Late-Stage Functionalisation of Peptides via Photocatalytic Modification of Tryptophan

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Peptides can be modified to show more favourable characteristics compared to their original analogue, allowing them to be used for numerous applications in the pharmaceutical industry including the production of novel drugs, aiding drug delivery, and providing techniques to gain insight into biological systems. However, to functionalise a peptide or protein, often modification of a single amino acid is required which is difficult, due to the complexity of native biomolecules. Frequently used is cysteine (Cys) modification, due to its low abundance (~ 2% relative abundance across the proteome), however Cys residues are often vital for protein folding, and/or are involved in the active site of enzymes, therefore functionalisation could hinder the protein's activity. A new strategy which targets residues with a low abundance and a less crucial role within the protein, such as Trp with ~ 1.4% relative abundance, is in high demand. Recent advances in the field of photoredox chemistry have unlocked novel methods for the selective functionalisation of amino acids under mild and more sustainable conditions; however, application of this chemistry to biomolecules is still relatively underdeveloped. The conditions associated with this chemistry often abide by multiple green principles; for instance, catalysis, the use of energy efficient single wavelength LEDs and safer solvents. However, despite the advances in this field, some procedures have drawbacks due to the use of additives and/ or certain components in excess creating waste. Also, these methods often employ precious metal catalysts which is unsustainable in the longer term. The development of a mild photochemical method for Trp functionalisation would be of broad value and would be likely to have applications in a range of fields.Proposed solution and methodologyThis project will develop a mild and efficient photocatalytic strategy for selectively modifying Trp within peptides and proteins, expanding upon the limited number of methods currently available for achieving this transformation. A key goal is to ensure the chemistry aligns with green principles to further enhance the impact of the research. Ultimately the products (small molecule-peptide conjugates) will find applications in drug delivery and in vivo imaging. The project will build upon existing methods for modifying an indole moiety using visible-light The initial aim will be to identify sustainable and biocompatible conditions enabling the conjugation of a small molecule to Trp. The reaction must be selective for Trp within peptides despite the presence of interfering/ competing amino acids. The reaction will be applied to a variety of more complex Trp-containing peptides (greater than or equal to 5 amino acids) to gain an understanding of the chemoselectivty. To expand the number of conjugates we make and enable further applications of the products, the small molecule will also be varied to create a library of modified peptides each with distinct properties. A range of small molecules can be synthesised from cheap, readily available starting materials.Small molecule-peptide conjugates synthesised via the more sustainable photocatalytic route can act as biological tools and this will be explored. A wide range of applications are envisaged depending on the small molecule attached. Examples include biological testing of products to determine if the modification has affected the peptide's activity. Alternatively, the chemistry could be used for protein profiling to probe all reactive Trp residues in a cell.