Parasitology Seminar Series
Title: "Antimalarial drug target discovery through gene expression perturbation"
Speaker: Jacquin Niles, MD, PhD
Associate Professor of Biological Engineering
Massachusetts Institute of Technology-Biological Engineering
Date: April 29, 2019
Time: 12-1 pm
131 Hill Pavilion
University of Pennsylvania School of Veterinary Medicine
380 S University Avenue, Philadelphia, PA 19104
Malaria is a major global health problem, with 219 million cases and 435,000 deaths estimated in 2017. Antimalarial drugs are critical for malaria treatment and eradication efforts. However, resistance to clinically approved drugs is rapidly spreading. At the same time, the pipeline of new antimalarial drugs is limited. Phenotypic screens have been valuable in discovering promising lead compounds, but identifying the targets of these compounds is a separate, time-consuming process. Towards overcoming this critical bottleneck in lead compound discovery and optimization, we have combined genetic strategies for conditionally and specifically perturbing essential parasite protein expression with chemical screens to identify functional interactions between compounds and target proteins. In this way, we can simultaneously obtain evidence of a compound's antimalarial activity and its likely mode of action on a rapid timescale. We show that this approach efficiently detects interactions between specific compounds and their targets, and importantly, also allows targets to be ruled out in mode of action studies. We envision this target-based phenotypic screening approach will be scalable, and are integrating it with high throughput screening platforms towards the goal of improving the efficiency with which promising lead antimalarial compounds can be advanced towards clinical translation.
Dr. Niles completed combined medical and graduate school training at Harvard University Medical School and the Massachusetts Institute of Technology. His graduate work focused on chemical characterization of DNA damage products induced by reactive oxygen and nitrogen species towards understanding how these modifications interact with DNA repair and replication mechanisms during carcinogenesis. As an NIH Postdoctoral Fellow at the University of California, Berkeley, he used RNA aptamers as intracellular perturbation tools for interrogating heme homeostasis in model systems and malarial parasites. He is now an Associate Professor at MIT in the Department of Biological Engineering, where his work emphasizes developing broadly enabling functional genetics technologies to achieve robust and facile genomic manipulations in P. falciparum. He uses these tools for both translational applications in antimalarial drug target identification and studying parasite biology. He is a recipient of the NIH Office of the Director New Innovator Award, Bill and Melinda Gates Grand Challenges Award and HHMI-Gates Faculty Scholar Awards. He is currently Co-Director of the Interdisciplinary Microbiology Program and Director of the Center for Environmental Health Sciences at MIT.