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Probing the Open Global Health Chemical Diversity Library for Multistage-Active Starting Points for Next-Generation Antimalarials

  • Abraham, Matthew1
  • Gagaring, Kerstin2
  • Martino, Marisa L.1
  • Vanaerschot, Manu3
  • Plouffe, David M.4
  • Calla, Jaeson1
  • Godinez-Macias, Karla P.1
  • Du, Alan Y.1
  • Wree, Melanie1
  • Antonova-Koch, Yevgeniya1
  • Eribez, Korina1
  • Luth, Madeline R.1
  • Ottilie, Sabine1
  • Fidock, David A.3, 3
  • McNamara, Case W.2
  • Winzeler, Elizabeth A.1
  • 1 University of California San Diego, United States , (United States)
  • 2 The Scripps Research Institute, United States , (United States)
  • 3 Columbia University Irving Medical Center, United States , (United States)
  • 4 Genomics Institute of the Novartis Research Foundation, United States , (United States)
Published Article
ACS Infectious Diseases
American Chemical Society
Publication Date
Feb 20, 2020
DOI: 10.1021/acsinfecdis.9b00482
PMID: 32078764
PMCID: PMC7155171
PubMed Central
  • Article


Most phenotypic screens aiming to discover new antimalarial chemotypes begin with low cost, high-throughput tests against the asexual blood stage (ABS) of the malaria parasite life cycle. Compounds active against the ABS are then sequentially tested in more difficult assays that predict whether a compound has other beneficial attributes. Although applying this strategy to new chemical libraries may yield new leads, repeated iterations may lead to diminishing returns and the rediscovery of chemotypes hitting well-known targets. Here, we adopted a different strategy to find starting points, testing ∼70,000 open source small molecules from the Global Health Chemical Diversity Library for activity against the liver stage, mature sexual stage, and asexual blood stage malaria parasites in parallel. In addition, instead of using an asexual assay that measures accumulated parasite DNA in the presence of compound (SYBR green), a real time luciferase-dependent parasite viability assay was used that distinguishes slow-acting (delayed death) from fast-acting compounds. Among 382 scaffolds with the activity confirmed by dose response (<10 μM), we discovered 68 novel delayed-death, 84 liver stage, and 68 stage V gametocyte inhibitors as well. Although 89% of the evaluated compounds had activity in only a single life cycle stage, we discovered six potent (half-maximal inhibitory concentration of <1 μM) multistage scaffolds, including a novel cytochrome bc1 chemotype. Our data further show the luciferase-based assays have higher sensitivity. Chemoinformatic analysis of positive and negative compounds identified scaffold families with a strong enrichment for activity against specific or multiple stages.

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