{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T22:41:43Z","timestamp":1792449703723,"version":"4.5.0"},"update-to":[{"DOI":"10.1371\/journal.pntd.0011992","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,3,11]],"date-time":"2024-03-11T00:00:00Z","timestamp":1710115200000}}],"reference-count":33,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2024,2,28]],"date-time":"2024-02-28T00:00:00Z","timestamp":1709078400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021856","name":"Ministero dell'Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["20154JRJPP"],"award-info":[{"award-number":["20154JRJPP"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021856","name":"Ministero dell'Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["20154JRJPP"],"award-info":[{"award-number":["20154JRJPP"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004462","name":"Consiglio Nazionale delle Ricerche","doi-asserted-by":"publisher","award":["CNR-CNCCS (Collezione Nazionale di Composti Chimici e Centro di Screening) \u201cRare, Neglected and Poverty Related Diseases Schistodiscovery Project\u201d (DSB.AD011.001.003"],"award-info":[{"award-number":["CNR-CNCCS (Collezione Nazionale di Composti Chimici e Centro di Screening) \u201cRare, Neglected and Poverty Related Diseases Schistodiscovery Project\u201d (DSB.AD011.001.003"]}],"id":[{"id":"10.13039\/501100004462","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100019470","name":"Lazio Innova","doi-asserted-by":"publisher","award":["POR FESR Lazio 2014 to 2020 HDACiPLAT Project A0375-2020-36575"],"award-info":[{"award-number":["POR FESR Lazio 2014 to 2020 HDACiPLAT Project A0375-2020-36575"]}],"id":[{"id":"10.13039\/100019470","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:p>Schistosomiasis is a major neglected parasitic disease that affects more than 240 million people worldwide caused by Platyhelminthes of the genus <jats:italic>Schistosoma<\/jats:italic>. The treatment of schistosomiasis relies on the long-term application of a single safe drug, praziquantel (PZQ). Unfortunately, PZQ is very effective on adult parasites and poorly on larval stage and immature juvenile worms; this can partially explain the re-infection in endemic areas where patients are likely to host parasites at different developmental stages concurrently. Moreover, the risk of development of drug resistance because of the widespread use of a single drug in a large population is nowadays a serious threat. Hence, research aimed at identifying novel drugs to be used alone or in combination with PZQ is needed. Schistosomes display morphologically distinct stages during their life cycle and epigenetic mechanisms are known to play important roles in parasite growth, survival, and development. Histone deacetylase (HDAC) enzymes, particularly HDAC8, are considered valuable for therapeutic intervention for the treatment of schistosomiasis. Herein, we report the phenotypic screening on both larvae and adult <jats:italic>Schistosoma mansoni<\/jats:italic> stages of structurally different HDAC inhibitors selected from the in-house Siena library. All molecules have previously shown inhibition profiles on human HDAC6 and\/or HDAC8 enzymes. Among them we identified a quinolone-based HDAC inhibitor, NF2839, that impacts larval and adult parasites as well as egg viability and maturation <jats:italic>in vitro<\/jats:italic>. Importantly, this quinolone-based compound also increases histone and tubulin acetylation in <jats:italic>S<\/jats:italic>. <jats:italic>mansoni<\/jats:italic> parasites, thus representing a leading candidate for the development of new generation anti-Schistosoma chemotherapeutics.<\/jats:p>","DOI":"10.1371\/journal.pntd.0011992","type":"journal-article","created":{"date-parts":[[2024,2,28]],"date-time":"2024-02-28T18:35:21Z","timestamp":1709145321000},"page":"e0011992","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Effects of structurally distinct human HDAC6 and HDAC6\/HDAC8 inhibitors against S. mansoni larval and adult worm stages"],"prefix":"10.1371","volume":"18","author":[{"given":"Roberto","family":"Gimmelli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuliana","family":"Papoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fulvio","family":"Saccoccia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristiana","family":"Lalli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Gemma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Campiani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2367-9709","authenticated-orcid":true,"given":"Giovina","family":"Ruberti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,2,28]]},"reference":[{"key":"pntd.0011992.ref001","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/s41572-018-0013-8","article-title":"Schistosomiasis.","volume":"4","author":"DP McManus","year":"2018","journal-title":"Nat Rev Dis Primers"},{"key":"pntd.0011992.ref002","doi-asserted-by":"crossref","first-page":"2255","DOI":"10.3390\/ijms23042255","article-title":"Vaccines for human schistosomiasis: recent progress, new developments, and future prospects.","volume":"23","author":"AJ Molehin","year":"2022","journal-title":"Int J Mol Sci."