Leveraging RC-12 for Radical Cure of Plasmodium Vivax

Objectives

The objective of this proposal, the first step in pursuit of the goal to leverage RC-12 to discover a new orally active single-dose antimalarial drug with high efficacy against hypnozoites and other exoerythrocytic stage parasites, is to identify the active metabolites of RC-12 that endow this chemotype with its high efficacy in the ‘gold-standard’ hypnozoite animal model – P. cynomolgi–infected rhesus monkeys.

The research team central hypothesis is that species-specific metabolism accounts for the dichotomy between the high efficacy of RC-12 against P. cynomolgi hypnozoites in rhesus monkeys and the lack of efficacy of RC-12 against P. vivax hypnozoites in humans.

The rationale that underlies this research is to provide tools to begin to elucidate the pharmacokinetics/pharmacodynamics (PK/PD) of RC-12 and to identify new leads (active metabolites) for drug discovery.

To do so, and to test our central hypothesis, the research team proposes the following three specific aims:

1. To synthesize the nine putative human, monkey, and rat RC-12 CYP450 metabolites to confirm their assigned structures;
2. To establish a baseline metabolic and pharmacokinetic profile for RC-12;
3. To assess RC-12 and its CYP450 metabolites for activity against P. cynomolgi hypnozoites in both rhesus and human hepatocytes.