Author
Listed:
- 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
Toronto General Hospital Research Institute)
- 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
Toronto General Hospital Research Institute)
- 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)
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.
Suggested Citation
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 & P, 2017.
"A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission,"
Nature Communications, Nature, vol. 8(1), pages 1-9, December.
Handle:
RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00572-x
DOI: 10.1038/s41467-017-00572-x
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Cited by:
- Josie L. Ferreira & Vojtěch Pražák & Daven Vasishtan & Marc Siggel & Franziska Hentzschel & Annika M. Binder & Emma Pietsch & Jan Kosinski & Friedrich Frischknecht & Tim W. Gilberger & Kay Grünewald, 2023.
"Variable microtubule architecture in the malaria parasite,"
Nature Communications, Nature, vol. 14(1), pages 1-17, December.
- Mariska Naude & Ashleigh van Heerden & Janette Reader & Mariëtte van der Watt & Jandeli Niemand & Dorè Joubert & Giulia Siciliano & Pietro Alano & Mathew Njoroge & Kelly Chibale & Esperanza Herreros &, 2024.
"Eliminating malaria transmission requires targeting immature and mature gametocytes through lipoidal uptake of antimalarials,"
Nature Communications, Nature, vol. 15(1), pages 1-15, December.
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