Molecular Mechanism of Action of Antimalarial Benzoisothiazolones: Species-Selective Inhibitors of the Plasmodium spp. MEP Pathway enzyme, IspD

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Price, KE, Armstrong, CM, Imlay, LS, Hodge, DM, Pidathala, C, Roberts, NJ, Park, J, Mikati, M, Sharma, R, Lawrenson, AS et al (show 4 more authors) (2016) Molecular Mechanism of Action of Antimalarial Benzoisothiazolones: Species-Selective Inhibitors of the Plasmodium spp. MEP Pathway enzyme, IspD. Scientific Reports, 6 (1). 36777-.

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Official URL: https://www.nature.com/articles/srep36777

Abstract

The methylerythritol phosphate (MEP) pathway is an essential metabolic pathway found in malaria parasites, but absent in mammals, making it a highly attractive target for the discovery of novel and selective antimalarial therapies. Using high-throughput screening, we have identified 2-phenyl benzo[d]isothiazol-3(2H)-ones as species-selective inhibitors of Plasmodium spp. 2-C-methyl-D-erythritol-4-phosphate cytidyltransferase (IspD), the third catalytic enzyme of the MEP pathway. 2-Phenyl benzo[d]isothiazol-3(2H)-ones display nanomolar inhibitory activity against P. falciparum and P. vivax IspD and prevent the growth of P. falciparum in culture, with EC50 values below 400 nM. In silico modeling, along with enzymatic, genetic and crystallographic studies, have established a mechanism-of-action involving initial non-covalent recognition of inhibitors at the IspD binding site, followed by disulfide bond formation through attack of an active site cysteine residue on the benzo[d]isothiazol-3(2H)-one core. The species-selective inhibitory activity of these small molecules against Plasmodium spp. IspD and cultured parasites suggests they have potential as lead compounds in the pursuit of novel drugs to treat malaria.

Item Type:	Article
Uncontrolled Keywords:	Plasmodium falciparum, Plasmodium vivax, Malaria, Falciparum, Erythritol, Choline-Phosphate Cytidylyltransferase, Sugar Phosphates, Recombinant Proteins, Antimalarials, Crystallography, X-Ray, Cloning, Molecular, Inhibitory Concentration 50, Binding Sites, Catalytic Domain, Benzothiazoles
Depositing User:	Symplectic Admin
Date Deposited:	15 Feb 2017 07:46
Last Modified:	19 Jan 2023 07:19
DOI:	10.1038/srep36777
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3005813