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.

Details

Title
Antimalarial activity of primaquine operates via a two-step biochemical relay
Author
Camarda, Grazia 1 ; Jirawatcharadech, Piyaporn 1 ; Priestley, Richard S 2   VIAFID ORCID Logo  ; Saif, Ahmed 3 ; March, Sandra 4 ; Wong, Michael H L 5   VIAFID ORCID Logo  ; Leung, Suet 5 ; Miller, Alex B 4 ; Baker, David A 6   VIAFID ORCID Logo  ; Alano, Pietro 7 ; Paine, Mark J I 8   VIAFID ORCID Logo  ; Bhatia, Sangeeta N 4 ; Paul M O’Neill 5 ; Ward, Stephen A 1 ; Biagini, Giancarlo A 1   VIAFID ORCID Logo 

1  Centre for Drugs and Diagnostics Research, Tropical Disease Biology Department, Liverpool School of Tropical Medicine, Liverpool, UK 
2  Centre for Drugs and Diagnostics Research, Tropical Disease Biology Department, Liverpool School of Tropical Medicine, Liverpool, UK; ARUK Oxford Drug Discovery Institute, University of Oxford, Oxford, UK 
3  Centre for Drugs and Diagnostics Research, Tropical Disease Biology Department, Liverpool School of Tropical Medicine, Liverpool, UK; Clinical Laboratory sciences Department, College of Applied Medical Sciences, Najran University, Najran, Saudi Arabia 
4  Health Sciences and Technology/Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA 
5  Department of Chemistry, University of Liverpool, Liverpool, UK 
6  Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK 
7  Dipartimento di Malattie Infettive, Istituto Superiore di Sanità, Rome, Italy 
8  Vector Biology Department, Liverpool School of Tropical Medicine, Liverpool, UK 
Pages
1-9
Publication year
2019
Publication date
Jul 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-11239-0
ProQuest document ID
2260417100
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.