Therapeutics/Drugs

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.

Jeffrey Withey of Wayne State University in the U.S. will test whether oral consumption of the unsaturated fatty acid linoleic acid could be used as a simple low-cost therapeutic to block the production of cholera toxin by the bacterium V. cholerae, which causes diarrhea. Linoleic acid could be used as a preventative therapy or as a supplement to the standard treatment of oral rehydration solution to improve recovery time for cholera patients.

Juan Cubillos-Ruiz at Weill Cornell Medical College in the U.S. will develop silica nanopore-based assays to capture unique low molecular weight proteins and identify biomarkers associated with host resistance to HIV. Identifying these biomarkers present in the small proportion of HIV-infected individuals who are able to suppress the virus over the long term could lead to new understanding of the processes mediating HIV resistance and to new therapies against the disease.

Anthony Baughn of the University of Minnesota in the U.S. will test a library of cyclic peptides to identify small molecules that impair the ability of the tuberculosis- causing bacterium M. tuberculosis to develop resistance to current drug therapies, for use in a new class of tuberculosis antibiotics.

Paul de Figueiredo and colleagues at Texas A&M University in the U.S. propose to develop a system whereby drugs for defeating new antibiotic-resistant strains of Mycobacterium tuberculosis can be developed in the laboratory before these strains emerge in human populations.