},{"key":"pntd.0011992.ref003","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.molbiopara.2014.06.002","article-title":"Schistosomiasis control: praziquantel forever?","volume":"195","author":"D Cioli","year":"2014","journal-title":"Mol Biochem Parasitol"},{"issue":"41","key":"pntd.0011992.ref004","doi-asserted-by":"crossref","first-page":"e2110711118","DOI":"10.1073\/pnas.2110711118","article-title":"Spillover, hybridization, and persistence in schistosome transmission dynamics at the human-animal interface","volume":"118","author":"A Borlase","year":"2011","journal-title":"Proc Natl Acad Sci USA"},{"key":"pntd.0011992.ref005","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1017\/S0031182016001190","article-title":"Hybridizations within the genus Schistosoma: implications for evolution, epidemiology and control","volume":"144","author":"E L\u00e9ger","year":"2017","journal-title":"Parasitology"},{"issue":"1","key":"pntd.0011992.ref006","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s40249-022-00958-0","article-title":"Hybridization increases genetic diversity in Schistosoma haematobium populations infecting humans in Cameroon.","volume":"26","author":"FFD Teukeng","year":"2022","journal-title":"Infect Dis Poverty"},{"issue":"1","key":"pntd.0011992.ref007","doi-asserted-by":"crossref","first-page":"319","DOI":"10.3201\/eid2701.204391","article-title":"Developing Endemicity of Schistosomiasis, Corsica, France","volume":"27","author":"C Rothe","year":"2021","journal-title":"Emerg Infect Dis"},{"key":"pntd.0011992.ref008","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.cbpa.2020.05.008","article-title":"Targeting histone acetylation\/deacetylation in parasites: an update (2017\u20132020).","volume":"57","author":"R Fioravanti","year":"2020","journal-title":"Curr Opin Chem Biol"},{"key":"pntd.0011992.ref009","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/s12276-020-0382-4","article-title":"Kim, JS A short guide to histone deacetylases including recent progress on class II enzymes","volume":"52","author":"SY Park","year":"2020","journal-title":"Exp Mol Med"},{"key":"pntd.0011992.ref010","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1016\/j.bbrc.2008.10.090","article-title":"The class I histone deacetylases of the platyhelminth parasite Schistosoma mansoni","volume":"377","author":"F Oger","year":"2008","journal-title":"Biochem Biophys Res Commun"},{"key":"pntd.0011992.ref011","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.molbiopara.2009.06.001","article-title":"Histone deacetylase inhibitors induce apoptosis, histone hyperacetylation and up-regulation of gene transcription in Schistosoma mansoni","volume":"168","author":"F Dubois","year":"2009","journal-title":"Mol Biochem Parasitol"},{"key":"pntd.0011992.ref012","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.meegid.2017.05.011","article-title":"Evolutionary relationships among protein lysine deacetylases of parasites causing neglected diseases","volume":"53","author":"LL Scholte","year":"2017","journal-title":"Infect Genet Evol"},{"key":"pntd.0011992.ref013","doi-asserted-by":"crossref","first-page":"e1003645","DOI":"10.1371\/journal.ppat.1003645","article-title":"Structural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni","volume":"9","author":"M Marek","year":"2013","journal-title":"PLoS Pathog"},{"key":"pntd.0011992.ref014","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.tips.2015.04.013","article-title":"HDAC8: a multifaceted target for therapeutic interventions","volume":"36","author":"A Chakrabarti","year":"2015","journal-title":"Trends Pharmacol Sci"},{"key":"pntd.0011992.ref015","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1186\/s13071-018-3268-8","article-title":"Identification of novel multi-stage histone deacetylase (HDAC) inhibitors that impair Schistosoma mansoni viability and egg production.","volume":"11","author":"A Guidi","year":"2018","journal-title":"Parasites Vectors"},{"key":"pntd.0011992.ref016","doi-asserted-by":"crossref","first-page":"2423","DOI":"10.1021\/acs.jmedchem.5b01478","article-title":"Structure-based design and synthesis of novel inhibitors targeting HDAC8 from Schistosoma mansoni for the treatment of schistosomiasis","volume":"59","author":"T Heimburg","year":"2016","journal-title":"J Med Chem"},{"key":"pntd.0011992.ref017","doi-asserted-by":"crossref","first-page":"10000","DOI":"10.1021\/acs.jmedchem.8b01087","article-title":"Characterization of Histone Deacetylase 8 (HDAC8) selective inhibition reveals specific active site structural and functional determinants","volume":"61","author":"M Marek","year":"2018","journal-title":"J Med Chem"},{"issue":"1","key":"pntd.0011992.ref018","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1021\/acsinfecdis.9b00224","article-title":"Screening and phenotypical characterization of Schistosoma mansoni Histone Deacetylase 8 (SmHDAC8) inhibitors as multistage antischistosomal agents.","volume":"6","author":"F Saccoccia","year":"2020","journal-title":"ACS Infect Dis"},{"key":"pntd.0011992.ref019","doi-asserted-by":"crossref","first-page":"80","DOI":"10.3390\/ph15010080","article-title":"Inhibitors