{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T07:03:21Z","timestamp":1791443001649,"version":"4.3.3"},"update-to":[{"DOI":"10.1371\/journal.pntd.0009432","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T00:00:00Z","timestamp":1623283200000}}],"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2021,5,25]],"date-time":"2021-05-25T00:00:00Z","timestamp":1621900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["DFG 1469\/15-1"],"award-info":[{"award-number":["DFG 1469\/15-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009945","name":"Merck KGaA","doi-asserted-by":"publisher","award":["Direct funding"],"award-info":[{"award-number":["Direct funding"]}],"id":[{"id":"10.13039\/100009945","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005713","name":"Technische Universit\u00e4t M\u00fcnchen","doi-asserted-by":"publisher","award":["Alexander Scheer Professorship"],"award-info":[{"award-number":["Alexander Scheer Professorship"]}],"id":[{"id":"10.13039\/501100005713","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:sec id=\"sec001\"><jats:title>Background<\/jats:title><jats:p>Anthelminthic treatment options against schistosomiasis are limited. The current treatment relies almost exclusively on a single drug, praziquantel (PZQ). As a consequence, the development of resistance to PZQ and limited activity of PZQ against earlier development stages are respectively a risk and a limitation to achieving the goals of the new WHO roadmap towards elimination. For the discovery of new chemical starting points, the<jats:italic>in vitro<\/jats:italic>drug screening on<jats:italic>Schistosoma mansoni<\/jats:italic>(<jats:italic>S<\/jats:italic>.<jats:italic>mansoni<\/jats:italic>) against newly transformed schistosomula (NTS) is still the most predominant approach. The use of only NTS in the initial screening limits sensitivity to potential new compounds which are predominantly active in later developmental stages. Using our recently described highly standardized, straightforward and reliable culture method that generates high rates of juvenile worms, we aimed to repurpose a subset of the National Center for Advancing Translational Sciences (NCATS) Pharmaceutical Collection (340 compounds) to identify new hits with an<jats:italic>in vitro<\/jats:italic>worm culture assay.<\/jats:p><\/jats:sec><jats:sec id=\"sec002\"><jats:title>Methodology\/Principal findings<\/jats:title><jats:p>Cercariae were mechanically transformed into skin-stage (SkS) schistosomula and continuously cultured for 3\u20136 weeks to the liver stage (LiS). A commercial source of serum was identified, and decrease of NTS\/well along with optimal drug testing conditions was established to test compounds on early and late LiS worms. The library was screened in 96-well format assays using praziquantel (PZQ) as a positive control. Primary screening allowed a 5.9% hit rate and generated two confirmed hits on adult worms; a prophylactic antianginal agent and an antihistaminic drug.<\/jats:p><\/jats:sec><jats:sec id=\"sec003\"><jats:title>Conclusion<\/jats:title><jats:p>With this standardized and reliable<jats:italic>in vitro<\/jats:italic>assay, important<jats:italic>S<\/jats:italic>.<jats:italic>mansoni<\/jats:italic>developmental stages up to LiS worms can be generated and cultured over an extended period. When exposed to a subset of the NCATS Pharmaceutical Collection, 3 compounds yielded a defined anti-schistosomal phenotype on juvenile worms. Translation of activity on perfused adult<jats:italic>S<\/jats:italic>.<jats:italic>mansoni<\/jats:italic>worms was achieved only for perhexiline (a prophylactic antianginal agent) and astemizole (an antihistaminic drug).<\/jats:p><\/jats:sec>","DOI":"10.1371\/journal.pntd.0009432","type":"journal-article","created":{"date-parts":[[2021,5,25]],"date-time":"2021-05-25T17:32:10Z","timestamp":1621963930000},"page":"e0009432","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Identification of hit compounds with anti-schistosomal activity on in vitro generated juvenile worms in cell-free medium"],"prefix":"10.1371","volume":"15","author":[{"given":"Nermina","family":"Vejzagi\u0107","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich