Optimization of Cysteine Protease Inhibitors Targeting Trypanosoma Brucei

Sponsor: Drugs for Neglected Diseases Initiative (DNDi)

Location(s): United States


Human African Trypanosomiasis (HAT), also known as African Sleeping Sickness is a parasitic disease that is transmitted through the bite of an infected tsetse fly. The early stages of the disease can include flu-like symptoms and in some cases can include heart abnormalities. During the advance stages of the disease, the parasites enter the brain leading to encephalitis, coma and death. HAT is 100% fatal if left untreated. Most of the exposures to the tsetse fly and therefore the parasite occur in rural populations, which are poor and lack adequate health systems. Currently treatments rely on medications that are toxic, painful, expensive and are becoming ineffective due to parasite resistance. Thus, due to limited health care and poor treatment options, infection typically results in death. Development of effective, safe treatments is desperately needed for this devastating disease.

The CDIPD has had a long-standing interest in the biological function of the trypanosome proteases and we continue to explore proteases as a potential target class as well as to gain better understanding of key trypanosome pathways.

In collaboration with Jack Taunton’s laboratory at UCSF, we have also been probing the biology of several Trypanosoma brucei kinases. Through these efforts we have identified several possible drug targets. We are currently focusing on screening of these kinases, as well as whole parasite screening of kinase inhibitor libraries.

We continue to do a significant amount of whole parasite screening to identify compounds that may be relevant hits for lead development. Compounds with anti-trypansomal activity may also be useful tools to explore parasite biology and identify new targets and pathways of interest. Some of our collaborations in this area include a collaboration in natural products chemistry with Roger Linington at UCSC. This collaboration has continued to identify compounds that may become promising tools and leads. We also are collaborating with researchers at Stanford to test FDA approved compounds for activity against T. brucei with the goal of repurposing for use in treatment of this disease. Finally, we continue to have numerous small collaborations, such as those with Pharmadyn testing focused compound libraries against T. brucei to identify possible new lead series to pursue in our drug development efforts.