Plasmodium falciparum ATP4 inhibitors to treat malaria: worthy successors to artemisinin?

• Published in: The Lancet infectious diseases Vol. 20; no. 8; pp. 883 - 885
• Main Authors: Ashley, Elizabeth A, Phyo, Aung Pyae
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01.08.2020; Elsevier Limited
• Subjects: Adenosine triphosphatase; Allergic reactions; Artemisinin; Artesunate; Cations; Creatine; Creatine kinase; Drug dosages; Fatalities; Half-life; Homeostasis; Hypersensitivity; Infectious diseases; Inhibitors; Insecticide resistance; Insecticides; Malaria; Minimum inhibitory concentration; Mutation; Parasites; Pharmacokinetics; Plasmodium falciparum; Sodium; Studies; Vector-borne diseases
• ISSN: 1473-3099; 1474-4457; 1474-4457
• DOI: 10.1016/S1473-3099(20)30139-0

Progress in controlling malaria has slowed in recent years and the annual death toll remains above 400 000 globally, with most deaths caused by Plasmodium falciparum.1 The joint threats of increasing resistance to insecticides, artemisinin derivatives, and almost all other antimalarials in current use make the development of new classes of antimalarials a high priority. Studies done over the past 10 years have identified the malaria parasite cation ATPase P falciparum ATP4 as a promising target for novel antimalarials by phenotypic screening.2 It plays a role in maintaining low intracellular sodium cation concentrations in P falciparum.3 Inhibition of P falciparum ATP4 disrupts sodium ion homeostasis and is lethal for the parasite. Artefenomel Artesunate before 2008* Artesunate after 2008 Cipargamin Ganaplacide SJ733 (600 mg dose) Drug class Synthetic trioxolane Artemisinin derivative Artemisinin derivative Plasmodium falciparum ATP4 inhibitor Imidazolopiperazine P falciparum ATP4 inhibitor Median parasite clearance half-life (h)† 3·6 3·2 5·3 0·9 3·5 3·6 Mean terminal elimination half-life (h) 62·3 (for 400 mg cohort) <1 <1 20·8 40·8 17·4 (median value) Adverse events Raised creatine phosphokinase concentrations Allergic reactions (<1 in 3000) Allergic reactions (<1 in 3000) Raised aminotransferase concentrations Raised aminotransferase concentrations Raised aminotransferase concentrations Resistance P falciparum kelch13 mutations P falciparum kelch13 mutations P falciparum kelch13 mutations P falciparum ATP4 mutations P falciparum carl mutations P falciparum ATP4 mutations Mean minimum inhibitory concentration (ng/mL) 4·1 2·2 2·2 0·1 58 122 Table Characteristics of SJ733 compared with other fast-acting antimalarial drugs