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

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Camarda, Grazia, Jirawatcharadech, Piyaporn, Priestley, Richard, Saif, Ahmed, March, Sandra, Wong, Michael H. L., Leung, Suet, Miller, Alex, Baker, David A., Alano, Pietro, Paine, Mark ORCID: https://orcid.org/0000-0003-2061-7713, Bhatia, Sangeeta N., O'Neill, Paul M., Ward, Steve ORCID: https://orcid.org/0000-0003-2331-3192 and Biagini, Giancarlo ORCID: https://orcid.org/0000-0001-6356-6595 (2019) 'Antimalarial activity of primaquine operates via a two-step biochemical relay'. Nature Communications, Vol 10, p. 3226.

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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.

Item Type: Article
Subjects: QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 258 Primaquine. Quinacrine
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 765 Prevention and control
Faculty: Department: Biological Sciences > Department of Tropical Disease Biology
Biological Sciences > Vector Biology Department
Digital Object Identifer (DOI): https://doi.org/10.1038/s41467-019-11239-0
Depositing User: Martin Chapman
Date Deposited: 22 Jul 2019 13:03
Last Modified: 22 Jul 2019 13:03
URI: https://archive.lstmed.ac.uk/id/eprint/11093

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