Identification and characterization of GAP50 binders with the goal to identify novel antimalarials

Malaria continues to be a killer disease even in the modern world. Indeed, vaccines and drugs have a lot to learn from the malaria parasite before they can be successful. Here, using a filter for glideosomal anchor protein PfGAP50, we have explored a plethora of small molecules to shortlist eight GAP50 binders with promising antiplasmodial activity (IC50 < 3 µM) that are also highly selective. Of these, Hayatinine, Curine, MMV689758 (Bedaquiline), MMV1634402 (Brilacidin), and MMV688271 with PfINDO IC50 ≤ 1 µM were found to stall merozoite invasion by inhibiting IMC formation besides increasing oxidant levels in trophozoites. Bedaquiline pre-treated and washed healthy RBCs showed prophylactic ability to prevent intraerythrocytic development of malaria parasite. Synergistic activities with ΣFIC values as low as 0.22 (Curine and Artemisinin) or 0.37 (Bedaquiline and Artemisinin) augur well for the development of drug combinations to combat malaria effectively. Interestingly, orally delivered Bedaquiline (50 mg/Kg b. wt.) showed substantial suppression of parasitemia in a mouse model of malaria.