Grant: Project Grant

High blood pressure is a major risk factor for stroke and is often caused by cellular miscommunication due to defective signaling by a messenger molecule called cyclic guanosine monophosphate (cGMP). Dysfunctional cGMP signaling can also result in retinal degeneration, blindness, and life-threatening ruptures of blood vessels (i.e., aneurysms). Furthermore, cGMP plays a critical role in the life cycle of the malaria parasite, Plasmodium falciparum. We study a cGMP-binding protein called protein kinase G (PKG), which controls cell signaling in both humans and P. falciparum. Our goal is to determine how promising drug leads for diseases caused by dysfunctional cGMP signalling affect PKG's activity. For example, PKG-activating compounds called nitroxyl donors are being developed to treat high blood pressure, while compounds that inhibit PKG by mimicking cGMP are promising drug leads against retinal degeneration, which is currently uncurable. Similarly, cGMP mimics that inhibit PKG in P. falciparum are promising antimalarial drug leads. However, further molecular understanding is needed to improve the potency and selectivity of current drug leads and decrease their side effects. To this end, we and our international network of collaborators are using assays to measure PKG activity and nuclear magnetic resonance (NMR) spectroscopy. NMR is ideally suited to reveal how cGMP, its analogues, nitroxyl donors, and disease mutations modify the structure and dynamics of PKG. By studying both human and P. falciparum PKG, we will identify features unique to the Plasmodium protein to improve the selectivity of antimalarial drug leads. This work will accelerate the development and clinical use of promising drugs for retinal degeneration and cardiovascular diseases, which affect 25% of Canadians, as well as malaria, a threat to 40% of the global population.