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Industrial scale high-throughput screening delivers multiple fast acting macrofilaricides.

Rachel H Clare1, Catherine Bardelle2, Paul Harper2

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|January 4, 2019
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Researchers screened a large compound library to find new drugs targeting Wolbachia bacteria, essential for nematodes causing neglected tropical diseases like lymphatic filariasis and onchocerciasis. Five novel compounds showed faster kill rates than current treatments, offering potential for improved therapies.

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Area of Science:

  • Drug discovery and development
  • Microbiology
  • Parasitology

Background:

  • Nematodes responsible for lymphatic filariasis and onchocerciasis depend on Wolbachia endosymbionts for survival and reproduction.
  • Targeting Wolbachia presents a promising strategy for treating these neglected tropical diseases (NTDs).

Purpose of the Study:

  • To identify novel chemotypes with potent in vitro activity against Wolbachia.
  • To discover anti-Wolbachia compounds with faster kill kinetics than existing macrofilaricidal drugs.

Main Methods:

  • A high-throughput screening campaign of AstraZeneca's 1.3 million compound library was conducted.
  • Cheminformatics was employed for rational prioritization and triage of compounds, balancing chemical diversity and drug-like properties.
  • In vitro kill rates of identified compounds were assessed.

Main Results:

  • Five novel chemotypes demonstrating rapid in vitro kill rates (less than 2 days) were identified.
  • These compounds exhibited superior time-kill kinetics compared to currently available anti-Wolbachia drugs.
  • The screening was a large-scale industrial effort resulting from a partnership between A∙WOL and AstraZeneca.

Conclusions:

  • The identified novel chemotypes represent promising leads for developing improved macrofilaricidal drugs.
  • These compounds have the potential to enhance current therapeutic options for lymphatic filariasis and onchocerciasis.
  • Further development could lead to safer and more selective treatments for these NTDs.