Identification of novel, potent, and selective compounds against malaria using Glideosomal Associated Protein 50 as a drug Target

Abstract

Abstract Phylum apicomplexan consists of parasites like Plasmodium and Toxoplasma. These obligate intracellular parasites enter host cells via an energy-dependent process using a specialized machinery called glideosome. In the present study, we used Plasmodium falciparum GAP 50, a glideosome-associated protein as a target to screen 951 different compounds from diverse chemical libraries. Using different screening methods, eight compounds, Hayatinine, Curine, MMV689758 (Bedaquiline), MMV1634402 (Brilacidin), and MMV688271, MMV782353, MMV642550, and USINB4-124-8 were identified which showed promising binding affinity (KD < 75 µM) along with sub-micromolar range anti-parasitic efficacy and selectivity index for malaria parasite > 100 fold. These eight compounds were effective against the chloroquine-resistant PfINDO and artemisinin-resistant, PfCam 3.1R359T strain. Studies on the effect of these compounds at asexual blood stages showed that these eight compounds act differently at different developmental stages, indicating the binding of these compounds to other Plasmodium proteins besides binding to PfGAP50. We further studied the effect of compounds in vivo P. berghei mouse model of malaria. Importantly, orally delivered Bedaquiline (50 mg/Kg b. wt.) showed substantial suppression of parasitemia, and three out of seven mice were cured of the infection. Thus, our study provides new scaffolds for the development of antimalarials that may act at multiple Plasmodium life cycle stages.