The malaria parasite cation ATPase PfATP4 and its role in the mechanism of action of a new arsenal of antimalarial drugs

• Published in: International journal for parasitology -- drugs and drug resistance Vol. 5; no. 3; pp. 149 - 162
• Main Authors: Spillman, Natalie Jane, Kirk, Kiaran
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2015; Elsevier
• Subjects: Antimalarial; Antimalarials - pharmacology; Calcium-Transporting ATPases - genetics; Calcium-Transporting ATPases - metabolism; Cipargamin; Drug discovery; Erythrocytes - metabolism; Erythrocytes - parasitology; Gene Expression Regulation, Enzymologic - drug effects; Humans; Invited Review; Malaria, Falciparum - drug therapy; Malaria, Falciparum - parasitology; PfATP4; Plasmodium; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Resistance selection; Plasmodium; Antimalarial; PfATP4; Drug discovery; Resistance selection; Cipargamin
• ISSN: 2211-3207; 2211-3207
• DOI: 10.1016/j.ijpddr.2015.07.001

The intraerythrocytic malaria parasite, Plasmodium falciparum, maintains a low cytosolic Na+ concentration and the plasma membrane P-type cation translocating ATPase ‘PfATP4’ has been implicated as playing a key role in this process. PfATP4 has been the subject of significant attention in recent years as mutations in this protein confer resistance to a growing number of new antimalarial compounds, including the spiroindolones, the pyrazoles, the dihydroisoquinolones, and a number of the antimalarial agents in the Medicines for Malaria Venture's ‘Malaria Box’. On exposure of parasites to these compounds there is a rapid disruption of cytosolic Na+. Whether, and if so how, such chemically distinct compounds interact with PfATP4, and how such interactions lead to parasite death, is not yet clear. The fact that multiple different chemical classes have converged upon PfATP4 highlights its significance as a potential target for new generation antimalarial agents. A spiroindolone (KAE609, now known as cipargamin) has progressed through Phase I and IIa clinical trials with favourable results. In this review we consider the physiological role of PfATP4, summarise the current repertoire of antimalarial compounds for which PfATP4 is implicated in their mechanism of action, and provide an outlook on translation from target identification in the laboratory to patient treatment in the field. [Display omitted] •PfATP4 is proposed to function as a Na+/H+-ATPase, regulating parasite Na+.•There is evidence that multiple, unrelated chemical classes target PfATP4.•One such compound, cipargamin, exhibited promising results in Phase II trials.•The precise mechanism by which such compounds kill parasites remains unclear.