Jean
Gariepy

Drug Development and Disease Diagnostics
Molecular basis of drug targets and diseases

Ontario Cancer Institute
610 University Ave, Rm 7-117
Toronto ON M5G 2M9
Canada

The process of drug discovery needs to be accelerated if our society is to cope with rapidly rising numbers of cancer patients, newly unveiled mechanisms of drug resistance and the realization that cancer represents a collection of diseases that will require the tailoring of more selective therapies. Synthetic, combinatorial and genetic approaches are being applied in our laboratory to design peptide-based delivery shuttles or to re-engineer large structural templates such as bacterial toxins with the view to generating selective vehicles for cancer cells and other eukaryotic cell targets. The principles developed in our laboratory will be applicable to other disease states.

Recent projects include:

The enzymatic assembly of glycopeptides: MUC1, the prototypic human mucin, is a ubiquitous membrane-associated glycoprotein that is abundant on the apical cell-surfaces of epithelial tissue. Tumor cells overexpress and aberrantly glycosylate MUC1 creating unique addresses on such cells. Our laboratory is focusing on the biosynthesis of such tumour markers with a view to using them as validated targets in our drug discovery program or as potential antigens in the preparation of cancer vaccines.

Combinatorial strategies leading to drug discovery: Small molecular weight drugs presently used in cancer therapies have inherent limitations in terms of their ability to code for multiple functions within the context of a small structural template. In many instances, present day classes of chemotherapeutic drugs will not cure cancer and have side effects that limit the quality of life of treated patients. A powerful strategy for developing more promising anti-tumour agents relies on the development of combinatorial libraries where molecular templates (organic molecules, peptides, nucleic acids or proteins) are either selectively or randomly modified to create vast arrays of related compounds. Our laboratory is constructing and mining protein and nucleic acid libraries with the objective of discovering new diagnostic and therapeutic agents.

Intracellular delivery agents: The utility of a drug is dependent on its ability to reach its molecular target in relation to all other cellular targets. To address this issue, we are designing and assembling small peptide-based structures able to carry out multiple routing tasks and thus guide the process of drug delivery into cells. These peptide vehicles are also designed to harbour functional domains such as metal chelating sites that can be readily radiolabeled with common isotopes such as Tc 99m and used as radiopharmaceuticals.

Publications

PubMed