Infectious Disease

Joseph DeRisi of the University of California, San Francisco in the U.S. will generate a strain of apicoplast-free P. falciparum parasites to identify anti-malarial compounds from the Malaria Box that specifically target this organelle, which is essential for malaria parasite survival.

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.

Manuel Llinás of Pennsylvania State University in the U.S. will characterize the 400 candidate anti-malarial compounds in the so-called "Malaria Box" by mass spectrometry to help select those likely to be the most effective drugs for clinical development. The Malaria Box is a collection of compounds that display some anti- parasitic activity, but how they work and whether they would make valuable new anti-malarial drugs are unknown. They will analyze red blood cells infected with the malarial parasite P.

Dyann Wirth of the Harvard School of Public Health in the U.S. is building a platform to identify combinations of anti-malarial compounds that inhibit the development of drug resistance, which is a major barrier to combatting the disease. Their approach involves predicting how the Plasmodium falciparum malaria parasite will evolve to become resistant to a specific anti-malarial compound, and then designing a second compound that will target these resistant parasites.

Koen Dechering of TropIQ Health Sciences in the Netherlands is developing a high-throughput functional assay to identify new compounds that specifically block transmission of the malaria parasites to their vector hosts, which is a difficult stage to target, and to test candidate drugs. The assay incorporates luciferase- expressing parasites, which emit light as they develop in the mosquito midgut, along with barcoded chemical libraries.

Ronald Quinn of Griffith University in Australia will use anti-malarial compounds as probes to trap protein targets. Mass spectrometry followed by electron capture dissociation (ECD) and electron-transfer dissociation (ETD) will be used to identify individual binding domains between the anti-malarial compounds in the Malaria Box and the malaria parasite proteome that can be used as specific drug targets.

Marek Cyrklaff of the University of Heidelberg in Germany seeks to test whether the protection against malaria seen in individuals with sickle cell anemia is caused by increased hemoglobin oxidation in sickle cells, and whether this can be transferred to healthy human blood cells to produce the same effect. Screening of the anti- malarial compounds in the Malaria Box for oxidative activity will determine if they could be used for malaria protection.

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.

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.

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.