for the treatment of Schistosomiasis.","volume":"15","author":"E Ghazy","year":"2022","journal-title":"Pharmaceuticals"},{"issue":"18","key":"pntd.0011992.ref020","doi-asserted-by":"crossref","first-page":"e202100622","DOI":"10.1002\/cmdc.202100622","article-title":"Phenotypic screening of Histone Deacetylase (HDAC) inhibitors against Schistosoma mansoni.","volume":"17","author":"MM Hassan","year":"2022","journal-title":"Chem Med Chem"},{"issue":"10","key":"pntd.0011992.ref021","doi-asserted-by":"crossref","first-page":"102375","DOI":"10.1016\/j.jbc.2022.102375","article-title":"Crystal structures of Schistosoma mansoni histone deacetylase 8 reveal a novel binding site for allosteric inhibitors","volume":"298","author":"F Saccoccia","year":"2022","journal-title":"J Biol Chem"},{"issue":"3","key":"pntd.0011992.ref022","doi-asserted-by":"crossref","first-page":"e202200510","DOI":"10.1002\/cmdc.202200510","article-title":"Chemically diverse S. mansoni HDAC8 inhibitors reduce viability in worm larval and adult stages.","volume":"18","author":"B Noce","year":"2023","journal-title":"Chem Med Chem"},{"issue":"14","key":"pntd.0011992.ref023","doi-asserted-by":"crossref","first-page":"9960","DOI":"10.1021\/acs.jmedchem.1c00184","article-title":"Harnessing the role of HDAC6 in idiopathic pulmonary fibrosis: design, synthesis, structural analysis, and biological evaluation of potent inhibitors","volume":"64","author":"G Campiani","year":"2021","journal-title":"J Med Chem"},{"issue":"11","key":"pntd.0011992.ref024","doi-asserted-by":"crossref","first-page":"2268","DOI":"10.1021\/acsmedchemlett.0c00395","article-title":"Spiroindoline-capped selective HDAC6 Inhibitors: design, synthesis, structural analysis, and biological evaluation","volume":"11","author":"AP Saraswati","year":"2020","journal-title":"ACS Med Chem Lett"},{"key":"pntd.0011992.ref025","doi-asserted-by":"crossref","first-page":"112998","DOI":"10.1016\/j.ejmech.2020.112998","article-title":"Novel quinolone-based potent and selective HDAC6 inhibitors: synthesis, molecular modeling studies and biological investigation","volume":"212","author":"N Relitti","year":"2021","journal-title":"Eur J Med Chem"},{"key":"pntd.0011992.ref026","doi-asserted-by":"crossref","first-page":"114409","DOI":"10.1016\/j.ejmech.2022.114409","article-title":"Azetidin-2-one-based small molecules as dual hHDAC6\/HDAC8 inhibitors: investigation of their mechanism of action and impact of dual inhibition profile on cell viability","volume":"238","author":"S Federico","year":"2022","journal-title":"Eur J Med Chem"},{"key":"pntd.0011992.ref027","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays","volume":"65","author":"T. Mosmann","year":"1983","journal-title":"J. Immunol. Meth"},{"key":"pntd.0011992.ref028","doi-asserted-by":"crossref","first-page":"e0143333","DOI":"10.1371\/journal.pone.0143333","article-title":"MET Gene Amplification and MET Receptor Activation Are Not Sufficient to Predict Efficacy of Combined MET and EGFR Inhibitors in EGFR TKI-Resistant NSCLC Cells.","volume":"10","author":"D Presutti","year":"2015","journal-title":"PloS One"},{"key":"pntd.0011992.ref029","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."},{"key":"pntd.0011992.ref030","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/978-1-0716-0635-3_18","article-title":"Luminescence-based, low- and medium-throughput assays for drug screening in Schistosoma mansoni larval stage","volume":"2151","author":"A Guidi","year":"2020","journal-title":"Met Mol Biol"},{"key":"pntd.0011992.ref031","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":"5","key":"pntd.0011992.ref032","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s00427-009-0285-9","article-title":"The embryonic development of Schistosoma mansoni eggs: proposal for a new staging system","volume":"219","author":"AD Jurberg","year":"2009","journal-title":"Dev Genes Evol"},{"key":"pntd.0011992.ref033","doi-asserted-by":"crossref","first-page":"921","DOI":"10.2307\/3277120","article-title":"Evolution and characteristics of Schistosoma mansoni eggs laid in vitro","volume":"54","author":"RM Michaels","year":"1968","journal-title":"J Parasitol"}],"updated-by":[{"DOI":"10.1371\/journal.pntd.0011992","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,3,11]],"date-time":"2024-03-11T00:00:00Z","timestamp":1710115200000}}],"container-title":["PLOS Neglected Tropical Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0011992","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,11]],"date-time":"2024-03-11T17:46:42Z","timestamp":1710179202000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0011992"}},"subtitle":[],"editor":[{"given":"Aaron R.","family":"Jex","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,2,28]]},"references-count":33,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,2,28]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pntd.0011992","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pntd.0011992","asserted-by":"object"}]},"ISSN":["1935-2735"],"issn-type":[{"value":"1935-2735","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,28]]}}}