{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T21:27:06Z","timestamp":1772227626982,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.ppat.1012946","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T00:00:00Z","timestamp":1757980800000}}],"reference-count":46,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T00:00:00Z","timestamp":1757548800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI155413"],"award-info":[{"award-number":["R01AI155413"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"name":"E.A. Benbrook Endowed Chair for Pathology"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    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\u2009K channel activator, is a promising candidate for the treatment of onchocerciasis due to its macrofilaricidal activity against\n                    <jats:italic>\n                      <jats:italic>Onchocerca volvulus<\/jats:italic>\n                    <\/jats:italic>\n                    . Nevertheless, it is less effective against adult\n                    <jats:italic>\n                      <jats:italic>Brugia malayi,<\/jats:italic>\n                    <\/jats:italic>\n                    one of the causative agents of human lymphatic filariasis. Characterizing molecular and pharmacological disparities between highly conserved splice variant isoforms of\n                    <jats:italic>\n                      <jats:italic>B. malayi<\/jats:italic>\n                    <\/jats:italic>\n                    and\n                    <jats:italic>\n                      <jats:italic>O. volvulus<\/jats:italic>\n                    <\/jats:italic>\n                    SLO-1\u2009K channels and identifying allosteric modulators that can increase emodepside potency on\n                    <jats:italic>\n                      <jats:italic>B. malayi<\/jats:italic>\n                    <\/jats:italic>\n                    SLO-1\u2009K channels is necessary for therapeutic advance. In this study, we tested the effects of emodepside and the mammalian BK channel activator, GoSlo-SR-5\u201369 alone and in combination on\n                    <jats:italic>\n                      <jats:italic>Xenopus<\/jats:italic>\n                    <\/jats:italic>\n                    expressed\n                    <jats:italic>\n                      <jats:italic>B. malayi<\/jats:italic>\n                    <\/jats:italic>\n                    SLO-1F and\n                    <jats:italic>\n                      <jats:italic>O. volvulus<\/jats:italic>\n                    <\/jats:italic>\n                    SLO-1A channels. Additionally, binding poses of emodepside, and GoSlo-SR-5\u201369 were predicted on both channels using molecular docking. We observed that\n                    <jats:italic>\n                      <jats:italic>Ovo<\/jats:italic>\n                    <\/jats:italic>\n                    -SLO-1A was more sensitive to emodepside than\n                    <jats:italic>\n                      <jats:italic>Bma<\/jats:italic>\n                    <\/jats:italic>\n                    -SLO-1F, with EC\n                    <jats:sub>50<\/jats:sub>\n                    values of 0.40\u2009\u00b1\u20090.05 \u00b5M and 1.4\u2009\u00b1\u20090.2 \u00b5M for\n                    <jats:italic>\n                      <jats:italic>Ovo<\/jats:italic>\n                    <\/jats:italic>\n                    -SLO-1A and\n                    <jats:italic>\n                      <jats:italic>Bma<\/jats:italic>\n                    <\/jats:italic>\n                    -SLO-1F respectively. GoSlo-SR-5\u201369 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\n                    <jats:italic>\n                      <jats:italic>Bma<\/jats:italic>\n                    <\/jats:italic>\n                    -SLO-1F and\n                    <jats:italic>\n                      <jats:italic>Ovo<\/jats:italic>\n                    <\/jats:italic>\n                    -SLO-1A. In contrast, GoSlo-SR-5\u201369 binds at the RCK1 pocket. This study reveals for the first time, allosteric modulation of filarial nematode SLO-1\u2009K channels by a mammalian BK channel activator and highlights its ability to increase emodepside potency on the\n                    <jats:italic>\n                      <jats:italic>B. malayi<\/jats:italic>\n                    <\/jats:italic>\n                    SLO-1\u2009K channel.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1012946","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T17:49:26Z","timestamp":1757612966000},"page":"e1012946","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Positive allosteric modulation of emodepside sensitive Brugia malayi SLO-1F and Onchocerca volvulus SLO-1A potassium channels by GoSlo-SR-5-69"],"prefix":"10.1371","volume":"21","author":[{"given":"Mark","family":"McHugh","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charity N.","family":"Njeshi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathaniel","family":"Smith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sudhanva S.","family":"Kashyap","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Real","family":"Datta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan P.","family":"Robertson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2422-1847","authenticated-orcid":true,"given":"Richard J.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,9,11]]},"reference":[{"issue":"9747","key":"ppat.1012946.ref001","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1016\/S0140-6736(10)60586-7","article-title":"Lymphatic filariasis and onchocerciasis","volume":"376","author":"MJ Taylor","year":"2010","journal-title":"Lancet"},{"key":"ppat.1012946.ref002","unstructured":"WHO. 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