The overall aim and long-term objective of this project is to design and synthesis anti-protozoal compounds that maybe clinically useful, based on the inhibition of the protozoal enzyme trans-sialidase of Trypanosoma cruzi. and the sialidase of Cryptosporidium parvum. A number of significant disease sates are caused by protozoa for example, Chagas' disease, eimeriosis and African sleeping sickness, and cryptosporidiosis. The overall aim will be achieved by addressing a number of scientific questions including, what is the mechanism of catalysis, what is the minimal pharmacophore, what functional groups on the sialic acid can be manipulated to enhance binding affinity. The methods to be used in answering these questions are derived from a combination of sciences including organic synthesis, computational chemistry, NMR spectroscopy, and biochemistry. Specifically, the synthesis of modified substrates and pseudo-substrates will be undertaken so as to afford a structure-activity relationship from which a minimal pharmacophore can be developed. Inhibitors, designed by molecular modelling studies, will be then prepared and evaluated for biological activity. In parallel the mechanism of catalysis will be investigated by standard biochemical methods such as kinetic isotope effect experiments and pH studies. NMR spectroscopy will also be used too elucidate the mechanism of catalysis through a range of experiments on both labelled and unlabelled substrates. In effect a solution-based picture of the products of reaction or binding mode of substrate may be gained from such studies. The methods described above have been used by us in the discovery of anti-influenza drugs which target influenza virus sialidase and one of these drug candidates is presently inhuman clinical trials.
| Takano-Lee, Miwako; Edman, John D (2002) Lack of manipulation of Rhodnius prolixus (Hemiptera: Reduviidae) vector competence by Trypanosoma cruzi. J Med Entomol 39:44-51 |
| Takano-Lee, Miwako; Edman, John D; Herrera, Enrique M et al. (2002) Parasite polymorphism may serve to enhance fitness in different host environments. Vector Borne Zoonotic Dis 2:29-36 |
| Chuenkova, M; Pereira, M; Taylor, G (1999) trans-sialidase of Trypanosoma cruzi: location of galactose-binding site(s). Biochem Biophys Res Commun 262:549-56 |
| Pereira, M E; Zhang, K; Gong, Y et al. (1996) Invasive phenotype of Trypanosoma cruzi restricted to a population expressing trans-sialidase. Infect Immun 64:3884-92 |
