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

David A. Baker (), Lindsay B. Stewart, Jonathan M. Large, Paul W. Bowyer, Keith H. Ansell, María B. Jiménez-Díaz, Majida El Bakkouri, Kristian Birchall, Koen J. Dechering, Nathalie S. Bouloc, Peter 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 B. Ferrer, Raymond Hui, Teun Bousema, Iñigo Angulo-Barturén, Andy T. Merritt, Simon L. Croft, Winston E. Gutteridge, Catherine A. Kettleborough and Simon A. Osborne
Additional contact information
David A. Baker: London School of Hygiene & Tropical Medicine
Lindsay B. Stewart: London School of Hygiene & Tropical Medicine
Jonathan M. Large: LifeArc, Accelerator Building
Paul W. Bowyer: London School of Hygiene & Tropical Medicine
Keith H. Ansell: LifeArc, Accelerator Building
María B. Jiménez-Díaz: Tres Cantos Medicines Development Campus-Diseases of the Developing World
Majida El Bakkouri: University of Toronto
Kristian Birchall: LifeArc, Accelerator Building
Koen J. Dechering: TropIQ Health Sciences
Nathalie S. Bouloc: LifeArc, Accelerator Building
Peter J. Coombs: LifeArc, Accelerator Building
David Whalley: LifeArc, Accelerator Building
Denise J. Harding: LifeArc, Accelerator Building
Ela Smiljanic-Hurley: LifeArc, Accelerator Building
Mary C. Wheldon: LifeArc, Accelerator Building
Eloise M. Walker: London School of Hygiene & Tropical Medicine
Johannes T. Dessens: London School of Hygiene & Tropical Medicine
María José Lafuente: Tres Cantos Medicines Development Campus-Diseases of the Developing World
Laura M. Sanz: Tres Cantos Medicines Development Campus-Diseases of the Developing World
Francisco-Javier Gamo: Tres Cantos Medicines Development Campus-Diseases of the Developing World
Santiago B. Ferrer: Tres Cantos Medicines Development Campus-Diseases of the Developing World
Raymond Hui: University of Toronto
Teun Bousema: Radboud University Medical Center
Iñigo Angulo-Barturén: Tres Cantos Medicines Development Campus-Diseases of the Developing World
Andy T. Merritt: LifeArc, Accelerator Building
Simon L. Croft: London School of Hygiene & Tropical Medicine
Winston E. Gutteridge: London School of Hygiene & Tropical Medicine
Catherine A. Kettleborough: LifeArc, Accelerator Building
Simon A. Osborne: LifeArc, Accelerator Building

Nature Communications, 2017, vol. 8, issue 1, 1-9

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-00572-x

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