The human malaria parasite is endemic in 87 countries, putting 2.5 billion people in the poorest nations of the tropics at risk for the disease. Despite intensive efforts to control malaria through combination drug therapy and insect control programs, malaria remains one of the largest global health problems. Widespread drug resistance has compromised the effectiveness of malaria control programs.
Pyrimidine biosynthesis provides a significant opportunity for the development of new chemotherapeutic agents against the malaria parasite. Plasmodium species rely exclusively on de novo pyrimidine biosynthesis to provide precursors for DNA and RNA synthesis. Blocking pyrimidine biosynthesis would selectively kill the parasite; mammalian cells would be resistant becasue they have salvage pathways to reuse DNA and RNA precursors.
Our research focuses on dihydroorotate dehydrogenase (DHODH), which catalyzes the fourth step in de novo pyrimidine biosynthesis. We identified a number of chemical scaffolds that are potent and species selective inhibitors of P. falciaprum DHODH by high throughput screening. A triazolopyrimidine-based series emerged from this screen that has potent activity against malaria parasites in vitro, and which suppress parasites in a mouse model of the disease. We solved the X-ray structures of PfDHODH bound to inhibitors from this series utilizing the X-ray structure to inform the medicinal chemistry to optimize both the potency and in vivo pharmacokinetic properties of the compound series. We successfully identified a clinical candidate from this work (DSM265), which is currently in Phase I clinical trials.
The lab is part of a large multidisciplinary project that is funded by the NIH and sponsored by Medicines for Malaria Venture to develop our lead compounds into new anti-malarial chemotherapy. The team includes three academic labs. We are currently focused on identifying additional DHODH inhibitors to serve as backups in case the clinical candidate fails. We also have an ongoing project to use X-ray structure and biophysical methods to further understand species-selective binding to DHODH.
New directions in malaria research in the lab extend to identifying new targets for drug discovery.