Therapeutics/Drugs

Reto Brun (Swiss Tropical and Public Health Institute) and Isabel Roditi (University of Bern) in Switzerland seek to identify small molecules that prematurely induce African trypanosomes, which are parasites that cause fatal sleeping sickness, to differentiate into the life stages necessary for transmission of the parasite. Forcing this transformation within the mammalian host could be the basis for new methods to kill trypanosomes, and this concept might be applied to other vector-borne disease .

Ronald Quinn of Griffith University's Eskitis Institute in Australia and colleagues are seeking to discover chemical fragments drawn from a variety of natural sources that bind to proteins expressed by the malaria parasite in its latent stage and the tuberculosis microorganism. In their Phase I and Phase II research, the team is working on identifying compounds that target proteins involved in key metabolic and energy pathways of latency as the basis for new drug therapies.

Antibodies and the complement system work together to specifically detect and clear viruses, but they are circumvented by HIV, which hides itself and the cells it infects by hijacking host proteins such as CD59. Qigui Yu of Indiana University School of Medicine in U.S. will attempt to unmask HIV and HIV-infected cells and render them susceptible to antibody-complement attack. In this project’s Phase I research, Yu and his team identified a potent, specific, and non-toxic inhibitor of human CD59, which is used by HIV to escape destruction by antibody-complement attack.

Manoj Duraisingh of the Harvard School of Public Health in the U.S. will use RNAi screening to identify critical determinants in human red blood cells (erythrocytes) that are required for invasion and growth of the malaria parasite, Plasmodium falciparum. In this project’s Phase I research, Duraisingh’s group developed a RNAi-based approach for genetic analysis of the erythrocyte in vitro, and demonstrated that the major surface protein Glycophorin A is required for efficient invasion by some strains of P. falciparum.

Keith Jerome of the University of Washington in the U.S. will utilize a class of proteins called homing endonucleases, which have the ability to cut DNA sequences, to target the DNA sequences unique to HIV, thus disabling the virus from making any more copies of itself. This project’s Phase I research demonstrated that homing endonucleases can find a model virus hidden in the genes of infected cells. In Phase II, Jerome’s team is now modifying these proteins in hopes of producing several that can specifically target and destroy HIV within infected cells.

Dan Feldheim of the University of Colorado in the U.S. will test his hypothesis that gold nanocrystals coated with drug compounds can effectively inhibit protein-protein interactions that often drive disease pathogenesis, will be less susceptible to evolutionary mechanisms that lead to drug resistance, and offer enhanced drug delivery characteristics. This project’s Phase I research demonstrated that gold nanocrystals can be tailored to circumvent many viral and bacterial evolutionary drug resistance mechanisms.

To fight emergence of drug and vaccine resistance in rapidly evolving parasites, Pradipsinh K. Rathod of the University of Washington in the U.S. will identify the parts of the malaria genome which contribute to rapid increases in mutations, and will screen for small molecules that inhibit these mechanisms. This project’s Phase I research demonstrated that hypermutagenesis does play a strong role in the development of drug resistance.

Xilin Zhao of the University of Medicine and Dentistry of New Jersey will test whether anaerobic gas, which causes rapid depletion of oxygen, will kill the tuberculosis bacteria without permanent damage to surrounding tissue.

An estimated 2 billion individuals - a third of the world's population - have been exposed to Mycobacterium tuberculosis (MTB) and carry the infection in its latent form, retaining a lifelong risk of developing TB disease. Programs to control tuberculosis now focus on childhood vaccination and treatment for people with active disease. Reversing TB's spread, however, requires an intervention that will prevent disease in those who are already infected. The lack of knowledge about the biology of latent TB infection stands in the way of the development of such an intervention. Dr.

Dr. Finlay's team is investigating a new approach to treating bacterial and parasitic infections by enhancing the body's innate defense mechanisms. By acting on the cells of the immune system rather than on the disease-causing microbe directly, investigators expect to lessen the risk of developing drug-resistant organisms and the potential for broad-spectrum activity. The project team is focusing on a number of bacterial and parasitic pathogens, including enteric bacteria, Mycobacterium tuberculosis, and Plasmodium falciparum.