High Throughput Assay to Identify New Drugs Against Vivax Malaria Liver Stages
DESCRIPTION (provided by applicant): Plasmodium vivax (Pv) is the 2nd most important human malaria parasite, causing more than 80 million cases annually, and significant severe disease and mortality that were previously unrecognized. Recent data indicate that the impact of Pv malaria on health and economies of the developing world has been dramatically underestimated. Pv is responsible for at least 30% of malaria in U.S. travelers. Efforts to prevent and control Pv malaria have had less than expected success due to emergence of drug resistant strains and repeated relapses from dormant liver stage called the hypnozoite. The international malaria research community has recently emphasized the critical need for increased research on Pv, if there is be successful elimination of this parasite. Modern approaches to development of new drugs against Pv, including hypnozoites are urgently needed. Sanaria is the only laboratory in the world, which has a functional assay in place for studying the effects of drugs against Pv liver stages and inventory of Pv sporozoites (PvSPZ) that can be used in such an assay. Many drug libraries are available for screening, but cannot be screened against Pv, because of lack of a medium or high throughput assay. The goal of this Phase ISBIR is to build on our current assay and inventory of PvSPZ to develop such an assay, initiate the screen for drugs against the liver stages of Pv, including hypnozoites. The long-term goal is to use the system to identify and develop new drugs that willeliminate all Pv liver stage parasites, including hypnozoites. Such drugs will be ideal for chemoprophylaxis of malaria in travelers and for mass-administration to eliminate Pv from defined geographic areas, therefore having both developed- and developing-world markets estimated to exceed 1 billion annually. Specifically we will: 1) Develop a reproducible, consistent, robust system for culturing liver stages of Pv and use it to screen for drugs against the liver stages of Pv. This will include assessing the use of HepG2 cells, primary human hepatocytes (PHH), and induced pluripotent stem cell-derived human hepatocytes (iPSDH) to establish an optimal cell- based screening system. 2) In collaboration with the Bhatia lab at MIT develop a reproducible, consistent, robust system of culturing Pv liver stages for at least 3-6 wks to identify and enrich for hypnozoites and screen drugs for activity against Pv hypnozoites. A micro-patterned co-culture system using PHH or iPSDH is being optimized to attain this goal. 3) In collaboration with the Inglese group at the NIH Chemical Genomics Center (NCGC) use the methods developed in Specific Aims 1 and 2 to screen a 2,500 compound library to identify target compounds with activity against liver stage parasites, including hypnozoites. 4) In collaboration with the Wellems group at NIAID/NIH produce, purify, and cryopreserve at least 2x108 fully infectious PvSPZ. In 2010, in collaboration with the Wellems group, we produced 108 fully infectious PvSPZ. These additional PvSPZwill be used in Phase II to conduct full scale screening of large compound libraries to identify and then characterize and develop lead compounds for development as anti-liver stage drugs. 1 PUBLIC HEALTH RELEVANCE: Plasmodium vivax (Pv) is the 2nd most important human malaria parasite, causing more than 80 million cases annually, and significant severe disease, mortality, and economic impact that were previously unrecognized. Modern approaches to development of new drugs against Pv are urgently needed. The goal of this project is develop an assay system to identify and develop new drugs that will be ideal for chemoprophylaxis of malaria in travelers and for mass-administration to eliminate Pv from a geographic area.
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