Awards

Ralph Mazitschek of the Massachusetts General Hospital in the U.S. will explore whether inhibitors of tRNA-synthetases, which are enzymes that are essential for survival of the malaria parasite, are effective antimalarial drugs. New classes of drugs that work in different ways are urgently needed because current antimalarials can induce clinical resistance rendering them ineffective. Once they have developed an assay to measure tRNA-synthetase inhibition, it will be used to screen a compound library including the 400 antimalarial compounds in the so-called Malaria Box collection to identify selective inhibitors for further testing.

Gregory Goldgof, Elizabeth Winzeler and colleagues from the University of California, San Diego in the U.S. have developed a drug-sensitive yeast strain by deleting the main multi-drug export pumps to help identify the mechanisms of action of the 400 next-generation anti-malarial drug candidates in the Malaria Box. This will help optimize drug safety and efficacy for clinical trials. In Phase I, they successfully screened the Malaria Box compounds and identified 30 that were active in their assay. They also performed directed evolution studies by exposing the yeast to increasing sublethal concentrations of 21 of the active compounds. Resistant yeast clones were then sequenced to identify the likely molecular targets. In Phase II, they will exploit the same yeast strain to identify targets for compounds with activity specifically against either the liver stage of the malaria parasite, which could be used to cure infected patients, or the gametocyte stage, which could reduce the rate of malaria transmission. Their approach is particularly valuable for these types of compounds as they cannot be used for directed evolution studies in the malaria parasites themselves.

Choukri Ben Mamoun of Yale University in the U.S. will employ optogenetics technology to identify antimalarial compounds in the so-called Malaria Box collection that specifically target membrane biogenesis in the parasite Plasmodium falciparum, which transmits the disease. Compounds targeting membrane biogenesis are known to inhibit both infection and transmission, as well as potently inhibiting drug-resistant parasites, which are becoming increasingly common. The optogenetics approach involves genetically engineering parasites to carry lipid biosensors composed of a fluorescent protein that can bind to a specific membrane phospholipid. Levels of phospholipids can then be monitored and quantified in the presence of a drug to identify those that affect membrane biogenesis.

Kirsten Hanson from the Instituto de Medicina Molecular in Portugal has developed a screening strategy to identify compounds that specifically block the final maturation stage of the malaria-causing Plasmodium parasite that occurs in human liver. These compounds could prevent the symptoms and establishment of malaria in humans (i.e. act as prophylactics), and block transmission back to the mosquitoes. In addition, high antigen levels will result from drug-killed late liver-stage parasites in humans that could act like a vaccine and provide immune protection against subsequent infected mosquito bites. In Phase I, they developed an assay suitable for high-throughput screens to quantify late Plasmodium liver-stage development in vitro using Plasmodium berghei infection of HepG2 hepatoma cells, and screened the 400 compounds in the Malaria Box, identifying nine hits (compounds that specifically disrupt late liver-stage development according to their assay). In Phase II, they are modifying their criteria for defining a compound as a hit in order to identify those most likely to act as a chemoprophylactic and provide protective immunity in humans, and will perform high-throughput screens using additional compound libraries with candidate hits being tested first in a rodent malaria model.

Sangeeta Bhatia of the Massachusetts Institute of Technology in the U.S. will analyze the 400 compounds with antimalarial activity in the Malaria Box to identify those that might inhibit the efficacy of drugs used to treat HIV and tuberculosis (TB) when administered to the same person. They will use their in vitro human microliver model, which consists of organized liver and stromal cells, in a low-cost, scalable and high-throughput assay to determine the effect of the antimalarial compounds on the expression of a broad panel of human metabolizing enzymes. These data will help to predict drug performances of anti-malarials, anti-HIV, and anti-TB regimens and prioritize the development of drug candidates.

Michael Klemba of Virginia Polytechnic Institute and State University in the U.S. will identify anti-malarial compounds from the Malaria Box that function as inhibitors of the cytostomal endocytic pathway used by the malaria parasite P. falciparum to internalize host erythrocyte proteins. Characterizing the molecular mechanisms of this process could lead to the discovery of new anti-malarial compounds.

Jacquin Niles of the Massachusetts Institute of Technology in the U.S. is developing a method to switch individual genes on and off in the malaria-causing parasite Plasmodium falciparum for evaluating candidate and existing antimalarial drugs. In Phase I, they built and tested a scalable TetR-aptamer system for rapidly and easily manipulating gene expression in the parasite genome, and showed that it could be used to validate the target of a 4-aminoquinoline antimalarial drug. In Phase II they will use the system to produce a reference panel of over 150 stable parasite lines in which target genes of interest can be conditionally regulated. This resource, which can be expanded, will be valuable for investigating basic parasite biology as well as for drug development. They will use these lines to screen known and candidate antimalarial compounds to identify their targets and help improve their activity.

Daniel Irimia and Anh Hoang of Massachusetts General Hospital in the U.S. seek to develop a microfluidic device that can be used to screen anti-malarial drugs for the development of drug resistance with single cell resolution. The device will be validated using a subset of anti-malarial compounds from the Malaria Box. The ability to monitor single cells for resistance will greatly reduce the time needed to screen drugs for acquired resistance, allowing for much earlier and more accurate assessment of effective drugs to control and eradicate malaria.

David Sullivan of the Johns Hopkins Bloomberg School of Public Health in the U.S., along with Martin N. Martinov of Gradient Biomodeling LLC, will create a quantum physics computer model of liver-stage malaria parasite infection to screen existing commercial drug and compound databases to identify molecules that possess liver-stage specific anti-malarial activity. Those molecules will then be tested in vivo and in vitro, and the ones that are effective will be optimized via computer modeling for future pre-clinical development.

Choukri Ben Mamoun of Yale University in the U.S. will work to provide proof-of-principle that a new technology for down-regulating the expression of genes in the malaria-causing parasite P. falciparum can be used to identify specific drug targets. Antimalarial compounds in the Malaria Box will be screened against altered parasite strains to determine modes of action and to identify specific cellular targets to be pursued in future drug development.