Positive allosteric modulation of emodepside sensitiveBrugia malayiSLO-1F andOnchocerca volvulusSLO-1A potassium channels by GoSlo-SR-5-69
Authors: McHugh Mark , Njeshi Charity N , Smith Nathaniel , Kashyap Sudhanva S. , Datta Real , Sun Han , Robertson Alan P. , Martin Richard J. 
Published: February 2025

AbstractHuman 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, the introduction of drugs with adulticidal activity is paramount. The broad-spectrum anthelmintic emodepside, a nematode selective SLO-1 K channel activator, has been considered a promising candidate for the treatment of onchocerciasis due to its macrofilaricidal activity againstOnchocerca volvulus. Nevertheless, it is less effective against adultBrugia malayi,one of the causative agents of human lymphatic filariasis. Characterizing molecular and pharmacological disparities between highly conserved splice variant isoforms ofB. malayiandO. volvulusSLO-1 K channels and identifying allosteric modulators that can increase emodepside potency onB. malayiSLO-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 onXenopusexpressedB. malayiSLO-1F andO. volvulusSLO-1A channels. Additionally, binding poses of emodepside, and GoSlo-SR-5-69 were predicted on both channels using molecular docking.Ovo-SLO-1A was more sensitive to emodepside thanBma-SLO-1F. GoSlo-SR- 5-69 was a positive allosteric modulator, potentiating the effects of emodepside. Emodepside was docked at the S6 pocket below the selectivity filter forBma-SLO-1F andOvo-SLO-1A. The binding of emodepside in the S6 pocket indicated a stabilizingπ-πinteraction between F342 and the phenyl rings of emodepside which may contribute to the potency of emodepside on these filaria channels. Molecular docking suggested that 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 theB. malayiSLO-1 K channel.Author SummaryB. malayiis one of the causative agents of lymphatic filariasis, whileO. volvuluscauses onchocerciasis. Elimination of adultB. malayiandO. volvulusis impeded by anthelmintics lacking adequate macrofilaricidal activity. The anthelmintic emodepside has microfilaricidal and macrofilaricidal activity. However, it exhibits poor efficacy against adultB. malayi in vivo.Here, we conducted a comparative pharmacological characterization of two closely related splice variants SLO-1 K channels ofB. malayiandO. volvulus. Using voltage clamp, we tested the effects of emodepside and GoSlo-SR-5-69 independently and in combination onXenopusexpressedB. malayiSLO-1F andO. volvulusSLO-1A channels. Binding poses of emodepside, and GoSlo-SR-5-69 were predicted on both channels using molecular docking. We demonstrate that theO. volvulusSLO-1A receptor is more sensitive to emodepside than theB. malayiSLO-1F receptor. GoSlo-SR-5-69 is also a potentiator of emodepside responses. Homology modelling revealed that emodepside probably binds in the pore region of the B.malayiSLO-1F andO. volvulusSLO-1A channels, while GoSlo-SR-5-69 probably binds to the RCK1 domain of the channels. Our study provides new insights into similarities and differences shared between SLO-1 K channels of each species and reveals positive allosteric modulation by a mammalian SLO-1 K activator.