Developing New Tools for the Chemical Diversification of Peptide Scaffolds

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.

The CDT has five primary beneficiaries:
The CDT cohort
Our students will receive an innovative training experience making them highly employable and equipping them with the necessary knowledge and skillset in science and enterprise to become future innovators and leaders. The potential for careers in the field is substantial and students graduating from the CDT will be sought after by employers. The Life Sciences Industrial strategy states that nearly half of businesses cite a shortage of graduates as an issue in their ability to recruit talent. Collectively, the industrial partners directly involved in the co-creation of the proposal have identified recruitment needs over the next decade that already significantly exceed the output of the CDT cohort.
Life science industries
The cohort will make a vital contribution to the UK life sciences industry, filling the skills gap in this vital part of the economy and providing a talented workforce, able to instantly focus on industry relevant challenges. Through co-creation, industrial partners have shaped the training of future employees. Additional experience in management and entrepreneurship, as well as peer-to-peer activities and the beginning of a professional network provided by the cohort programme will enable graduates to become future leaders. Through direct involvement in the CDT and an ongoing programme of dissemination, stakeholders will benefit from the research and continue to contribute to its evolution. Instrument manufacturers will gain new applications for their technologies, pharmaceutical and biotech companies will gain new opportunities for drug discovery projects through new insight into disease and new methods and techniques.
Health and Society
Research outputs will ultimately benefit healthcare providers and patients in relevant areas, such as cancer, ageing and infection. Pathways to such impact are provided by involvement of industrial partners specialising in translational research and enabling networks such as the Northern Health Science Alliance, the First for Pharma group and the NHS, who will all be partners. Moreover, graduates of the CDT will provide future healthcare solutions throughout their careers in pharmaceuticals, biotechnology, contract research industries and academia.
UK economy
The cohort will contribute to growth in the life sciences industry, providing innovations that will be the vehicle for economic growth. Nationally, the Life Sciences Industrial Strategy Health Advanced Research Programme seeks to create two entirely new industries in the field over the next ten years. Regionally, medicines research is a central tenet of the Northern Powerhouse Strategy. The CDT will create new opportunities for the local life sciences sector, Inspiration for these new industries will come from researchers with an insight into both molecular and life sciences as evidenced by notable successes in the recent past. For example, the advent of Antibody Drug Conjugates and Proteolysis Targeting Chimeras arose from interdisciplinary research in this area, predominantly in the USA and have led to significant wealth and job creation. Providing a cohort of insightful, innovative and entrepreneurial scientists will help to ensure the UK remains at the forefront of future developments, in line with the aim of the Industrial Strategy of building a country confident, outward looking and fit for the future.
Institutions
Both host institutions will benefit hugely from hosting the CDT. The enhancement to the research culture provided by the presence of a diverse and international cohort of talented students will be beneficial to all researchers allied to the theme areas of the programme, who will also benefit from attending many of the scientific and networking events. The programme will further strengthen the existing scientific and cultural links between Newcastle and Durham and will provide a vehicle for new collaborative research.