|Project Theme||Development of anti-trypanosome drugs targeting nucleotides biosynthesis and red-ox regulatory pathways|
|Project Theme (short)||Trypanosome enzyme inhibitors|
|Principal Investigator||Kiyoshi Kita|
|Affiliation||Graduate School of Medical Science, The University of Tokyo|
|Backgrounds||- Trypanosomiases are diseases caused by parasitic protozoan trypanosomes
- A half million people suffer from African trypanosomiasis, sleeping sickness, caused by Trypanosoma brucei, while American trypanosomiasis, Chagas disease, caused by Trypanosoma cruzi causes 21,000 deaths per year in Latin America
- Developments of therapeutic agents for the both diseases are urgently needed
|Highlights||- We could identify compounds that repress the proliferation of T. cruzi based on our structural determinations of DHOD (dihydroorotate dehydrogenase)-inhibitor complexes
- Structures of several enzymes of both T. cruzi and T.brucei have been determined
|Outline|| Trypanosomiases are diseases caused by parasitic protozoan trypanosomes. A half million people suffer from African trypanosomiasis, sleeping sickness, caused by Trypanosoma brucei, while American trypanosomiasis, Chagas disease, caused by Trypanosoma cruzi causes 21,000 deaths per year in Latin America.
Promising target proteins for trypanosomiasis drugs are enzymes in the biosynthesis pathway for the nucleic acids of the protozoa and enzymes in the electron transport pathway of the protozoan cells. Trypanosoma brucei possesses an oxidase TAO which is resistant to the poison cyanide and absent in mammalian cells. Ascofuranone produced by mycotic has been found to inhibit TAO. The fourth enzyme DHOD in the biosynthesis pathway for pyrimidine from which nuecleobases are derived is indispensable for protozoan trypanosomes and thereby one of potential targets.
We would like to accomplish our rational design anti-trypanosomiasis drugs based on accurate structural analyses and computational chemistry.