Chemoprotective antimalarials identified through quantitative high-throughput screening of Plasmodium blood and liver stage parasites
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 22, 2021
- Source ID
- 10.1038/s41598-021-81486-z
Entities
People
- Ajit Jadhav
- Alexey V. Zakharov
- Andrew T. Girvin
- Anton Simeonov
- Benjamin A. Sigmon
- Bryan T. Mott
- Carleen Klumpp-thomas
- Daniel C. Talley
- Daniel Jansen
- David A. Fidock
- David J. Maloney
- Dorjbal Dorjsuren
- Elizabeth Winzeler
- Hongmao Sun
- Juan Jose Marugan
- Kathryn J. Wicht
- Leila S. Ross
- Norma Roncal
- Norman C. Waters
- Paul M. Will
- Pranav Shah
- Richard J Sciotti
- Richard T. Eastman
- Robert F. Campbell
- Sachel Mok
- Stephan Meister
- Tomas Yeo
- Wenwei Huang
- Xin Xu
- Yevgeniya Antonova-koch
Organizations
- National Institute of Allergy and Infectious Diseases
- United States Department of Defense