Open-source discovery of chemical leads for next-generation chemoprotective antimalarials.

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Science (New York, N.Y.), Volume: 362, Issue: 6419
December 7, 2018
Yevgeniya Antonova-Koch Y, Stephan Meister S, Matthew Abraham M, Madeline R Luth MR, Sabine Ottilie S, Amanda K Lukens AK, Tomoyo Sakata-Kato T, Manu Vanaerschot M, Edward Owen E, Juan Carlos Jado JC, Steven P Maher SP, Jaeson Calla J, David Plouffe D, Yang Zhong Y, Kaisheng Chen K, Victor Chaumeau V, Amy J Conway AJ, Case W McNamara CW, Maureen Ibanez M, Kerstin Gagaring K, Fernando Neria Serrano FN, Korina Eribez K, Cullin McLean Taggard CM, Andrea L Cheung AL, Christie Lincoln C, Biniam Ambachew B, Melanie Rouillier M, Dionicio Siegel D, François Nosten F, Dennis E Kyle DE, Francisco-Javier Gamo FJ, Yingyao Zhou Y, Manuel Llinás M, David A Fidock DA, Dyann F Wirth DF, Jeremy Burrows J, Brice Campo B, Elizabeth A Winzeler EA

To discover leads for next-generation chemoprotective antimalarial drugs, we tested more than 500,000 compounds for their ability to inhibit liver-stage development of luciferase-expressing spp. parasites (681 compounds showed a half-maximal inhibitory concentration of less than 1 micromolar). Cluster analysis identified potent and previously unreported scaffold families as well as other series previously associated with chemoprophylaxis. Further testing through multiple phenotypic assays that predict stage-specific and multispecies antimalarial activity distinguished compound classes that are likely to provide symptomatic relief by reducing asexual blood-stage parasitemia from those which are likely to only prevent malaria. Target identification by using functional assays, in vitro evolution, or metabolic profiling revealed 58 mitochondrial inhibitors but also many chemotypes possibly with previously unidentified mechanisms of action.

Courtesy of the U.S. National Library of Medicine