MICA: Defining the two-step relay mechanism of action of the 8-aminoquinolines: A precondition for optimal combination therapies for relapse malaria

The 8-aminoquinolines (8AQs) that include primaquine (PQ) and tafenoquine (TQ), are the only licensed drugs capable of treating relapse malaria. TQ possesses improved pharmacokinetic properties over PQ and is likely to replace PQ in future treatment regimens. However it is very significant, that a recent Phase III trial of TQ + dihydroartemisinin-piperaquine for the radical cure of P. vivax, failed to demonstrate the prevention of relapses. This observation raises a major public health issue for future deployment of TQ in countries where ACTs are standard therapy. It has been recently shown that the MoA of PQ operates via a two-step biochemical relay. Step 1 of the MoA relates to the metabolic generation of redox-active metabolites, whilst Step 2 describes the mechanism by which redox-active metabolites exert parasite killing. In an expansion of this model to include TQ and other 8-AQs, it is hypothesised that there is convergence amongst 8-AQs for step 2 and that parasite killing occurs as a result of H2O2 production, via the cycling of redox-active metabolites. However, it is further hypothesised that PQ and TQ and other 8-AQ, display significant differences in Step 1 of the MoA, specifically the routes and rates of generation of redox-active metabolites. The team presents initial supporting evidence for this hypothesis including evidence that the choice of combination partner drug can significantly affect the generation H2O2 and in vitro malaria parasite liver-stage efficacy. Significant knowledge gaps remain with regards to Step1 the identity of TQ metabolites is not known, the antimalarial efficacy and toxicity of the metabolites is unknown and critically there is no information of the routes and rates of metabolite generation. This information is central to defining the therapeutic window of this drug class, and central to understanding why malaria relapse prevention by TQ and PQ is affected by the choice of the drug combination partner.

Project details

Basic Science
Drug-based Strategies

Sep 2021 — Sep 2024

$897,066

United Kingdom