessment of synthetic strategies and activity profiles.

ABSTRACT: All-hydrocarbon, i, i+7 stapled peptide inhibitors of the p53-Mdm2 interaction have emerged as promising new leads for cancer therapy. Typical chemical synthesis via olefin metathesis results in the formation of both E- and Z-isomers, an observation that is rarely disclosed but may be of importance in targeting PPI. In this study, we evaluated the effect of staple geometry on the biological activity of five p53-reactivating peptides. We also present strategies for the modulation of the E/Z ratio and attainment of the hydrogenated adduct through repurposing of the metathesis catalyst.

SUBMITTER: Yuen TY

PROVIDER: S-EPMC6610352 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Stereoisomerism of stapled peptide inhibitors of the p53-Mdm2 interaction: an assessment of synthetic strategies and activity profiles.

Yuen Tsz Ying TY Brown Christopher J CJ Xue Yuezhen Y Tan Yaw Sing YS Ferrer Gago Fernando J FJ Lee Xue Er XE Neo Jin Yong JY Thean Dawn D Kaan Hung Yi Kristal HYK Partridge Anthony W AW Verma Chandra S CS Lane David P DP Johannes Charles W CW

Chemical science 20190530 26

All-hydrocarbon, i, i+7 stapled peptide inhibitors of the p53-Mdm2 interaction have emerged as promising new leads for cancer therapy. Typical chemical synthesis via olefin metathesis results in the formation of both E- and Z-isomers, an observation that is rarely disclosed but may be of importance in targeting PPI. In this study, we evaluated the effect of staple geometry on the biological activity of five p53-reactivating peptides. We also present strategies ...[more]

PMID: 31316744

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