Cell Permeable Cyclic Peptide Library Generation for Target-Based Screening

Most drugs on the market are small molecules. Whilst these typically have good oral bioavailability, small molecule drugs do not always have a high selectivity for their targets. This can lead to increased toxicity from off-target effects. Likewise, small molecules are unable to selectively target proteins with large binding surfaces, such as those that are involved in protein-protein interactions. Large biologics such as proteins and antibodies exhibit very high selectivity for these targets but are not cell permeable and can thus only bind onto extracellular proteins. Furthermore, biologics are costly to manufacture compared to synthetic molecules. Peptides are promising therapeutics as they lie between the spectrum of small molecules and biologics whereby they have high selectivity for their targets, are able to probe a larger chemical space by targeting proteins with large binding surfaces and have relatively low production costs. However, the issue of low cell permeability, rapid metabolism and thus low oral bioavailability still persists for peptides and is a major limiting factor in their use as therapeutics.

It has been observed that cyclisation of peptides has several structural benefits, such as eliminating the N- and C- termini to prevent proteolytic degradation, increasing rigidity and reducing the polar surface area to improve cell permeability and metabolic stability, leading to increased oral bioavailability.

Over 1000 naturally occurring cyclic peptides have been discovered and some have been developed into widely used clinically available drugs, such as vancomycin, cyclosporin A and actinomycin D. However, the physicochemical properties underlying cyclic peptide cell permeability are unclear. The design of small molecule drugs is guided by Lipinski's Rule of 5 which defines the physicochemical properties that a drug should have to be orally bioavailable. Such rules include having a molecular weight <500, logP <5, number of hydrogen bond donors <5 and number of hydrogen bond acceptors <10. Due to the larger size of peptides, they do not conform to these rules and thus they cannot be used for the design of orally bioavailable cyclic peptides.

This project aims to elucidate the physicochemical properties underlying the cell permeability of cyclic peptides. By ascertaining these properties, they can be used as screening filters in mRNA-display based cyclic peptide libraries to efficiently identify cell permeable cyclic peptide hits against target proteins of interest. This has the potential of vastly improving the landscape for cyclic peptide drug development by eliminating the need for modulating cell permeability of hit peptides, which can be highly time-consuming and difficult. Following the generation of these libraries, they can undergo screening against targets for the discovery of cell permeable peptides with therapeutic potential.

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.