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

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

Chemical Science

10.1039/c9sc01456j

https://doi.org/10.1039/c9sc01456j

Tsz Ying Yuen, Christopher J. Brown, Yuezhen Xue, Yaw Sing Tan, Fernando J. Ferrer Gago, Xue Er Lee, Jin Yong Neo, Dawn Thean, Hung Yi Kristal Kaan, Anthony W. Partridge, Chandra S. Verma, David P. Lane, Charles A. Johannes

30 May 2019

Yuen, T. Y., Brown, C. J., Xue, Y., Tan, Y. S., Ferrer Gago, F. J., Lee, X. E., Neo, J. Y., Thean, D., Kaan, H., Partridge, A. W., Verma, C. S., Lane, D. P., & Johannes, C. W. (2019). Stereoisomerism of stapled peptide inhibitors of the p53-Mdm2 interaction: an assessment of synthetic strategies and activity profiles. Chemical science, 10(26), 6457–6466. https://doi.org/10.1039/c9sc01456j

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.

http://creativecommons.org/licenses/by-nc/4.0/

Funded by the A*STAR JCO Visiting Investigatorship Programme (JCO 1235d00048) and the Industry Alignment Fund (Pre-positioning, HBMS domain H17/01/a0/010).

https://oar.a-star.edu.sg/communities-collections/articles/15418

2041-6520
2041-6539

Bioinformatics Institute