A drug repurposing screen for whipworms informed by comparative genomics.

Area of Science:

• Parasitology
• Drug Discovery
• Infectious Diseases

Background:

• Hundreds of millions globally suffer from whipworm (Trichuris trichiura) infections.
• Current treatments like albendazole exhibit limited efficacy, necessitating novel therapeutic strategies.

Purpose of the Study:

• To investigate the potential of repurposing existing human-approved drugs as novel anti-whipworm agents.
• To identify compounds targeting parasitic worm proteins for whipworm treatment.

Main Methods:

• Comparative genomics identified 409 approved drugs predicted to target parasitic worm proteins.
• Ex vivo screening assessed the motility of adult Trichuris muris (murine whipworm) in the presence of these drugs.
• Promising compounds were further evaluated in vivo in a mouse model.

Main Results:

• 14 compounds demonstrated efficacy (EC50 ≤50 microM) against T. muris ex vivo.
• In vivo testing of nine selected compounds resulted in a maximum worm burden reduction of only 19%.
• High ex vivo efficacy contrasted with low in vivo results, indicating challenges with drug properties and pharmacokinetics.

Conclusions:

• The study successfully identified approved drugs targeting whipworm proteins, validating the genomics approach.
• Drug absorption by the host and limited uptake by worms hinder in vivo efficacy.
• Future development requires identifying drug analogues with reduced host absorption and enhanced worm uptake for effective whipworm treatment.