Design and Synthesis of unnatural Carbohydrates as potential modulators of PST-1 and STX

The surfaces of cells in the body are decorated by many complex molecules, including carbohydrates. These molecules play significant roles in how cells communicate with and adhere to each other - important everyday functions of normal cells. Polysialic acid (PSA) is a long polymer, made up of approx 10-200 units of sialic acid, an unusual sugar molecule. PSA synthesis is regulated by two enzymes - polysialyltransferases known as PST-1 and STX.This polymer is produced on the surface of a particular protein, the neural cell adhesion molecule (NCAM), during normal growth and development in early childhood. By adulthood, PSA is only found in certain areas of the brain. The only cells that express this polymer in adulthood are certain bacteria and cancer cells. My hypothesis is that inhibition of these enzymes (PST-1 and STX) will interfere with the PSA found on the surface of these cells. This would then alter the surface properties of the cell, which could affect how cells move around and stick together, having implications in normal cell function. The aim is to design and synthesise small molecules capable of inhibiting PSA polymer synthesis. The project aims to produce unnatural sugar analogues of sialic acid, which either inhibit the enzymes (thereby preventing the synthesis of the PSA polymer) or prevent chain extension once attached. Following these efforts, these compounds will then be evaluated in biological systems, specifically for their effects on normal cell functions.The effects of PSA in cell adhesion, motility, adhesiveness are poorly understood, and this project will inform greater understanding in these complex areas. The findings will also have wider implications for disease states, such as the treatment of cancer and bacterial infection. Resistance in cancer cells is a major problem. Most anti-cancer drugs also kill normal cells as well as the tumour cells. PSA is found on the surface of many cancer cells, when they begin to migrate to other parts of the body (metastasis). Since PSA is not found on the surface of normal cells, any effects by potential drugs would only affect these cells. Targeting metastasis would be a new approach to therapy. The over-use of antibiotics has led, in part, to resistance in bacteria. PSA is also found on the surface of certain bacteria, and protects the organism from the body's defences. Therefore, there is an urgent need for new therapies in both bacterial infection and in cancer therapies designed to overcome resistance and to treat these conditions in new ways. This project addresses this need.The principal aim of this project is to synthesise molecules and to develop methods by which to achieve this. However, through collaboration, the efforts from this project will feed into wider activities, funding for which is not requested here. The ongoing design process will be aided by computational chemistry (Dr Mire Zloh, The School of Pharmacy, University of London). Detailed structure-activity relationships will be studied in-house with regard to direct effects on the enzyme (Dr Jason Gill, Institute of Cancer Therapeutics, University of Bradford). In addition, the global effects on cell motility and adhesion will be evaluated (Prof. Paul Smith, The School of Medicine, University of Cardiff). This will determine whether these agents are likely to be of benefit in vivo.