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Fragment-Based Phenotypic Lead Discovery: Cell-Based Assay to Target Leishmaniasis

Abstract : A rapid and practical approach for the discovery of new chemical matter for targeting pathogens and diseases is described. Fragment-based phenotypic lead discovery (FPLD) combines aspects of traditional fragment-based lead discovery (FBLD), which involves the screening of small-molecule fragment libraries to target specific proteins, with phenotypic lead discovery (PLD), which typically involves the screening of drug-like compounds in cell-based assays. To enable FPLD, a diverse library of fragments was first designed, assembled, and curated. This library of soluble, low-molecular-weight compounds was then pooled to expedite screening. Axenic cultures of Leishmania promastigotes were screened, and single hits were then tested for leishmanicidal activity against intracellular amastigote forms in infected murine bone-marrow-derived macrophages without evidence of toxicity toward mammalian cells. These studies demonstrate that FPLD can be a rapid and effective means to discover hits that can serve as leads for further medicinal chemistry purposes or as tool compounds for identifying known or novel targets.
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https://hal-riip.archives-ouvertes.fr/pasteur-01854637
Contributor : Michel Courcelles <>
Submitted on : Monday, August 6, 2018 - 9:20:07 PM
Last modification on : Monday, October 8, 2018 - 5:44:05 PM

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Yann Ayotte, Francois Bilodeau, Albert Descoteaux, Steven Laplante. Fragment-Based Phenotypic Lead Discovery: Cell-Based Assay to Target Leishmaniasis. ChemMedChem, Wiley-VCH Verlag, 2018, 13 (14), pp.1377 - 1386. ⟨10.1002/cmdc.201800161⟩. ⟨pasteur-01854637⟩

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