Visible Light-Modulated Photoswitches for peptide stapling

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Year 1: Generic training activities for all first-year student members of the CDT.Year 2-4: Due to their unique size and composition, peptide-based drugs offer several advantages over small molecules which have previously dominated the therapeutic landscape. They are highly potent, selective and display low levels of toxicity and immunogenicity. Despite these advantages, unmodified peptides are often characterised by poor cell membrane permeability and poor enzymatic stability, limiting their application in drug discovery. Various synthetic strategies, including peptide stapling, have been developed to overcome these limitations. Peptide stapling is a method of macrocyclisation that intramolecularly links two peptide side chains, with and without the aid of a linker. Incorporating a linker, able to undergo cis-trans isomerisation upon irradiation with light, forms photoswitchable peptides. Azobenzene-containing stapled peptides have been reported to improve peptide helicity, cell permeability and biological activity. However, all examples reported require the use of skin-damaging and weakly skin-penetrating UV light. This project will develop a novel two component peptide stapling methodology for the incorporation of azobenzene photoswitches into unprotected peptides via cysteine conjugation. For the sake of synthetic simplicity, initial stapling with m,p- diazobenzene will be performed. The stapling of visible light modulated ortho-fluoroazobenzenes will then be attempted in the future, to prevent the required use of UV light.