Protein kinases are key mediators of translation signals, transmitting interpretations of the environment and coordinating intracellular processes. Among serine/threonine kinases, of particular interest, there is the family of trypanosomatids Neks, involved in diverse cellular functions. Their large number in trypanosomatids suggests that some may have unique functions in these organisms. The trypanosomatids are parasites of both invertebrates and vertebrates and some species are etiological agents of human diseases that pose as public health problem in tropical countries, such as Chagas disease, caused by Trypanosoma cruzi, and Leishmaniasis, caused by Leishmania species. Although the role of Nek kinases is of broad interest, little is known about the basic mechanism in protists. Because protein kinases are directly involved in proliferation and/or feasibility stages of the parasites' life cycle, its study as potential drug targets is interesting. However, drugs currently in use have been developed decades ago and have serious side effects and resistance for many patients, indicating the need for development of effective, cheap and safe new substances for the treatment of leishmaniasis and Chagas' disease. Thus, this project aims to structurally characterization by crystallographic and biophysical methods as well as select potential inhibitors to NEK kinases of L. braziliensis. These information at atomic level are essential to a better understanding of physiological functions and mechanisms of NEK kinases in parasites and strictly necessary for studies of search and drug design. High-throughput approaches such as differential scanning fluorometry (DSF) will be used in searching for potential ligands and analytical techniques such as enzyme kinetics and isothermal titration calorimetry to characterize the interactions. Once identified, the ligands will be taken for screening in vitro and in vivo to assess the effect of these drugs on the parasite.
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