Grant: Discovery Grants Program - Individual

Natural product (NP) chemistry is one of the major contributors of lead compounds to the drug discovery process due to its enormous chemical diversity. One aspect of this process is the identification of NPs with enzyme-inhibiting activities. Enzymes, essential to human life, perform biochemical processes including metabolism, cellular signal transduction, cell cycling, and development. Malfunction in these biochemical systems often leads to disease that can be caused by the dysfunction/overexpression/hyperactivation of the enzymes involved. An understanding of diseases at the molecular level has provided several enzyme inhibitors in clinics. For instance, lovastatin, a cholesterol-lowering agent, works by inhibiting the activity of enzyme (3S)-hydroxymethylglutaryl- coenzyme A reductase, involved in its biosynthesis. The purpose of this research is to chemically investigate ethnomedicinal plants, a source of a wide array of valuable NPs, to identify bioactive NPs that make them active. We have collected several plants from the Prairie Provinces of Canada and South Africa based on their ethnomedical uses by traditional healers to treat various ailments and their crude extracts exhibited various enzyme inhibitory activities including anti-acetylcholinesterase (AChE), anti-glutathione S-transferase (GST), anti-alpha-glucosidase, anti-Plasmodium falciparum Enoyl-ACP reductase (PfENR), anti-Mycobacterium tuberculosis Enoyl-ACP reductase (MtENR) and anti-renin activities. All of these enzymes (AChE, alpha-glucosidase, GST, PfENR, MtENR and renin) are reported to be involved in the pathogenesis of Alzheimer's disease/Parkinson's disease, diabetes, improving anti-cancer chemotherapy, malaria, TB and hypertension, respectively. The proposed NP research will validate their ethnomedicinal use and help to identify novel NPs that inhibit the enzymes, involved in the pathogenesis of aforementioned diseases, as their molecular target. The major objectives of the proposed research are to identify: (i) lead bioactive NPs from aforementioned plants using a combination of bioactivity and metabolomics profiling approach; (ii) endophytic fungi as an alternative source of these NPs; (iii) and to study their structure-activity relationships. This interdisciplinary research integrates advanced chemical instrumentation methods (HPLC, NMR spectroscopic and LC-MS techniques for the purification and identification of NPs), microbial reactions, synthetic organic chemistry, computational chemistry, biochemistry and microbiology. In carrying out this research, students will be trained as future scientists for many Canadian institutions including biotechnological, food, chemical or pharmaceutical industries. The successful completion of this discovery grant will provide new NPs with therapeutic activities that will be of benefit to Canadian's health.