Yuen, T. Y.; Brown, C. J.; Xue, Y. Z.; Tan, Y. S.; Ferrer Gago, F. J.; Lee, X. E.; Neo, J. Y.; Thean, D.; Kaan, H. Y. K.; Partridge, A. W.; Verma, C. S.; Lane, D. P.; Johannes, C. W., Stereoisomerism of stapled peptide inhibitors of the p53-Mdm2 interaction: an assessment of synthetic strategies and activity profiles. Chemical Science 2019, 10 (26), 6457-6466.
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.
This work was supported by the Industry Alignment Fund - Pre-Positioning Programme (IAF-PP) of Agency for Science, Technology and Research (A*STAR) (H1701a0010) and the JCO Visiting Investigatorship Programme of Agency for Science, Technology and Research (A*STAR) (JCO 1235d00048).