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.

Courtesy of the U.S. National Library of Medicine