Malaria

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.

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.

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.

Brad Stone of the Benaroya Research Institute in the U.S., along with Sean Murphy of the University of Washington, will produce large and complex "mini-gene" libraries of DNA fragments encoding thousands of peptides from malaria parasite proteins, and use them for rapid production and testing of complex malaria vaccine formulations.

Thomas Neumann of Nortis, Inc. in the U.S. will develop a tissue-engineered model of the mosquito midgut for use in an in vitro assay on a disposable, chip-like microfluidic device. This device could be developed into a standardized and automated platform to screen anti-malarial compounds that target the parasite in the mosquito before transmission to human hosts.