Development of Malaria Transmission-Blocking Drugs

National Center For Advancing Translational Sciences

Investigators

Linked publications, trials & patents

Abstract

The project team screened 5,215 known bioactive compounds and approved drugs for gametocytocidal activity against the P. falciparum parasite. One compound with favorable pharmacokinetics (Torin2) was selected as the first candidate for further evaluation, including testing in an in vivo rodent malaria transmission model. Two 4 mg/kg doses completely blocked parasites’ ability to infect mosquitoes, and a 2 mg/kg dose gave a partial blockade, confirming the transmission-blocking activity of Torin2. Preliminary data indicate that the Torin2 target in P. falciparum is distinct from the mammalian target, allowing the design of malaria-specific derivatives. Pilot studies between the lead collaborator and NCATS scientists used a gametocyte viability assay, a cellular mTOR assay and an in vivo rodent malaria transmission model to identify new malaria-specific Torin2 analogues. This work resulted in identification of a series of compounds suitable for lead optimization. The activities this year were focused on tuning the lead compounds to decrease the undesirable activities against human lipid kinases and to improve the in vivo pharmacokinetic properties to meet the requirements for a single-dose, oral treatment. The project team designed and synthesized hundreds of analogues, some of which were prepared on scales to supply materials for animal studies. The team extensively characterized a small set of compounds in preparation for selecting compounds for toxicological studies, with the goal of identifying a safe and effective compound with single-dose activity against P. falciparum malaria. The team developed and characterized a computational binding model of the lead compounds with their putative parasite protein target, P. falciparum phosphatidylinositol 4-kinase (PfPI4K). The model revealed key binding interactions that were used to interpret the observed structure-activity relationship. Guided by the calculation results utilizing density functional theory, the team separated selected lead compounds into pairs of enantiomers of axial chirality, which were shown to have distinct activity profiles. The project currently is in late-stage lead optimization towards identifying a single-dose treatment for P. falciparum malaria.