Developing New Tools for the Chemical Diversification of Peptide Scaffolds

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Peptides are useful leads for the development of new drugs against a wide range of diseases. They occupy the chemical space between small molecules and antibodies and as such they can selectively inhibit targets that these other molecules cannot. Within the peptide field developing routes for the chemical diversification of peptide scaffolds is of considerable interest as this allows challenges like in vivo stability to be overcome. We will develop new synthetic chemistry that can be used to chemically diversify peptide scaffolds. Specifically, we will develop synthetic approaches to chemically modify "natural" peptides with the aim of improving their biological and physical properties. The chemistry established will then be utilized to modify and enhance the properties of "lead peptides" previously identified by Prof Kawamura (Newcastle). It will also be exploited in the preparation of novel ligands for emerging cancer targets with Professor Waring (Newcastle). WP1: Preparation of Perfluorinated Amino Acids: As part of a program to develop new approaches to accessing novel amino acids we recently exploited perfluoroheteroaromatics, such as pentafluoropyridine, to access a range of novel fluorinated amino acids [e.g. https://www.cobbgroupdurham.com/ Org. Biomol. Chem 2019, Org. Biomol. Chem 2017]. We will design fluorinated amino acids that can be used as 19F NMR probes, as reactive handles for the selective chemical modification of peptides or to access novel cyclic peptide scaffolds. WP2: The Application of Electrochemistry in Peptide Science: The use of electrochemical organic synthetic techniques to functionalise amino acids or large complex bio-molecules such as peptides is yet to be explored. We will use electrochemistry to modify and functionalise both single amino acids and full peptides. WP3: Assessing the Effect of Novel Amino Acids in a Biological Context The Kawamura group has identified active peptides against a range of biomedically important proteins (e.g. Nat. Comm, 2017). We will incorporate novel amino acids (WP1, WP2) into selected hit peptide sequences and assess the effect on target affinity, cellular permeability and bioactivity. In addition within the Newcastle Cancer Drug Discovery Group a range of thus far intractable cancer targets involving protein-protein interactions have been identified. As part of a related MoSMed project (Waring), novel hit peptides will be identified and into these we will incorporate a range of the novel amino acids prepared.