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Positive allosteric modulation of emodepside sensitive Brugia malayi SLO-1F and Onchocerca volvulus SLO-1A potassium

Mark McHugh1, Charity N Njeshi1, Nathaniel Smith2,3

  • 1Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, Iowa, United States of America.

Plos Pathogens
|September 11, 2025
PubMed

Insights

A new study shows that a mammalian BK channel activator can enhance the efficacy of emodepside against Brugia malayi, a key parasite in lymphatic filariasis. This finding offers a promising strategy to improve treatments for Neglected Tropical Diseases (NTDs).

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Tropical Medicine

Background:

  • Human lymphatic filariasis and onchocerciasis are Neglected Tropical Diseases (NTDs) requiring new treatments targeting adult worms.
  • Current anthelmintics are effective against microfilariae but not adult worms, necessitating drugs with adulticidal activity.
  • Emodepside shows promise for onchocerciasis but is less effective against Brugia malayi, a cause of lymphatic filariasis.

Purpose of the Study:

  • To characterize molecular and pharmacological differences between B. malayi and O. volvulus SLO-1 K+ channels.
  • To identify allosteric modulators that can enhance emodepside's potency against B. malayi SLO-1 K+ channels.
  • To advance therapeutic strategies for filarial diseases by improving emodepside efficacy.

Main Methods:

  • Studied the effects of emodepside and GoSlo-SR-5-69 on Xenopus-expressed B. malayi SLO-1F and O. volvulus SLO-1A channels.
  • Utilized molecular docking to predict binding poses of emodepside and GoSlo-SR-5-69 on both channel isoforms.
  • Assessed emodepside potency and the allosteric modulation effects of GoSlo-SR-5-69.

Main Results:

  • Ovo-SLO-1A (0.40 ± 0.05 µM) was more sensitive to emodepside than Bma-SLO-1F (1.4 ± 0.2 µM).
  • GoSlo-SR-5-69 acted as a positive allosteric modulator, potentiating emodepside's effects on B. malayi SLO-1 K+ channels.
  • Molecular docking revealed distinct binding sites for emodepside (S6 pocket) and GoSlo-SR-5-69 (RCK1 pocket).

Conclusions:

  • Mammalian BK channel activator GoSlo-SR-5-69 allosterically modulates filarial nematode SLO-1 K+ channels.
  • This modulation significantly increases emodepside potency against the B. malayi SLO-1 K+ channel.
  • The findings present a novel strategy to enhance emodepside efficacy for treating lymphatic filariasis.

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