Development of Malaria Transmission-Blocking Drugs

National Center For Advancing Translational Sciences

Investigators

Linked publications & trials

Abstract

The project team screened 5,215 known bioactive compounds and approved drugs for gametocytocidal activity. 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 project currently is in late-stage lead optimization, with the goal of identifying a safe and effective compound with single-dose activity against all stages of the disease.