Inhibitors of Cruzain as Therapeutic Leads for Chagas Disease
Cruzain is a key cysteine protease in Trypanosoma cruzi (T. cruzi); it is essential for the parasite survival and replication, and has been validated as a drug target for this organism. T. cruzi, a protozoan parasite, is the causative agent of Chagas disease. This is a major neglected tropical disease affecting over 16 million people, primarily in Central and South America. Discovering novel inhibitors of cruzain and determining their enzyme-bound structures is expected to provide a platform for drug-discovery efforts against this resistance target. This probe exhibits potent near-stoichiometric inhibition of cruzain and should be useful as both a potent effector of the enzyme in vitro and as a starting point for development of anti-trypanosomal agents. The majority of current advanced cruzain inhibitors act via irreversible covalent inhibition, such as the probe detailed within. Our probe acts via reversible covalent inhibition, and to the best of our knowledge, we provide the first co-crystallization of nitrile-based inhibitor to cruzain.
National Center for Advancing Translational Sciences
Anton Simeonov, Ph.D.
Bryan Mott, M.S.
Ganesha Rai, Ph.D.
David Maloney, Ph.D.
University of California, San Francisco
Brian Shoichet, Ph.D.
Public Health Impact
The chemical probes developed in this project serve as starting points for drug development to combat Chagas disease, a major neglected tropical disease affecting over 16 million people. The compound targets the protozoan parasite Trypanosoma cruzi, which causes the devastating disease. The compound acts as a reversible covalent inhibitor of the cysteine protease cruzain.
Mott BT, Ferreira RS, Simeonov A, et al. Identification and optimization of inhibitors of Trypanosomal cysteine proteases: cruzain, rhodesain, and TbCatB. J Med Chem, 2010;53;52-60.
Ferreira RS, Simeonov A, Jadhav A, et al. Complementarity between a docking and a high-throughput screen in discovering new cruzain inhibitors. J Med Chem, 2010;8;53:4891-4905.
Jadhav A, Ferreira RS, Klumpp C, et al. Quantitative analyses of aggregation, autofluorescence, and reactivity artifacts in a screen for inhibitors of a thiol protease. J Med Chem, 2010;53:37-51.
Taking Aim at Trypanosomes. February 2010.