{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:21:02Z","timestamp":1760059262231,"version":"build-2065373602"},"reference-count":102,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T00:00:00Z","timestamp":1749081600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institutes of Health, National Institute of Allergy and Infectious Diseases Award","doi-asserted-by":"publisher","award":["AI137667"],"award-info":[{"award-number":["AI137667"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Schistosomiasis is a parasitic disease caused by helminth parasites of the genus Schistosoma, affecting &gt;200 million people worldwide. Current schistosomiasis treatment relies on a single drug, praziquantel, highlighting the urgent need for new therapies. We have identified a non-neuronal tegumental acetylcholinesterase from Schistosoma mansoni (SmTAChE) as a rational and molecularly defined drug target. Molecular modeling reveals significant structural differences between SmTAChE and human AChE, suggesting the potential for identifying parasite-specific inhibitors. Here, we screened recombinant SmTAChE (rSmTAChE) against two chemical libraries: the Broad Institute Drug Repurposing Hub (5440 compounds) and the Diversity-Oriented Synthesis (DOS)-A library (3840 compounds). High-throughput screening identified 116 hits from the Repurposing Hub (2.13% hit rate) and 44 from the DOS-A (1.14% hit rate) library that inhibited rSmTAChE \u226560% at 20 \u00b5M. Dose\u2013response assays using both rSmTAChE and recombinant human AChE (rHsAChE) revealed 19 Repurposing Hub compounds (IC50: 0.4\u201324 \u00b5M) and four DOS-A scaffolds (IC50: 13\u201329 \u00b5M), with higher selectivity for rSmTAChE. Selective inhibitors such as cepharanthine, primaquine, mesalazine, and embelin emerged as promising candidates for further evaluation in schistosomiasis treatment. These 23 newly identified selective hits provide a foundation for the further development of novel anti-schistosome therapies.<\/jats:p>","DOI":"10.3390\/ijms26115415","type":"journal-article","created":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T08:34:32Z","timestamp":1749112472000},"page":"5415","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["High-Throughput Screens of Repurposing Hub and DOS Chemical Libraries Reveal Compounds with Novel and Potent Inhibitory Activity Against the Essential Non-Neuronal Acetylcholinesterase of Schistosoma mansoni (SmTAChE)"],"prefix":"10.3390","volume":"26","author":[{"given":"Patrick J.","family":"Skelly","sequence":"first","affiliation":[{"name":"Molecular Helminthology Laboratory, Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3318-9623","authenticated-orcid":false,"given":"Akram A.","family":"Da\u2019dara","sequence":"additional","affiliation":[{"name":"Molecular Helminthology Laboratory, Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/S1473-3099(06)70521-7","article-title":"Schistosomiasis and water resources develop-ment: Systematic review, meta-analysis, and estimates of people at risk","volume":"6","author":"Steinmann","year":"2006","journal-title":"Lancet Infect. 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