Impacts of Cipargamin on Na+-ATPase and Osmoregulation of Trypanosoma cruzi

The subfamily ENA of the P-ATPases family transports Na+ and H+ in opposite directions and, for this reason, they are called Na+-ATPases. They are physiologically important at high pH and high salt conditions in which other Na+ transporters cannot operate. This is the case, for example, of Aspergilus and Arabidopsis, respectively. Since, during their lifecycle, the parasitic protozoa face alkaline and/or high-saline environments, we postulated that the ENA subfamily could be a target for the treatment of serious and common illnesses driven by parasitic protozoa, as in the case of Chagas disease. The subgroup ATP4 ATPases, which is found in Plasmodium falciparum and Toxoplasma gondii, can be compared —through phylogenetic analysis—with the classic IID P-type ENA subfamily. Thus, some drugs that target PfATP4 ATPase and affect Na+ homeostasis are undergoing clinical trial, including spiroindolones. ENA-type ATPases (P-type ATPase IID) and ATP-type ATPase do not have structural homologs in mammals, appearing only in plants, fungi, and protozoan parasites, such as Trypanosoma cruzi, Leishmania sp., T. gondii, and P. falciparum. Therefore, this exclusivity points to Na+-ATPases as promising targets for medical projects aiming at new treatments contributing to the academic community.