Title:Antimalarials Targeting the Malaria Parasite Cation ATPase P. falciparum
ATP4 (PfATP4)
Volume: 23
Issue: 3
Author(s): Agnieszka Zagórska*Anna Jaromin*
Affiliation:
- Department of Medicinal Chemistry, Jagiellonian University Medical College, 30-688, Kraków, Poland
- Department
of Lipids and Liposomes, Faculty of Biotechnology, University of Wrocław, 50-383, Wrocław, Poland
Keywords:
Plasmodium falciparum, Malaria, Antimalarial drugs, Drug resistance, Parasite plasma membrane, PfATP4, Clinical and pre-clinical development, Malaria clinical trials.
Abstract:
Malaria, caused by parasites of the Plasmodium species and transmitted through the bites
of infected female Anopheles mosquitoes, is still a fatal and dangerous disease in mainly tropical
and subtropical regions. The widespread resistance of P. falciparum to antimalarial drugs forces the
search for new molecules with activity against this parasite. While a large number of compounds
can inhibit P. falciparum growth in vitro, unfortunately, only a limited number of targets have been
identified so far. One of the most promising approaches has been the identification of effective inhibitors
of P-type cation-transporter ATPase 4 (PfATP4) in P. falciparum. PfATP4 is a Na+ efflux
pump that maintains a low cytosolic Na+ in the parasite. Thus, upon treatment with PfATP4 inhibitors,
the parasites rapidly accumulate Na+, which triggers processes leading to parasite death.
PfATP4 is present in the parasite plasma membrane but is absent in mammals; its exclusivity thus
makes it a good antimalarial drug target.
The current review presents PfATP4 function in the context of the pharmacological influence of its
inhibitors. In addition, compounds with inhibitory activities belonging to spiroindolones, dihydroisoquinolones,
aminopyrazoles, pyrazoleamides, and 4-cyano-3-methylisoquinolines, are also reviewed.
Particular emphasis is placed on the results of preclinical and clinical studies in which their
effectiveness was tested. PfATP4-associated antimalarials rapidly cleared parasites in mouse models
and preliminary human trials. These findings highlight a fundamental biochemical mechanism
sensitive to pharmacological intervention that can form a medicinal chemistry approach for antimalarial
drug design to create new molecules with potent PfATP4 inhibitory activity.
