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

Area of Science:

• Medicinal Chemistry
• Parasitology
• Drug Discovery

Background:

• Traditional fragment-based lead discovery (FBLD) targets specific proteins.
• Phenotypic lead discovery (PLD) uses cell-based assays for drug-like compounds.
• A combined approach, FPLD, offers a novel strategy for identifying therapeutic agents.

Purpose of the Study:

• To describe a rapid and practical method for discovering new chemical matter.
• To evaluate the efficacy of fragment-based phenotypic lead discovery (FPLD) in identifying anti-parasitic compounds.
• To demonstrate the utility of FPLD for generating leads for medicinal chemistry and target identification.

Main Methods:

• Designed, assembled, and curated a diverse library of soluble, low-molecular-weight fragments.
• Screened pooled fragments against axenic cultures of Leishmania promastigotes.
• Tested identified hits for leishmanicidal activity against intracellular amastigotes in macrophages, assessing mammalian cell toxicity.

Main Results:

• Successfully identified fragment hits with leishmanicidal activity.
• Demonstrated activity against intracellular Leishmania amastigotes.
• Confirmed lack of toxicity toward mammalian cells, indicating a favorable therapeutic window.

Conclusions:

• Fragment-based phenotypic lead discovery (FPLD) is a rapid and effective strategy for identifying potential drug leads.
• FPLD can accelerate the discovery of compounds targeting pathogens and diseases.
• The identified hits can serve as starting points for medicinal chemistry optimization or as tool compounds for target validation.