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Issue 6, 2016
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Hydrocarbon constrained peptides – understanding preorganisation and binding affinity

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Abstract

The development of constrained peptides represents an emerging strategy to generate peptide based probes and hits for drug-discovery that address challenging protein–protein interactions (PPIs). In this manuscript we report on the use of a novel α-alkenylglycine derived amino acid to synthesise hydrocarbon constrained BH3-family sequences (BIM and BID). Our biophysical and structural analyses illustrate that whilst the introduction of the constraint increases the population of the bioactive α-helical conformation of the peptide in solution, it does not enhance the inhibitory potency against pro-apoptotic Bcl-xL and Mcl-1 PPIs. SPR analyses indicate binding occurs via an induced fit mechanism whilst X-ray analyses illustrate none of the key interactions between the helix and protein are disturbed. The behaviour derives from enthalpy–entropy compensation which may be considered in terms of the ground state energies of the unbound constrained and unconstrained peptides; this has implications for the design of preorganised peptides to target protein–protein interactions.

Graphical abstract: Hydrocarbon constrained peptides – understanding preorganisation and binding affinity

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Supplementary files

Article information


Submitted
25 Oct 2015
Accepted
15 Feb 2016
First published
29 Feb 2016

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2016,7, 3694-3702
Article type
Edge Article
Author version available

Hydrocarbon constrained peptides – understanding preorganisation and binding affinity

J. A. Miles, D. J. Yeo, P. Rowell, S. Rodriguez-Marin, C. M. Pask, S. L. Warriner, T. A. Edwards and A. J. Wilson, Chem. Sci., 2016, 7, 3694
DOI: 10.1039/C5SC04048E

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