Fabien","family":"Prodjinotho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1472-5566","authenticated-orcid":true,"given":"Nagwa","family":"El-Khafif","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8886-8311","authenticated-orcid":true,"given":"Ruili","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4523-9977","authenticated-orcid":true,"given":"Anton","family":"Simeonov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5654-8919","authenticated-orcid":true,"given":"Thomas","family":"Spangenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7996-4838","authenticated-orcid":true,"given":"Clarissa","family":"Prazeres da Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,5,25]]},"reference":[{"key":"pntd.0009432.ref001","doi-asserted-by":"crossref","DOI":"10.1007\/978-1-4939-0915-5","volume-title":"Digenetic trematodes","author":"R Toledo","year":"2014"},{"key":"pntd.0009432.ref002","volume-title":"Schistosomiasis fact sheet","author":"WHO","year":"2018"},{"key":"pntd.0009432.ref003","volume-title":"Accelerating Work to Overcome The Global Impact Of Neglected Tropical Diseases -A Roadmap For Implementation-","author":"WHO","year":"2012"},{"key":"pntd.0009432.ref004","volume-title":"Ending the neglect to attain the sustainable development goals: a road map for neglected tropical diseases 2021\u20132030","author":"WHO","year":"2020"},{"key":"pntd.0009432.ref005","volume-title":"Water, Sanitation & hygiene for accelerating and sustaining progress on Neglected Tropical Diseases","author":"WHO"},{"key":"pntd.0009432.ref006","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1186\/s13071-015-0766-9","article-title":"The roles of water, sanitation and hygiene in reducing schistosomiasis: a review","volume":"8","author":"JE Grimes","year":"2015","journal-title":"Parasit Vectors"},{"issue":"9","key":"pntd.0009432.ref007","first-page":"1151","article-title":"Reduced Efficacy of Praziquantel Against Schistosoma mansoni Is Associated With Multiple Rounds of Mass Drug Administration","volume":"63","author":"T Crellen","year":"2016","journal-title":"Clin Infect Dis"},{"issue":"3","key":"pntd.0009432.ref008","article-title":"Neglected tropical diseases\u2014the present and the future","volume":"138","author":"AS Winkler","year":"2018","journal-title":"Tidsskr Nor Laegeforen"},{"issue":"10","key":"pntd.0009432.ref009","doi-asserted-by":"crossref","first-page":"e0140147","DOI":"10.1371\/journal.pone.0140147","article-title":"The Role of Efflux Pumps in Schistosoma mansoni Praziquantel Resistant Phenotype","volume":"10","author":"A Pinto-Almeida","year":"2015","journal-title":"PLoS One"},{"issue":"8","key":"pntd.0009432.ref010","doi-asserted-by":"crossref","first-page":"e504","DOI":"10.1371\/journal.pntd.0000504","article-title":"Reduced susceptibility to praziquantel among naturally occurring Kenyan isolates of Schistosoma mansoni","volume":"3","author":"SD Melman","year":"2009","journal-title":"PLoS Negl Trop Dis"},{"issue":"5","key":"pntd.0009432.ref011","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1007\/s00436-012-3151-z","article-title":"Susceptibility or resistance of praziquantel in human schistosomiasis: a review","volume":"111","author":"W Wang","year":"2012","journal-title":"Parasitol Res"},{"issue":"3","key":"pntd.0009432.ref012","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/S1471-4922(01)02209-7","article-title":"Interpreting low praziquantel cure rates of Schistosoma mansoni infections in Senegal","volume":"18","author":"A Danso-Appiah","year":"2002","journal-title":"Trends Parasitol"},{"key":"pntd.0009432.ref013","volume-title":"The principle of Humane Experimental Technique","author":"WMS Russell","year":"1959"},{"issue":"1","key":"pntd.0009432.ref014","doi-asserted-by":"crossref","first-page":"e0006590","DOI":"10.1371\/journal.pntd.0006590","article-title":"A novel cell-free method to culture Schistosoma mansoni from cercariae to juvenile worm stages for in vitro drug testing","volume":"13","author":"S Frahm","year":"2019","journal-title":"PLoS Negl Trop Dis"},{"issue":"80","key":"pntd.0009432.ref015","doi-asserted-by":"crossref","first-page":"80ps16","DOI":"10.1126\/scitranslmed.3001862","article-title":"The NCGC pharmaceutical collection: a comprehensive resource of clinically approved drugs enabling repurposing and chemical genomics","volume":"3","author":"R Huang","year":"2011","journal-title":"Sci Transl Med"},{"issue":"2","key":"pntd.0009432.ref016","doi-asserted-by":"crossref","first-page":"179","DOI":"10.2307\/3280632","article-title":"Cultivation of Schistosoma mansoni in vitro. I. Establishment of cultures from cercariae and development until pairing","volume":"67","author":"PF Basch","year":"1981","journal-title":"J Parasitol"},{"key":"pntd.0009432.ref017","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/0014-4894(65)90037-8","article-title":"In