{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T19:25:08Z","timestamp":1780341908781,"version":"3.54.1"},"posted":{"date-parts":[[2023,9,22]]},"group-title":"Microbiology","reference-count":26,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,9,22]]},"abstract":"<jats:p>\n                  <jats:bold>\n                    Diseases caused by parasitic flatworms impart a considerable healthcare burden worldwide. Many of these diseases \u2013 for example, the parasitic blood fluke infection, schistosomiasis \u2013 are treated with the drug praziquantel (PZQ). However, PZQ is ineffective against disease caused by liver flukes from the genus\n                    <jats:italic>Fasciola<\/jats:italic>\n                    . This is due to a single amino acid change within the target of PZQ, a transient receptor potential ion channel (TRPM\n                    <jats:sub>PZQ<\/jats:sub>\n                    ), in\n                    <jats:italic>Fasciola<\/jats:italic>\n                    species. Here we identify benzamidoquinazolinone analogs that are active against\n                    <jats:italic>Fasciola<\/jats:italic>\n                    TRPM\n                    <jats:sub>PZQ<\/jats:sub>\n                    . Structure-activity studies define an optimized ligand (BZQ) that caused protracted paralysis and damage to the protective tegument of these liver flukes. BZQ also retained activity against\n                    <jats:italic>Schistosoma mansoni<\/jats:italic>\n                    comparable to PZQ and was active against TRPM\n                    <jats:sub>PZQ<\/jats:sub>\n                    orthologs in all profiled species of parasitic fluke. This broad spectrum activity was manifest as BZQ adopts a pose within the binding pocket of TRPM\n                    <jats:sub>PZQ<\/jats:sub>\n                    dependent on a ubiquitously conserved residue. BZQ therefore acts as a universal activator of trematode TRPM\n                    <jats:sub>PZQ<\/jats:sub>\n                    and a first-in-class, broad spectrum flukicide.\n                  <\/jats:bold>\n                <\/jats:p>","DOI":"10.1101\/2023.09.22.559026","type":"posted-content","created":{"date-parts":[[2023,9,23]],"date-time":"2023-09-23T00:00:22Z","timestamp":1695427222000},"source":"Crossref","is-referenced-by-count":2,"title":["Target-based discovery of a broad spectrum flukicide"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0709-3284","authenticated-orcid":false,"given":"Daniel J.","family":"Sprague","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang-Kyu","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svenja","family":"Gramberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Bauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0065-7160","authenticated-orcid":false,"given":"Claudia M.","family":"Rohr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8030-6031","authenticated-orcid":false,"given":"Evgeny G.","family":"Chulkov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emery","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7734-0105","authenticated-orcid":false,"given":"Louis","family":"Scampavia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9080-4226","authenticated-orcid":false,"given":"Timothy P.","family":"Spicer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Haeberlein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6592-0877","authenticated-orcid":false,"given":"Jonathan S.","family":"Marchant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2023092708100722000_2023.09.22.559026v1.1","doi-asserted-by":"publisher","DOI":"10.1002\/med.2610030204"},{"key":"2023092708100722000_2023.09.22.559026v1.2","doi-asserted-by":"crossref","unstructured":"Waechtler, A. et al. 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