Positive allosteric modulation of emodepside sensitive Brugia malayi SLO-1F and Onchocerca volvulus SLO-1A potassium channels by GoSlo-SR-5-69.

Abstract

Human lymphatic filariasis and onchocerciasis are Neglected Tropical Diseases (NTDs), of major public health concern. Prophylaxis and treatment rely on anthelmintics that effectively eliminate migrating microfilariae but lack efficacy against adult filarial worms. To expedite the elimination of both diseases, drugs with adulticidal activity are needed. The broad-spectrum anthelmintic emodepside, a nematode selective SLO-1 K channel activator, is a promising candidate for the treatment of onchocerciasis due to its macrofilaricidal activity against Onchocerca volvulus. Nevertheless, it is less effective against adult Brugia malayi, one of the causative agents of human lymphatic filariasis. Characterizing molecular and pharmacological disparities between highly conserved splice variant isoforms of B. malayi and O. volvulus SLO-1 K channels and identifying allosteric modulators that can increase emodepside potency on B. malayi SLO-1 K channels is necessary for therapeutic advance. In this study, we tested the effects of emodepside and the mammalian BK channel activator, GoSlo-SR-5-69 alone and in combination on Xenopus expressed B. malayi SLO-1F and O. volvulus SLO-1A channels. Additionally, binding poses of emodepside, and GoSlo-SR-5-69 were predicted on both channels using molecular docking. We observed that Ovo-SLO-1A was more sensitive to emodepside than Bma-SLO-1F, with EC50 values of 0.40 ± 0.05 µM and 1.4 ± 0.2 µM for Ovo-SLO-1A and Bma-SLO-1F respectively. GoSlo-SR-5-69 lacked agonist activity on both channel isoforms but acted as a positive allosteric modulator, potentiating the effects of emodepside. Molecular docking analysis revealed that emodepside binds at the S6 pocket below the selectivity filter for Bma-SLO-1F and Ovo-SLO-1A. In contrast, GoSlo-SR-5-69 binds at the RCK1 pocket. This study reveals for the first time, allosteric modulation of filarial nematode SLO-1 K channels by a mammalian BK channel activator and highlights its ability to increase emodepside potency on the B. malayi SLO-1 K channel.