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 <i>Aspergilus</i> and <i>Arabidopsis</i>, 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 <i>Plasmodium falciparum</i> and <i>Toxoplasma gondii</i>, 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 <i>Trypanosoma cruzi</i>, <i>Leishmania</i> sp., <i>T. gondii</i>, and <i>P. falciparum</i>. Therefore, this exclusivity points to Na⁺-ATPases as promising targets for medical projects aiming at new treatments contributing to the academic community.