Structural studies on Trypanosoma cruzi P21 protein as a strategy for Chagas Disease treatment

Abstract

Cell invasion by the different infective forms of Trypanosoma cruzi, the causative parasite of Chagas disease, involves several mechanisms which culminate in entry of T. cruzi into host cells. Numerous studies have been conducted in order to identify surface proteins related to cell invasion, but mostly from metacyclic and tissue culture trypomastigotes forms. However, little attention has been given to the extracellular amastigote, also capable to invade cells, so that molecules involved in its invasion process still poorly known or studied. These molecules open up the possibility of an alternative life cycle of T. cruzi, which may be significant to its survival under high cytotoxic conditions afforded by the host cells. In this context a new protein, named P21, has been recently identified. Its invasion mechanism cannot yet be explained at molecular level, but experiments suggest that P21 interacts with the CXCR4 chemokine receptor, activating phagocytosis in macrophages and promoting actin polymerization in mammalian cells. This fact, coupled with the knowledge that activation of CXCR4 is strongly dependent on its 38 residues N-terminal peptide (NterCXCR4), opens up a new step towards a therapy based on peptides, which may change the current worldwide scenario on the Chagas disease treatment. This project has two objectives: (I) to determine the three-dimensional structure of the P21 T. cruzi protein by high-resolution Nuclear Magnetic Resonance techniques, aiding to understand how the protein complex fits into the alternative invasion process, (II) to analyze its interaction with inhibitory peptides derived from NterCXCR4, aiming to disrupt its interaction with the CXCR4 as a strategy for the treatment of Chagas disease in the acute and chronic phases of infection. (AU)