Therapeutics/Drugs

Nigel Yarlett of Pace University in the U.S. will determine whether a virus that infects the intestinal parasite Cryptosporidium is a valuable target for developing drugs against the associated chronic diarrheal disease, which causes substantial morbidity and mortality in young children in low-resource settings. The double-stranded RNA Cryspoviruses are not harmful to the parasite, and instead likely enhance the parasite's ability to infect and harm humans.

Gregory Goldgof and Elizabeth Winzler of the University of California, San Diego in the U.S. will use a genetically modified drug-sensitive yeast strain to quickly and inexpensively identify the cellular target of compounds that can kill the parasite Cryptosporidium, which is a major cause of diarrhea-associated deaths of young children in developing countries. Currently, there is only one treatment available and it is of limited use in some of the more severe cases. The yeast strain has been modified to lack transporter proteins that remove toxic compounds from the yeast cells.

James Nataro of the University of Virginia in the U.S. is developing new mouse models of environmental enteric dysfunction (EED) to explore how enteric pathogens commonly found among children in developing countries can affect intestinal function and cause growth retardation. In Phase I, they developed mouse models for five of the common pathogens and found that, as in humans, malnutrition (protein or zinc deficiency) enhanced the severity of infection, associated growth retardation, or the presence of intestinal inflammation.

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.

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.

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.

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.

Robert Abramovitch of Michigan State University in the U.S. will use their high-throughput drug discovery platform to identify new drugs for treating chronic tuberculosis and for potentially shortening the current treatment time of six to nine months. Their platform exploits a genetic region known as the DosR regulon thought to underlie the behavior of the causative bacteria in humans under low oxygen conditions, when they become dormant and thereby resistant to current drugs.

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.

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.