Miles, JA, Yeo, DJ, Rowell, P et al. (5 more authors) (2016) Hydrocarbon constrained peptides – understanding preorganisation and binding affinity. Chemical Science, 7 (6). pp. 3694-3702. ISSN 2041-6520
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | This Open Access Article is licensed under a Creative Commons Attribution-Non Commercial 3.0 Unported Licence |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Inorganic Chemistry (Leeds) The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 10 Mar 2016 16:42 |
Last Modified: | 23 Jun 2023 22:00 |
Published Version: | http://dx.doi.org/%2010.1039/C5SC04048E |
Status: | Published |
Publisher: | Royal Society of Chemistry |
Identification Number: | 10.1039/C5SC04048E |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:96120 |