Professor of Chemistry
Adjunct Professor of Global Health
Director, NIH International Center of Excellence for Malaria Research for South Asia (South Asia ICEMR)
Ph.D. Oregon Health Sciences University, 1982
(Malaria Pharmacology, Functional Genomics)
Malaria is a major cause of morbidity and mortality in the world, with about two million deaths and over 500 million infections per year. With the emergence of resistance against traditional drugs, there is an urgent need for new, affordable medicines against Plasmodium. Faithful, disciplined application of chemical principles to increasingly sophisticated understanding of biology can lead to new drug targets, candidate drugs, and can help reveal new principles in biology. The Rathod group currently pursues four main research directions in the area of malaria pharmacology.
The Rathod group is targeting high-value pyrimidine biosynthesis enzymes with selectivity by starting with host-parasite protein differences at the active-site, by appropriate pro-drugs, by supplementing non-selective antifolates with rescuing nutrients that only the host can use, or by disrupting unique protein-protein interactions. The enzymes targeted by the group are malarial thymidylate synthase and dihydroorotate dehydrogenase (the latter with M. Phillips at the University of Texas Southwestern Medical Center).
The Rathod group now has a detailed model for the phenotype which drives the acquisition of drug resistance in malaria parasites and has identified the genomic loci involved in the process.
The Rathod group discovered that some malarial drug targets may be uniquely sensitive to inhibitors in part due to tight parasite-specific protein-nucleic acid interactions. Such insights have allowed for improved strategies for expressing malaria proteins in the functional form.
The Rathod group is creating and employing new tools and techniques to assist in research, including: 1) DNA microarrays, used to understand malaria gene regulation, particularly in the context of drug action; 2) QTL mapping, which assists in the dissection of resistance traits and control of gene expression; 3) Microfluidics, used to help model malaria pathobiology; and 4) Cell-free protein expression, which allows access to functional malarial proteins.
"Estimating physical splenic filtration of Plasmodium falciparum-infected red blood cells in malaria patients." Herricks, T.; Seydel, K.B.; Molyneux, M.; Taylor, T.; Rathod, P.K. Cellular Microbiology 2012 (in press).
"Bioisosteric transformations and permutations in the triazolopyrimidine scaffold to identify the minimum pharmacophore required for inhibitory activity against Plasmodium falciparum dihydroorotate dehydrogenase." Marwaha, A.; White, J.; El Mazouni, F.; Creason, S.A.; Kokkonda, S.; Buckner, F.S.; Charman, S.A.; Phillips, M.A.; Rathod, P.K. J. Med. Chem. 2012, 55(17), 7425-7436.
"Malaria-attributed death rates in India." Kumar, A.; Dua, V.K.; Rathod, P.K. The Lancet 2011, 377(9770), 991-992.
"A genetically hard-wired metabolic transcriptome in Plasmodium falciparum fails to mount protective responses to lethal antifolates."
Ganesan, K.; Ponmee, N.; Jiang, L.; Fowble, J.W.; White, J.; Kamchonwongpaisan, S.; Yuthavong, Y.; Wilairat, P.; Rathod, P.K. PLoS Pathog. 2008, 4(11): e1000214.