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

著者: David A. Baker, Lindsay B. Stewart, Jonathan M. Large, Paul W. Bowyer, Keith H. Ansell, Marı́a Belén Jiménez-Dı́az, M. El Bakkouri, Kristian Birchall, Koen J. Dechering, Nathalie Bouloc, P.J. Coombs, David Whalley, Denise J. Harding, Ela Smiljanic-Hurley, Mary C. Wheldon, Eloise M. Walker, Johannes T. Dessens, María José Lafuente, Laura M. Sanz, Francisco‐Javier Gamo, Santiago Ferrer, Raymond Hui, Teun Bousema, Íñigo Angulo‐Barturen, Andy Merritt, Simon L. Croft, Winston E. Gutteridge, Catherine Kettleborough, Simon A. Osborne - Nature Communications 2017 被引用: 185

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.