UMYMFOR   05516
UNIDAD DE MICROANALISIS Y METODOS FISICOS EN QUIMICA ORGANICA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Drug Design and Discovery for Chagas' Disease
Autor/es:
RODRIGUEZ, JUAN BAUTISTA
Lugar:
Trieste, Italia
Reunión:
Conferencia; International Conference Drug Design and Discovery for Developing Countries; 2008
Institución organizadora:
International Centre for Science and High Technology ICS UNIDO
Resumen:
Trypanosoma cruzi is the hemoflagellated protozoan parasite that causes American trypanosomiasis (Chagas' disease), which is an endemic disease widespread from southern United States to southern Argentina. In addition, Chagas' disease is a well-recognized opportunistic infection in AIDS patients. It has been estimated that close to 18 million people are infected and over 40 million are at risk of infection by T. cruzi. Chemotherapy for Chagas' disease is still unsatisfactory. The two drugs available for Chagas’ disease treatment, nifurtimox (now discontinued), and benznidazole are associated to long-term treatment and severe side effects. One pathway that has been particularly useful for the identification of new targets against T. cruzi is the isoprenoid pathway. Enzymes studied so far that are involved in the synthesis of sterols and farnesyl diphosphate, and in protein prenylation, have been reported to be excellent drug targets against pathogenic parasites such as farnesyl pyrophosphate synthase (FPPS). Another interesting pathway is trypanothione biosynthesis. Trypanothione is the bisconjugated product between the tripeptide glutathione and the polyamine spermidine: N1,N8-bis-(L-g-glutamyl-L-cysteinylglycyl)spermidine. The uniqueness of this metabolite and its biosynthetic pathway in parasites of the order Kinetoplastida, confer to the involved enzymes of its biosynthesis a great usefulness as a molecular target. Because of the absence of this metabolite in the host mammalian cells, there is an opportunity to design highly selective antiparasitic drugs against leishmaniasis and trypanosomiases without toxic effects. Bearing in mind our hypothesis that the isoprenoid pathway and trypanothione biosynthesis constitute major targets for the treatment of Chagas' disease and other tropical diseases, we have investigated the effect of bisphosphonates (pyrophosphate analogues) derived from fatty acids against T. cruzi FPPS and SPPS, and in vitro against T. cruzi, and perform structure-activity relationship studies to assist drug design. In addition, we have studied the effect of aryloxyethyl thiocyanate derivatives against T. cruzi squalene synthase (TcSQS), and also against T. cruzi cells taken 4-phenoxyphenoxyethyl thiocyanate as a lead drug. Finally, we have designed, synthesized and evaluated a series of phosphinopeptides structurally related to glutathione as antiproliferative agents against T. cruzi. The rationale for the synthesis of these compounds was supported on the basis that the presence of the phosphinic acid moiety would mimic the tetrahedral transition state of trypanothione synthase (TryS). It has been recently confirmed that the mentioned phosphinopeptides inhibited the enzymatic activity of TryS.