One trillion photoswitchable cyclic peptides: shining light on questions in chemical biology Thomas B. Jackson 1,2 , Prof. Matthew J. Fuchter 1 , Prof. Edward W. Tate 1,2 and Dr Louise J. Walport 1,2 1 Molecular Sciences Research Hub, Imperial College London, UK, 2 Francis Crick Institute, UK Cyclic peptides are an emerging class of exciting chemical tools, bridging the gap between small molecule therapeutics and larger biologics. They have recently gained traction probing classically undruggable protein targets of interest. Many powerful methodologies to identify novel cyclic peptides have been developed, including mRNA display-based RaPID ( Random Non-standard Peptide Integrated Discovery ). (1) Such platforms enable the screening of >1 trillion-member cyclic peptide libraries incorporating non-proteogenic amino acids, against any protein of interest. Despite the development of cyclic peptides as novel tools to answer questions in Chemical Biology, the fine-tuned druggability of complex biological pathways remains elusive. Light is an incredibly powerful non-invasive stimulus to introduce temporal control within a system. Photoswitches are small molecules that can undergo isomerisation via the stimulus of a specific wavelength of light. (2) This project focuses upon the integration of light controllable ‘photoswitches’ within every macrocycle of the trillion-member library, via genetic code re-programming, inducing global conformational changes within the macrocyclic peptides structure to give switchable binding. As a proof-of-concept, methodology for the identification of photoswitchable macrocyclic peptides has been developed against human Protein Arginine Deiminase II (hPADI2). Identified peptides show up to 16-fold differential binding and inhibition of hPADI2 between each of the two light-dependent (E/Z) macrocyclic isomers. Further work to improve the binding differential is underway, honing the methodology to allow the robust identification of light-dependent photoswitchable macrocyclic peptides against any protein target of interest within complex biological systems.
References 1. Chem. Commun. , 2017, 53 , 1931 2. J. Am. Chem. Soc., 2014, 136, 34 , 11878–11881
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