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

authors

  • Baker, David A.
  • Stewart, Lindsay B.
  • Large, Jonathan M.
  • Bowyer, Paul W.
  • Ansell, Keith H.
  • Jimenez Diaz, Maria B.
  • El Bakkouri, Majida
  • Birchall, Kristian
  • Dechering, Koen J.
  • Bouloc, Nathalie S.
  • Coombs, Peter J.
  • Whalley, David
  • Harding, Denise J.
  • Smiljanic Hurley, Ela
  • Wheldon, Mary C.
  • Walker, Eloise M.
  • Dessens, Johannes T.
  • Lafuente, Maria Jose
  • Sanz, Laura M.
  • Gamo, Francisco Javier
  • FERRER BAZAGA, SANTIAGO
  • Hui, Raymond
  • Bousema, Teun
  • Angulo Barturen, Iñigo
  • Merritt, Andy T.
  • Croft, Simon L.
  • Gutteridge, Winston E.
  • Kettleborough, Catherine A.
  • Osborne, Simon A.

publication date

  • September 2017

start page

  • 1

end page

  • 9

issue

  • 1, 430

volume

  • 8

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

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.

subjects

  • Biology and Biomedicine