STRUCTURE/FUNCTION OF PROTOZOAN SIALIDASES

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Trypanosoma cruzi is the etiological agent of Chagas, a chronic debilitating incurable disease afflicting millions of people in Latin America. Cryptosporidium parvum causes gastrointestinal illness in both immunocompetent and immunodeficient people, in particular those with AIDS, where infection can be unrelenting and fatal. Both T. cruzi and C. parvum express a protein with sialidase (SA) activity. T. cruzi SA has the ability to transfer sialic acid to galactose acceptors and thus is a trans-sialidase (TS). A large body of evidence suggest that TS is an important mediator of T. cruzi-host interactions, as it promotes trypanosome attachment to mammalian cells and potently enhances virulence in vivo. Cryptosporidium also expresses SA in two infective stages, sporozoites and merozoites. Cryptosporidium SA is immunologically related to the T. cruzi enzyme and it may play role in the genesis of diarrhea. This program project brings together top world experts in various fields with the common goal of upping understanding of the structure and function of the sialidases of T. cruzi and Cryptosporidium. Studies on the biology of TS in mammals will be performed by the principal investigator of New England Medical Center, Boston, the same site where Dr. Honorine Ward will molecularly characterize the cryptosporidium enzyme, which was recently discovered in her laboratory. Biological studies in the insect vector of T. cruzi will be done by Dr. John Edman in the University of Massachusetts, Amherst. Tridimensional structure and kinetic analysis will be carried out by Dr. Garry Taylor at Bath University, England. And synthesis of sialidase inhibitors based in molecular modeling and structural analysis will be performed at Monash University, Australia, by Dr. Mark von Itzstein, who, for the sake of this project, already synthesized sialic acid derivatives that are active against TS. Biological properties of the inhibitors will be assayed in Boston. A Scientific Advisory Committee made of three internationally celebrated authorities in the structure, biology, and molecular biology of carbohydrates and sialic acid-binding proteins (Drs. Don Wiley, Stephen Beverly, and Roland Schauer) will counsel the principal investigator and monitor progress of the proposed research. The committee and the investigators will meet once a year in Boston. Therefore, the program project should provide insights into the structure and biology of the sialidases expressed by parasites that cause two important diseases of mankind. It may also yield a chemotherapeutic agent to treat these diseases, as similar studies lead to the discovery of inhibitors of influenza virus sialidase (by Dr. Itzstein), currently in clinical trials in many parts of the world, including the United States.