Functionalized Double Strain-Promoted Stapled Peptides for Inhibiting the p53-MDM2 Interaction

Krishna Sharma; Alexander V Strizhak; Elaine Fowler; Wenshu Xu; Ben Chappell; Hannah F Sore; Warren R J D Galloway; Matthew N Grayson; Yu Heng Lau; Laura S Itzhaki; David R Spring

doi:10.1021/acsomega.9b03459

Functionalized Double Strain-Promoted Stapled Peptides for Inhibiting the p53-MDM2 Interaction

ACS Omega. 2020 Jan 7;5(2):1157-1169. doi: 10.1021/acsomega.9b03459. eCollection 2020 Jan 21.

Affiliations

¹ Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
² Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, U.K.
³ Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, U.K.
⁴ School of Chemistry, The University of Sydney, Eastern Avenue, Sydney, New South Wales 2006, Australia.

Abstract

The Sondheimer dialkyne reagent has previously been employed in strain-promoted double-click cycloadditions with bis-azide peptides to generate stapled peptide inhibitors of protein-protein interactions. The substituted variants of the Sondheimer dialkyne can be used to generate functionalized stapled peptide inhibitors with improved biological properties; however, this remains a relatively underdeveloped field. Herein, we report the synthesis of new substituted variants of Sondheimer dialkyne and their application in the stapling of p53-based diazido peptides to generate potent stapled peptide-based inhibitors of the oncogenic p53-MDM2 interaction. The functionalized stapled peptide formed from a meta-fluoro-substituted Sondheimer dialkyne was found to be the most potent inhibitor. Furthermore, through experimental studies and density functional theory calculations, we investigated the impact of the substituent on the strain-promoted double-click reactivity of Sondheimer dialkyne.