vitro cultivation of Schistosoma mansoni","volume":"16","author":"JA Clegg","year":"1965","journal-title":"Exp Parasitol"},{"key":"pntd.0009432.ref018","volume-title":"Data Analysis, Machine Learning and Applications; 2008","author":"MR Berthold","year":"2008"},{"issue":"2","key":"pntd.0009432.ref019","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1177\/108705719900400206","article-title":"A simple statistical parameter for use in evaluation and validation of high throughput screening assays","volume":"4","author":"J-H Zhang","year":"1999","journal-title":"Journal of biomolecular screening"},{"issue":"23","key":"pntd.0009432.ref020","doi-asserted-by":"crossref","first-page":"3815","DOI":"10.1093\/bioinformatics\/btv455","article-title":"Impact of normalization methods on high-throughput screening data with high hit rates and drug testing with dose\u2013response data","volume":"31","author":"J-P Mpindi","year":"2015","journal-title":"Bioinformatics"},{"issue":"2","key":"pntd.0009432.ref021","first-page":"233","article-title":"Comparison of geographical strains of Schistosoma mansoni in the mouse","volume":"46","author":"LA Anderson","year":"1972","journal-title":"Bull World Health Organ"},{"issue":"6","key":"pntd.0009432.ref022","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/0035-9203(67)90037-5","article-title":"A comparison of Puerto Rican, Brazilian, Egyptian and Tanzanian strains of Schistosoma mansoni in mice: penetration of cercariae, maturation of schistosomes and production of liver disease","volume":"61","author":"KS Warren","year":"1967","journal-title":"Transactions of the Royal Society of Tropical Medicine and Hygiene"},{"issue":"4","key":"pntd.0009432.ref023","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1128\/JCM.02382-10","article-title":"Isothermal microcalorimetry to study drugs against Schistosoma mansoni","volume":"49","author":"T Manneck","year":"2011","journal-title":"J Clin Microbiol"},{"issue":"11","key":"pntd.0009432.ref024","doi-asserted-by":"crossref","first-page":"e885","DOI":"10.1371\/journal.pntd.0000885","article-title":"A novel high throughput assay for anthelmintic drug screening and resistance diagnosis by real-time monitoring of parasite motility","volume":"4","author":"MJ Smout","year":"2010","journal-title":"PLoS Negl Trop Dis"},{"issue":"3","key":"pntd.0009432.ref025","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.ijpddr.2015.07.002","article-title":"Viability of developmental stages of Schistosoma mansoni quantified with xCELLigence worm real-time motility assay (xWORM)","volume":"5","author":"G Rinaldi","year":"2015","journal-title":"Int J Parasitol Drugs Drug Resist"},{"issue":"12","key":"pntd.0009432.ref026","doi-asserted-by":"crossref","first-page":"2613","DOI":"10.1021\/acssensors.8b01027","article-title":"Impedance-Based Microfluidic Assay for Automated Antischistosomal Drug Screening","volume":"3","author":"K Chawla","year":"2018","journal-title":"ACS Sens"},{"key":"pntd.0009432.ref027","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1186\/s13071-015-1233-3","article-title":"Fluorescence\/luminescence-based markers for the assessment of Schistosoma mansoni schistosomula drug assays","volume":"8","author":"G Panic","year":"2015","journal-title":"Parasit Vectors"},{"issue":"7","key":"pntd.0009432.ref028","doi-asserted-by":"crossref","first-page":"e759","DOI":"10.1371\/journal.pntd.0000759","article-title":"Development and validation of a quantitative, high-throughput, fluorescent-based bioassay to detect schistosoma viability","volume":"4","author":"E Peak","year":"2010","journal-title":"PLoS Negl Trop Dis"},{"issue":"8","key":"pntd.0009432.ref029","doi-asserted-by":"crossref","first-page":"e795","DOI":"10.1371\/journal.pntd.0000795","article-title":"Comparison of microscopy and Alamar blue reduction in a larval based assay for schistosome drug screening","volume":"4","author":"NR Mansour","year":"2010","journal-title":"PLoS Negl Trop Dis"},{"issue":"1","key":"pntd.0009432.ref030","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1186\/s13071-017-2240-3","article-title":"A high-throughput colorimetric assay for detection of Schistosoma mansoni viability based on the tetrazolium salt XTT","volume":"10","author":"PHN Aguiar","year":"2017","journal-title":"Parasit Vectors"},{"issue":"2","key":"pntd.0009432.ref031","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1128\/AAC.03809-14","article-title":"Lactate as a novel quantitative measure of viability in Schistosoma mansoni