A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission.

Baker, DA; Stewart, LB; Large, JM; Bowyer, PW; Ansell, KH; Jiménez-Díaz, MB; El Bakkouri, M; Birchall, K; Dechering, KJ; Bouloc, NS; Coombs, PJ; Whalley, D; Harding, DJ; Smiljanic-Hurley, E; Wheldon, MC; Walker, EM; Dessens, JT; Lafuente, MJ; Sanz, LM; Gamo, FJ; Ferrer, SB; Hui, R; Bousema, T; Angulo-Barturén, I; Merritt, AT; Croft, SL; Gutteridge, WE; Kettleborough, CA; Osborne, SA; (2017) A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission. Nature communications, 8 (1). p. 430. ISSN 2041-1723 DOI: https://doi.org/10.1038/s41467-017-00572-x

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To combat drug resistance, new chemical entities are urgently required for use in next generation anti-malarial combinations. We report here the results of a medicinal chemistry programme focused on an imidazopyridine series targeting the Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG). The most potent compound (ML10) has an IC50 of 160 pM in a PfPKG kinase assay and inhibits P. falciparum blood stage proliferation in vitro with an EC50 of 2.1 nM. Oral dosing renders blood stage parasitaemia undetectable in vivo using a P. falciparum SCID mouse model. The series targets both merozoite egress and erythrocyte invasion, but crucially, also blocks transmission of mature P. falciparum gametocytes to Anopheles stephensi mosquitoes. A co-crystal structure of PvPKG bound to ML10, reveals intimate molecular contacts that explain the high levels of potency and selectivity we have measured. The properties of this series warrant consideration for further development to produce an antimalarial drug.Protein kinases are promising drug targets for treatment of malaria. Here, starting with a medicinal chemistry approach, Baker et al. generate an imidazopyridine that selectively targets Plasmodium falciparum PKG, inhibits blood stage parasite growth in vitro and in mice and blocks transmission to mosquitoes.

Item Type: Article
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Pathogen Molecular Biology
Faculty of Infectious and Tropical Diseases > Dept of Immunology and Infection
Research Centre: Malaria Centre
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PubMed ID: 28874661
Web of Science ID: 409394300004
URI: http://researchonline.lshtm.ac.uk/id/eprint/4349230


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