Discovery of GPCR Antagonists with Potent In Vitro and In Vivo Macrofilaricidal Activity

Area of Science:

• Parasitology
• Drug Discovery
• Molecular Pharmacology

Background:

• Chronic filarial infections pose a significant global health challenge.
• Existing adulticidal therapies are limited, necessitating novel drug development.
• G-protein coupled receptor (GPCR) antagonists are explored for antiparasitic potential.

Purpose of the Study:

• To evaluate the antifilarial activity of repurposed human GPCR antagonists and novel analogs.
• To identify drug candidates with efficacy against filarial worms like Brugia pahangi and Onchocerca species.
• To investigate the mechanism of action and target identification for promising compounds.

Main Methods:

• Screening of 27 GPCR antagonists and analogs for in vitro adulticidal activity.
• In vivo efficacy studies in animal models to assess worm burden and fecundity reduction.
• GPCR expression analysis, radioligand binding assays, and Caenorhabditis elegans reverse genetics.

Main Results:

• 27 compounds demonstrated in vitro adulticidal activity.
• Clemizole and analog C-8 significantly reduced worm burden in vivo.
• Clemizole, C-8, and S-17 notably reduced worm fecundity and showed parasite selectivity.
• GAR-3 and SER-7 identified as potential nematode targets.

Conclusions:

• Clemizole and its analogs (C-8, S-17) are promising lead compounds for antifilarial drug development.
• Repurposing GPCR antagonists offers a viable strategy for discovering new treatments for filarial diseases.
• Further optimization of these compounds is warranted to combat filarial infections.