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

Grazia Camarda, Piyaporn Jirawatcharadech, Richard S. Priestley, Ahmed Saif, Sandra March, Michael H. L. Wong, Suet Leung, Alex B. Miller, David A. Baker, Pietro Alano, Mark J. I. Paine, Sangeeta N. Bhatia, Paul M. O’Neill, Stephen A. Ward and Giancarlo A. Biagini ()
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Grazia Camarda: Liverpool School of Tropical Medicine
Piyaporn Jirawatcharadech: Liverpool School of Tropical Medicine
Richard S. Priestley: Liverpool School of Tropical Medicine
Ahmed Saif: Liverpool School of Tropical Medicine
Sandra March: Massachusetts Institute of Technology
Michael H. L. Wong: University of Liverpool
Suet Leung: University of Liverpool
Alex B. Miller: Massachusetts Institute of Technology
David A. Baker: London School of Hygiene & Tropical Medicine
Pietro Alano: Istituto Superiore di Sanità
Mark J. I. Paine: Liverpool School of Tropical Medicine
Sangeeta N. Bhatia: Massachusetts Institute of Technology
Paul M. O’Neill: University of Liverpool
Stephen A. Ward: Liverpool School of Tropical Medicine
Giancarlo A. Biagini: Liverpool School of Tropical Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-9

Abstract: Abstract 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 H2O2, leading to parasite killing. This detailed understanding of the mechanism paves the way to rationally re-designed 8-aminoquinolines with improved pharmacological profiles.

Date: 2019
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DOI: 10.1038/s41467-019-11239-0

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