Development of Dynamic Combinatorial Libraries for Cruzipain Inhibition

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DESCRIPTION (provided by applicant): This Fogarty International Research Collaboration Award (FIRCA) application has been designed to expand and enhance the parent grant P01 CA78039 (Project PI Wipf, Peter), and to expand and increase the research capacity of the foreign scientist (Dr. Mahler, S. Graciela) and the foreign institution (University of the Republic, Montevideo Uruguay). Specific aims are: 1. Design and synthesis of new scaffolds to generate dynamic combinatorial libraries: (a) using pyrazolotriazinones and aldehydes as building blocks; (b) using new heterocyclic systems with aldehydes as building blocks. 2. Identify compounds with biological significance for Chagas disease: (a) test the libraries using the enzyme cruzipain in order to identify inhibitors by changes in the library distributionor by dynamic deconvolution; (b) compounds showing affinity to cruzipain will be submitted for in vitro cruzipain inhibition; (c) compounds having good inhibition activities will be submitted to a Trypanosoma cruzi growth inhibition assay in vitro, in order to evaluate the trypanocidal activity. The biological assay will be carried out by Prof. Cazzulo at Universidad Nacional de San Martin, San Martin, Provincia de Buenos Aires, Argentina. This proposal and the parent grant thus share common goals related to the development of dynamic combinatorial methodologies to achieve these objectives. Chagas disease, caused by Tripanosoma cruzi, is a major public health problem in Latin America, where it constitutes one of the largest parasitic disease burdens. The treatment of this condition has been controversial, but there is a growing consensus that elimination of T. cruzi could be a prerequisite to arrest the evolution of the disease. Currently available chemotherapy, based on a nifurtimox and benznidazol, is unsatisfactory because of their limited efficacy in the prevalent chronic stage of the disease and their toxic side effects. New approaches to specific chemotherapy are being advanced; biochemical routes like cruzipain-mediated proteolysis have been chemically validated and selective in vitro and in vivo anti-T. cruzi activities of inhibitors of this pathway have been demonstrated. Successful completion of the major aims of this program will provide a new lead in cruzipain inhibition abd open up the possibility to find a new drug-like molecule useful in Chagas disease as well as new exchange reactions useful for the generation of dynamic combinatorial libraries Chagas disease, caused by Tripanosoma cruzi, is a major public health problem in Latin America, where it constitutes one of the largest parasitic disease burdens. The treatment of this condition has been controversial, but there is a growing consensus that elimination of T. cruzi could be a prerequisite to arrest the evolution of the disease.