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

• DOI: 10.1021/acsinfecdis.9b00482
• Publication Date: 2020-02-20T22:20:40Z
• Authors: Matthew Abraham; Kerstin Gagaring; Marisa L. Martino; Manu Vanaerschot; David M. Plouffe; Jaeson Calla; Karla P. Godinez-...; Alan Y. Du; Melanie Wree; Yevgeniya Antonov...; Korina Eribez; Madeline R. Luth; Sabine Ottilie; David A. Fidock; Case W. McNamara; Elizabeth A. Winz...
• Keywords: High-Throughput Screening; Chemotype; Phenotypic screening

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