Optimisation of lead compounds targeting malaria parasite phosphodiesterases

Delayed parasite clearance and treatment failures with first-line artemisinin-based combinations are widespread in Southeast Asia and alarmingly resistance markers have been detected in several African countries. New antimalarial drugs with novel mechanisms of action, active against resistant strains are urgently needed. The researchers at LSHTM have identified potent inhibitors of malaria parasite phosphodiesterase (PDE) enzymes. They kill asexual blood stage parasites that cause disease, and two of their sub-series also kill gametocytes which mediate transmission, a property absent from most antimalarials. The inhibitors act at a similarly rapid rate to chloroquine. Importantly, PDEs have been targeted successfully and safely to treat a range of human disorders and importantly our series has excellent selectivity against human PDEs. One of the attractions of the chemotypes the researchers are developing here is that their profile in terms of drug-drug interactions is particularly benign. Thus, a new antimalarial targeting PDEs has clear potential in combination therapy.

Wellcome Trust awarded grant details

Basic Science

May 2022 — May 2024

$702,218

United Kingdom