drug sensitivity assays","volume":"59","author":"S Howe","year":"2015","journal-title":"Antimicrob Agents Chemother"},{"issue":"10","key":"pntd.0009432.ref032","doi-asserted-by":"crossref","first-page":"e0005994","DOI":"10.1371\/journal.pntd.0005994","article-title":"Discovery by organism based high-throughput screening of new multi-stage compounds affecting Schistosoma mansoni viability, egg formation and production","volume":"11","author":"A Guidi","year":"2017","journal-title":"PLoS Negl Trop Dis"},{"issue":"1","key":"pntd.0009432.ref033","doi-asserted-by":"crossref","first-page":"e0003484","DOI":"10.1371\/journal.pntd.0003484","article-title":"Development and validation of a luminescence-based, medium-throughput assay for drug screening in Schistosoma mansoni","volume":"9","author":"C Lalli","year":"2015","journal-title":"PLoS Negl Trop Dis"},{"issue":"7","key":"pntd.0009432.ref034","doi-asserted-by":"crossref","first-page":"e1762","DOI":"10.1371\/journal.pntd.0001762","article-title":"Whole organism high-content screening by label-free, image-based Bayesian classification for parasitic diseases","volume":"6","author":"RA Paveley","year":"2012","journal-title":"PLoS Negl Trop Dis"},{"issue":"4","key":"pntd.0009432.ref035","doi-asserted-by":"crossref","first-page":"e0004659","DOI":"10.1371\/journal.pntd.0004659","article-title":"High Throughput Screening Identifies Novel Lead Compounds with Activity against Larval, Juvenile and Adult Schistosoma mansoni","volume":"10","author":"NR Mansour","year":"2016","journal-title":"PLoS Negl Trop Dis"},{"issue":"1","key":"pntd.0009432.ref036","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1186\/s13071-018-2855-z","article-title":"Screening a repurposing library, the Medicines for Malaria Venture Stasis Box, against Schistosoma mansoni","volume":"11","author":"V Pasche","year":"2018","journal-title":"Parasit Vectors"},{"key":"pntd.0009432.ref037","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1186\/s13071-015-1023-y","article-title":"Repurposing of anticancer drugs: in vitro and in vivo activities against Schistosoma mansoni","volume":"8","author":"N Cowan","year":"2015","journal-title":"Parasit Vectors"},{"issue":"7","key":"pntd.0009432.ref038","doi-asserted-by":"crossref","first-page":"e478","DOI":"10.1371\/journal.pntd.0000478","article-title":"Drug discovery for schistosomiasis: hit and lead compounds identified in a library of known drugs by medium-throughput phenotypic screening","volume":"3","author":"MH Abdulla","year":"2009","journal-title":"PLoS Negl Trop Dis"},{"issue":"7","key":"pntd.0009432.ref039","doi-asserted-by":"crossref","first-page":"e0003962","DOI":"10.1371\/journal.pntd.0003962","article-title":"Activity Profile of an FDA-Approved Compound Library against Schistosoma mansoni","volume":"9","author":"G Panic","year":"2015","journal-title":"PLoS Negl Trop Dis"},{"key":"pntd.0009432.ref040","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.ijpddr.2020.05.002","article-title":"Identification of annotated bioactive molecules that impair motility of the blood fluke Schistosoma mansoni","volume":"13","author":"TB Duguet","year":"2020","journal-title":"Int J Parasitol Drugs Drug Resist"},{"issue":"8","key":"pntd.0009432.ref041","doi-asserted-by":"crossref","first-page":"e0004928","DOI":"10.1371\/journal.pntd.0004928","article-title":"Discovery and Characterization of Novel Anti-schistosomal Properties of the Anti-anginal Drug, Perhexiline and Its Impact on Schistosoma mansoni Male and Female Reproductive Systems","volume":"10","author":"A Guidi","year":"2016","journal-title":"PLoS Negl Trop Dis"}],"updated-by":[{"DOI":"10.1371\/journal.pntd.0009432","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T00:00:00Z","timestamp":1623283200000}}],"container-title":["PLOS Neglected Tropical Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0009432","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,4]],"date-time":"2023-11-04T04:32:10Z","timestamp":1699072330000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0009432"}},"subtitle":[],"editor":[{"given":"Winka","family":"Le Clec\u2019h","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,5,25]]},"references-count":41,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5,25]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pntd.0009432","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pntd.0009432","asserted-by":"object"}]},"ISSN":["1935-2735"],"issn-type":[{"value":"1935-2735","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,25]]}}}