One trillion Photoswitchable Cyclic Peptides: shining light on questions in Chemical Biology Thomas Jackson 1,2 , Prof. Matthew J. Fuchter 1 , Prof. Edward W. Tate 1,2 and Dr Louise J. Walport 1,2 1 Imperial College London, UK, 2 The 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 peptideshave been developed,including mRNA display-basedRaPID( Random Non-standard Peptide Integrated Discovery ). 1 Such platforms enable the screening of>1trillion-membercyclic 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 Thisproject 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 photo switchable macrocyclic peptides has been developed against human Peptidyl Arginine Deiminase II (hPADI2).Identified peptides show up to 16-fold differential binding and inhibition of hPADI2between each of the two light-dependent( E/Z )macrocyclicisomers. 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 , 1931-1940 2. J. Am. Chem. Soc. 2017, 139, 3 , 1261–1274
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