Regiospecific, Controlled Synthesis of Structurally Defined Peptide Scaffolds

Noncovalent interactions between proteins are used in all living systems as an essential means of transferring and processing information and as such protein-protein interactions are fundamental to regulating life on a cellular level. Disruption of natural binding partners or alterations in the expression levels of a particular protein can perturb the balance of this signaling process and lead to the onset of a range of diseases. Altered protein-protein interactions are present in cancers, HIV, and Alzheimer's and inhibiting the abnormal protein-protein interactions associated with these diseases offers an exciting new avenue to develop highly selective drug molecules.

However, despite considerable research efforts, identifying inhibitors of disease-associated protein-protein interactions has proven to be very challenging. The large binding surfaces present in most protein-protein interactions has meant that effective inhibitors based on small molecules have been hard to identify, but larger compounds, such as cyclic peptides that can be used to mimic protein binding surfaces, have emerged as a promising therapeutics leads.

At the cutting edge of this field is the application of multicyclic peptide scaffolds, as the 3-dimensional structure of these compounds can be designed to allow multiple binding regions on a protein interface to be targeted simultaneously. But progress into designing new inhibitors of protein-protein interactions using this approach is severely hampered by a lack of viable synthetic routes to multicyclic peptide scaffolds.

Utilising novel fluoropyridine amino acids as the key building blocks we will develop synthetic strategies to access multicyclic peptide scaffolds, each with a defined 3-dimensional structure. The methodology developed will also permit the formation of the peptide scaffolds in a highly controlled and regionspecific manner which is something that is not currently possible using existing technologies. Having access to multicyclic peptide scaffolds will help to accelerate the discovery of inhibitors of protein-protein interactions and thus the development of new drug molecules to target diseases such as cancer.

Rising life expectancies have meant that many of us living in the UK will unfortunately suffer from some form of age-related illness. Two of the most common are cancer and Alzheimer's, and developing new drugs to treat these illness, would have a significant impact on the quality of life and health of the UK population. Finding new avenues to target disease is becoming increasingly difficult, but one promising area that is emerging as a new class of therapeutic targets are protein-protein interactions and this is the area in which the proposed work is focused.

We will develop new synthetic methodologies that will facilitate the synthesis of structurally defined multicyclic peptide scaffolds. These peptide scaffolds represent excellent templates for the rationale design of inhibitors of disease associated protein-protein interactions and they will be of considerable benefit to both industrial and academic researchers, who are searching for ways to design new therapies that target such interactions.

In addition to having an impact on the health and well-being of the UK population the proposed work will also generate new knowledge in the field of chemical-biology, which is an area of UK research strength and expertise as recognised by EPSRC. The creation of innovative technologies such as those proposed to access multicylic peptide scaffolds address a knowledge gap and this is critical in maintaining the UK at the forefront of research in the field of chemical-biology.

It is also recognised, that the pharmaceutical industry will benefit from the delivery of highly skilled researchers with expertise in peptide chemistry, as there is currently a skills shortage in this area within the UK. The project will also generate new technologies to prepare cyclic peptides. Such techniques can be exploited by industry to help them address a major stumbling block in the development of new peptide therapeutics, which is their susceptibility to in vivo degradation. Therefore, in the long term the proposed research could function as an enabling technology to help accelerate the development of peptide based drugs to market.