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Diarylethene moiety as an enthalpy-entropy switch: photoisomerizable stapled peptides for modulating p53/MDM2 interaction

DOI: 10.1039/D0OB00831A DOI Help

Authors: Alexander V. Strizhak (University of Cambridge; Enamine Ltd) , Oleg Babii (Karlsruhe Institute of Technology (KIT)) , Sergii Afonin (Karlsruhe Institute of Technology (KIT)) , Iuliia Bakanovich (University of Cambridge; Enamine Ltd) , Teodors Pantelejevs (University of Cambridge) , Wenshu Xu (University of Cambridge) , Elaine Fowler (University of Cambridge) , Rohan Eapen (University of Cambridge) , Krishna Sharma (University of Cambridge) , Maxim O. Platonov (Enamine Ltd) , Vasyl V. Hurmach (Enamine Ltd; Taras Shevchenko National University of Kyiv) , Laura Itzhaki (University of Cambridge) , Marko Hyvonen (University of Cambridge) , Anne S. Ulrich (Karlsruhe Institute of Technology (KIT);) , David R. Spring (University of Cambridge) , Igor V. Komarov (Taras Shevchenko National University of Kyiv; Lumobiotics GmbH)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Organic & Biomolecular Chemistry , VOL 113

State: Published (Approved)
Published: May 2020
Diamond Proposal Number(s): 18548

Open Access Open Access

Abstract: Analogs of the known inhibitor (peptide pDI) of the p53/MDM2 protein–protein interaction are reported, which are stapled by linkers bearing a photoisomerizable diarylethene moiety. The corresponding photoisomers possess significantly different affinities to the p53-interacting domain of the human MDM2. Apparent dissociation constants are in the picomolar-to-low nanomolar range for those isomers with diarylethene in the “open” configuration, but up to eight times larger for the corresponding “closed” isomers. Spectroscopic, structural, and computational studies showed that the stapling linkers of the peptides contribute to their binding. Calorimetry revealed that the binding of the “closed” isomers is mostly enthalpy-driven, whereas the “open” photoforms bind to the protein stronger due to their increased binding entropy. The results suggest that conformational dynamics of the protein-peptide complexes may explain the differences in the thermodynamic profiles of the binding.

Subject Areas: Chemistry


Instruments: I03-Macromolecular Crystallography

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