Antimalarial activity of primaquine operates via a two-step biochemical relay

• Published in: Nature communications Vol. 10; no. 1; pp. 3226 - 9
• Main Authors: Camarda, Grazia, Jirawatcharadech, Piyaporn, Priestley, Richard S., Saif, Ahmed, March, Sandra, Wong, Michael H. L., Leung, Suet, Miller, Alex B., Baker, David A., Alano, Pietro, Paine, Mark J. I., Bhatia, Sangeeta N., O’Neill, Paul M., Ward, Stephen A., Biagini, Giancarlo A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.07.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 14/19; 631/154/436/2388; 631/326/22/1294; 692/699/255/1629; 9/10; Aminoquinolines; Aminoquinolines - pharmacology; Antimalarial activity; Antimalarial agents; Antimalarials - pharmacology; Bone marrow; Bone Marrow - metabolism; CYP2D6 protein; Cytochrome P-450 CYP2D6 - metabolism; Cytochrome P-450 Enzyme System; Cytochrome P450; Cytochromes P450; Direct reduction; Dose-Response Relationship, Drug; Effectiveness; Gametocytes; Humanities and Social Sciences; Humans; Hydrogen peroxide; Hydrogen Peroxide - metabolism; Liver; Liver - metabolism; Malaria, Falciparum - drug therapy; Metabolites; Mode of action; multidisciplinary; NADP; Oxidoreductase; Parasites; Pharmacokinetics; Pharmacology; Plasmodium falciparum; Plasmodium falciparum - drug effects; Primaquine; Primaquine - metabolism; Primaquine - pharmacology; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11239-0

Primaquine (PQ) is an essential antimalarial drug but despite being developed over 70 years ago, its mode of action is unclear. Here, we demonstrate that hydroxylated-PQ metabolites (OH-PQm) are responsible for efficacy against liver and sexual transmission stages of Plasmodium falciparum . The antimalarial activity of PQ against liver stages depends on host CYP2D6 status, whilst OH-PQm display direct, CYP2D6-independent, activity. PQ requires hepatic metabolism to exert activity against gametocyte stages. OH-PQm exert modest antimalarial efficacy against parasite gametocytes; however, potency is enhanced ca.1000 fold in the presence of cytochrome P450 NADPH:oxidoreductase (CPR) from the liver and bone marrow. Enhancement of OH-PQm efficacy is due to the direct reduction of quinoneimine metabolites by CPR with the concomitant and excessive generation of H 2 O 2 , leading to parasite killing. This detailed understanding of the mechanism paves the way to rationally re-designed 8-aminoquinolines with improved pharmacological profiles. Primaquine (PQ) is a widely used anti-malaria drug, but its mechanism of action is unclear. Here, Camarda et al. show that PQ’s activity against liver and sexual Plasmodium stages depends on generation of hydroxylated-PQ metabolites (OH-PQm), which, undergoing further reactions, results in production of H 2 O 2 .