Departmental Seminar: Dr. Marcus Lee

Event Date: 4.07.2014 Day: Monday Time: 12:00 pm Location: 601 Fairchild Event Type: Departmental

DR. MARCUS LEE
DEPT. OF MICROBIOLOGY AND IMMUNOLOGY
COLUMBIA UNIVERSITY MEDICAL CENTER

Title: “Targeting new pathways in Plasmodium to eliminate malaria”

Host: Dr. Liang Tong

Abstract
As the global malaria burden approaches 200 million infections per year, the single greatest problem facing malaria control efforts is the evolution of drug resistance. The magnitude of the problem can be appreciated by simply considering the numbers and genetic diversity of parasites extant in the human population: a single Plasmodium-infected patient may harbor over 10 billion parasites at any one time. Although current frontline therapies are effective, the threat of resistance has driven efforts to identify novel antimalarial targets. Furthermore, to eliminate malaria, medicines must be developed that are not only curative against the pathogenic asexual blood stage but that prevent the preceding liver stage infection from causing relapses, and that block transmission to the mosquito host of sexual forms known as gametocytes. However there are no known universal, drug-able and chemically validated targets for these multiple malarial life-stages. We have identified a parasite phosphatidylinositol-4 kinase (PfPI4K), a ubiquitous eukaryotic enzyme that modifies cellular lipids to regulate intracellular signaling and trafficking, as a key Plasmodium vulnerability that is the target of imidazopyrazines, a novel class of compound that act across all lifecycle stages. Evolved resistance, full genome scanning, and genome editing experiments, as well as biochemical data, show that imidazopyrazines exert their potent antimalarial activity through interaction with the ATP-binding pocket of this lipid kinase. Inhibiting PfPI4K activity blocks a late step in parasite development by disrupting plasma membrane ingression around developing daughter cells, a likely result of perturbed phosphatidylinositol 4-phosphate (PI4P) pools and disrupted Rab11A-mediated membrane trafficking. Our findings validate PfPI4K as the first drug target that appears to be required across all Plasmodium lifecycle stages, and future directions will exploit this essential pathway to delineate novel drug targets using the proven combination of evolved resistance and genome sequencing.