Developing New Tools for the Chemical Diversification of Peptide Scaffolds (EPSRC Funded CDT in Molecular Sciences for Medicine - MoSMed)
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]. These amino acids can be exploited as 19F NMR probes, as reactive handles for the selective chemical modification of peptides or to access novel cyclic peptide scaffolds. We will design a new generation of perfluorinated amino acids with the aim of: 1) selectively modifying peptide scaffolds; and 2) establishing new strategies for the bio-conjugation of peptides to other biomolecules via SN2 or SNAr reactions.
WP2: The Application of Electrochemistry in Peptide Science
Researchers have utilised electrochemistry extensively in the small molecule arena. However, 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. Our aims will be to: 1) gain access to new amino acid building blocks for the preparation of novel peptides; and 2) develop a new route of the late-stage functionalisation of peptide scaffolds (linear and cyclic).
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. histone demethylases, 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 activity using established assays in the group. Aims are: to see if the incorporation of novel/ perfluorinated amino acids can improve: 1) target engagement; 2) proteolytic stability and 3) cellular permeability / activity. 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 for these projects, which will incorporate perfluorinated amino acids (WP1). Active hits will be selected for further modification and the effects of novel amino acids will be assessed.
The award is available to UK/EU applicants only. Depending on how you meet the EPSRC’s eligibility criteria, you may be entitled to a full or a partial award.
Applicants should hold or expect to achieve an excellent Masters level degree in synthetic chemistry, medicinal chemistry or biochemistry. An excellent Bachelors degree with relevant experience will also be considered.
For more information regarding MoSMed please visit the webpage: https://research.ncl.ac.uk/mosmed. Please note that MoSMed is a joint venture between Durham and Newcastle Universities.
When making an application, please select the course code F1A201 and quote the project title and reference number MoSMed20-08.