Medicinal peptide chemistry

Led by Profs. Margaret Brimble, Peter Shepherd & Rod Dunbar

Throughout the body peptides are active regulators and information brokers and they provide interesting lead compounds for the drug discovery industry. The potential of peptide therapeutics has recently intensified due to the application of improved synthetic methods and techniques that render peptides more stable. The development of non-peptide compounds (peptidomimetics) that retain the initial biological activity of the lead peptide but with improved bioavailability and pharmacokinetic profile can be achieved whereby optimal physical, chemical and pharmacological properties are engineered through application of medicinal chemistry to transform a given lead peptide into a viable drug candidate. This provides a mechanism for further development of lead compounds emerging from the proteonomics platform. Synthesis of complex glycopeptides and large peptide constructs using native chemical ligation (NCL) also provides valuable peptide-based molecular tools for the study of cell signalling pathways and immunotherapy strategies based on synthetic vaccines.

SYNTHESIS OF GLYCOPEPTIDES FOR INVESTIGATIONS INTO THE ROLE OF CELL FUNCTION IN CANCER AND DIABETES

Many intracellular O-glycosylated proteins play critical roles in cell growth, division or metabolism. This O-glycosylation pathway provides a novel mechanism by which cells can respond to changes in glucose or glucosamine levels and therefore has major implications for the pathogenesis of diabetes, the hallmark of which is elevated glucose levels, and cancer for which tumour cells are often diagnosed by the nature of their highly glycosylated cell surface proteins. A range of glycopeptides are being synthesized based on sequences of potential glycosylation sites in the proteins under investigation in order to make antibodies that recognize specific glycosylation events on the proteins (“glycospecific antibodies”). These glycospecific antibodies are then used in the cell signaling theme of the Maurice Wilkins Center (theme 6) to better understand the role that glycosylation of intracellular proteins might play in cancer and diabetes.

SYNTHESIS OF SYNTHETIC PEPTIDE VACCINES

The MWC is working on the development of synthetic vaccines based on early-stage peptides discovered from Assoc. Prof. Rod Dunbar’s vaccine design programme. These peptide-based compounds are designed to deliver peptide vaccines to appropriate immune cell pathways in order to stimulate T cells, and have applications as both therapeutic vaccines for cancer and preventative vaccines for infectious diseases