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Fragment-Based Phenotypic Lead Discovery To Identify New Drug Seeds That Target Infectious Diseases
ACS Chemical Biology  (IF5.1),  Pub Date : 2021-10-26, DOI: 10.1021/acschembio.1c00657
Yann Ayotte, Eve Bernet, François Bilodeau, Mena Cimino, Dominic Gagnon, Marthe Lebughe, Maxime Mistretta, Paul Ogadinma, Sarah-Lisa Ouali, Aïssatou Aïcha Sow, Laurent Chatel-Chaix, Albert Descoteaux, Giulia Manina, Dave Richard, Frédéric Veyrier, Steven R. LaPlante

Fragment-based lead discovery has emerged over the last decades as one of the most powerful techniques for identifying starting chemical matter to target specific proteins or nucleic acids in vitro. However, the use of such low-molecular-weight fragment molecules in cell-based phenotypic assays has been historically avoided because of concerns that bioassays would be insufficiently sensitive to detect the limited potency expected for such small molecules and that the high concentrations required would likely implicate undesirable artifacts. Herein, we applied phenotype cell-based screens using a curated fragment library to identify inhibitors against a range of pathogens including Leishmania, Plasmodium falciparum, Neisseria, Mycobacterium, and flaviviruses. This proof-of-concept shows that fragment-based phenotypic lead discovery (FPLD) can serve as a promising complementary approach for tackling infectious diseases and other drug-discovery programs.