Researchers have taken significant steps in understanding the way that the anti-malarial drug primaquine (PQ) works, which they hope will lead to the development of new, safer and more effective treatments for malaria.
The work, which was predominantly funded following an award from the Medical Research Council, has been carried out by the LSTM's Centre for Drugs and Diagnostic (CDD). The results are published in the journal Nature Communications.
The senior author explained: "The antimalarial primaquine is a cornerstone of global efforts to eliminate malaria, for some 70 years it has been the only drug registered that has been demonstrated to be able to cure relapsing malaria and block transmission of the disease. However, little has previously been understood about the drug's mode of action, which is seriously undermining efforts to improve the safety and pharmacology profile of this important drug class."
The team was able to replicate the interaction between the drug and the host enzymes which catalyse the generation of cytotoxic amounts of hydrogen peroxide from metabolites of PQ. The experiments were able to demonstrate why the drug displays exquisite selectivity against specific parasite stages and also explains why only very small (nM) catalytic concentrations of metabolites are necessary to kill the parasites.
PQ requires hepatic metabolism to exert activity against gametocyte stages. The authors 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.
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.
The search for new antimalarials is vital in the drive towards global malaria elimination, especially given that PQ is potentially lethal to people with the genetic disorder glucose-6-phoshate dehydrogenase (G6PD) deficiency, which affects millions of people in malaria-endemic countries.
"This is why an understanding of how the drug works is central to replicating its most significant elements," continued the senior author.
Mechanism of action of the anti-malarial drug, primaquine
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