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Functionalized double strain-promoted stapled peptides for inhibiting the p53-MDM2 interaction

DOI: 10.1021/acsomega.9b03459 DOI Help

Authors: Krishna Sharma (University of Cambridge) , Alexander V. Strizhak (University of Cambridge) , Elaine Fowler (University of Cambridge) , Wenshu Xu (University of Cambridge) , Ben Chappell (University of Cambridge) , Hannah F. Sore (University of Cambridge) , Warren R. J. D. Galloway (University of Cambridge) , Matthew N. Grayson (University of Bath) , Yu Heng Lau (The University of Sydney) , Laura S. Itzhaki (University of Cambridge) , David R. Spring (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Omega

State: Published (Approved)
Published: January 2020
Diamond Proposal Number(s): 14043

Open Access Open Access

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.

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I04-Macromolecular Crystallography

Documents:
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