Chemoprotective antimalarials identified through quantitative high-throughput screening of Plasmodium blood and liver stage parasites.

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

Scientific reports, Volume: 11, Issue: 1
January 22, 2021
Dorjbal Dorjsuren D, Richard T Eastman RT, Kathryn J Wicht KJ, Daniel Jansen D, Daniel C Talley DC, Benjamin A Sigmon BA, Alexey V Zakharov AV, Norma Roncal N, Andrew T Girvin AT, Yevgeniya Antonova-Koch Y, Paul M Will PM, Pranav Shah P, Hongmao Sun H, Carleen Klumpp-Thomas C, Sachel Mok S, Tomas Yeo T, Stephan Meister S, Juan Jose Marugan JJ, Leila S Ross LS, Xin Xu X, David J Maloney DJ, Ajit Jadhav A, Bryan T Mott BT, Richard J Sciotti RJ, Elizabeth A Winzeler EA, Norman C Waters NC, Robert F Campbell RF, Wenwei Huang W, Anton Simeonov A, David A Fidock DA

The spread of Plasmodium falciparum parasites resistant to most first-line antimalarials creates an imperative to enrich the drug discovery pipeline, preferably with curative compounds that can also act prophylactically. We report a phenotypic quantitative high-throughput screen (qHTS), based on concentration-response curves, which was designed to identify compounds active against Plasmodium liver and asexual blood stage parasites. Our qHTS screened over 450,000 compounds, tested across a range of 5 to 11 concentrations, for activity against Plasmodium falciparum asexual blood stages. Active compounds were then filtered for unique structures and drug-like properties and subsequently screened in a P. berghei liver stage assay to identify novel dual-active antiplasmodial chemotypes. Hits from thiadiazine and pyrimidine azepine chemotypes were subsequently prioritized for resistance selection studies, yielding distinct mutations in P. falciparum cytochrome b, a validated antimalarial drug target. The thiadiazine chemotype was subjected to an initial medicinal chemistry campaign, yielding a metabolically stable analog with sub-micromolar potency. Our qHTS methodology and resulting dataset provides a large-scale resource to investigate Plasmodium liver and asexual blood stage parasite biology and inform further research to develop novel chemotypes as causal prophylactic antimalarials.