{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,26]],"date-time":"2025-10-26T15:10:10Z","timestamp":1761491410966,"version":"3.37.3"},"reference-count":11,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,5,15]],"date-time":"2022-05-15T00:00:00Z","timestamp":1652572800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,5,15]],"date-time":"2022-05-15T00:00:00Z","timestamp":1652572800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100009945","name":"Merck KGaA","doi-asserted-by":"publisher","award":["Merck KGaA"],"award-info":[{"award-number":["Merck KGaA"]}],"id":[{"id":"10.13039\/100009945","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005856","name":"Faculdade de Ci\u00eancias e Tecnologia, Universidade Nova de Lisboa","doi-asserted-by":"publisher","award":["PD\/BD\/128371\/2017"],"award-info":[{"award-number":["PD\/BD\/128371\/2017"]}],"id":[{"id":"10.13039\/501100005856","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Malar J"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Targeting the asymptomatic liver stage of <jats:italic>Plasmodium<\/jats:italic> infection through chemoprevention could become a key intervention to reduce malaria-associated incidence and mortality.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>M5717, a <jats:italic>Plasmodium<\/jats:italic>\u00a0elongation factor 2 inhibitor, was assessed in vitro and in vivo with readily accessible <jats:italic>Plasmodium berghei<\/jats:italic> parasites. In an animal refinement, reduction, replacement approach, the in vitro IC<jats:sub>99<\/jats:sub> value was used to feed a Population Pharmacokinetics modelling and simulation approach to determine meaningful effective doses for a subsequent <jats:italic>Plasmodium<\/jats:italic> sporozoite-induced volunteer infection study.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Doses of 100 and 200\u00a0mg would provide exposures exceeding IC<jats:sub>99<\/jats:sub> in 96 and 100% of the simulated population, respectively.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>This approach has the potential to accelerate the search for new anti-malarials, to reduce the number of healthy volunteers needed in a clinical study and decrease and refine the animal use in the preclinical phase.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Graphical Abstract<\/jats:title>\n                \n              <\/jats:sec>","DOI":"10.1186\/s12936-022-04171-0","type":"journal-article","created":{"date-parts":[[2022,5,15]],"date-time":"2022-05-15T06:16:04Z","timestamp":1652595364000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Translation of liver stage activity of M5717, a Plasmodium\u00a0elongation factor 2 inhibitor: from bench to bedside"],"prefix":"10.1186","volume":"21","author":[{"given":"Akash","family":"Khandelwal","sequence":"first","affiliation":[]},{"given":"Francisca","family":"Arez","sequence":"additional","affiliation":[]},{"given":"Paula M.","family":"Alves","sequence":"additional","affiliation":[]},{"given":"Lassina","family":"Badolo","sequence":"additional","affiliation":[]},{"given":"Catarina","family":"Brito","sequence":"additional","affiliation":[]},{"given":"Christoph","family":"Fischli","sequence":"additional","affiliation":[]},{"given":"Diana","family":"Fontinha","sequence":"additional","affiliation":[]},{"given":"Claude","family":"Oeuvray","sequence":"additional","affiliation":[]},{"given":"Miguel","family":"Prud\u00eancio","sequence":"additional","affiliation":[]},{"given":"Matthias","family":"Rottmann","sequence":"additional","affiliation":[]},{"given":"Justin","family":"Wilkins","sequence":"additional","affiliation":[]},{"given":"\u00d6zkan","family":"Yalkinoglu","sequence":"additional","affiliation":[]},{"given":"Wilhelmina M.","family":"Bagchus","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5654-8919","authenticated-orcid":false,"given":"Thomas","family":"Spangenberg","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2022,5,15]]},"reference":[{"key":"4171_CR1","volume-title":"World malaria report 2020","author":"WHO","year":"2020","unstructured":"WHO. World malaria report 2020. Geneva: World Heath Organization; 2020."},{"key":"4171_CR2","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1038\/nrmicro1529","volume":"4","author":"M Prud\u00eancio","year":"2006","unstructured":"Prud\u00eancio M, Rodriguez A, Mota MM. The silent path to thousands of merozoites: the Plasmodium liver stage. Nat Rev Microbiol. 2006;4:849\u201356.","journal-title":"Nat Rev Microbiol"},{"key":"4171_CR3","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1021\/jm201095h","volume":"55","author":"T Rodrigues","year":"2012","unstructured":"Rodrigues T, Prud\u00eancio M, Moreira R, Mota MM, Lopes F. Targeting the liver stage of malaria parasites: a yet unmet goal. J Med Chem. 2012;55:995\u20131012.","journal-title":"J Med Chem"},{"key":"4171_CR4","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.1016\/S1473-3099(21)00252-8","volume":"21","author":"JS McCarthy","year":"2021","unstructured":"McCarthy JS, Yalkinoglu \u00d6, Odedra A, et al. Safety, pharmacokinetics and antimalarial activity of the novel Plasmodium eukaryotic translation elongation factor 2 inhibitor M5717: a first in human, randomised, placebo-controlled, double-blind, single ascending dose study and a volunteer infection study. Lancet Infect Dis. 2021;21:1713\u201324.","journal-title":"Lancet Infect Dis"},{"key":"4171_CR5","doi-asserted-by":"publisher","first-page":"773","DOI":"10.3390\/v13050773","volume":"13","author":"F Arez","year":"2021","unstructured":"Arez F, Rodrigues AF, Brito C, Alves PM. Bioengineered liver cell models of hepatotropic infections. Viruses. 2021;13:773.","journal-title":"Viruses"},{"key":"4171_CR6","doi-asserted-by":"publisher","first-page":"642","DOI":"10.3390\/antibiotics10060642","volume":"10","author":"K Kulkeaw","year":"2021","unstructured":"Kulkeaw K. Next-generation human liver models for antimalarial drug assays. Antibiotics. 2021;10:642.","journal-title":"Antibiotics"},{"key":"4171_CR7","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1038\/laban.1217","volume":"46","author":"MJ Prescott","year":"2017","unstructured":"Prescott MJ, Lidster K. Improving quality of science through better animal welfare: the NC3Rs strategy. Lab Anim. 2017;46:152\u20136.","journal-title":"Lab Anim"},{"key":"4171_CR8","unstructured":"PK\/PD modelling of M5717 in malaria. \u00a0Accessed 15 Oct\u00a0\u00a02021."},{"key":"4171_CR9","doi-asserted-by":"publisher","first-page":"1831","DOI":"10.1021\/acsinfecdis.9b00144","volume":"5","author":"F Arez","year":"2019","unstructured":"Arez F, Rebelo SP, Fontinha D, Simao D, Martins TR, Machado M, et al. Flexible 3D cell-based platforms for the discovery and profiling of novel drugs targeting Plasmodium hepatic infection. ACS Infect Dis. 2019;5:1831\u201342.","journal-title":"ACS Infect Dis"},{"key":"4171_CR10","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1038\/nature14451","volume":"522","author":"B Baraga\u00f1a","year":"2015","unstructured":"Baraga\u00f1a B, Hallyburton I, Lee MC, Norcross NR, Grimaldi R, Otto TD, et al. A novel multiple-stage antimalarial agent that inhibits protein synthesis. Nature. 2015;522:315\u201320.","journal-title":"Nature"},{"key":"4171_CR11","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.cmpb.2003.11.003","volume":"75","author":"L Lindbom","year":"2004","unstructured":"Lindbom L, Ribbing J, Jonsson EN. Perl-speaks-NONMEM (PsN)\u2014a\u00a0Perl module for NONMEM related programming. Comput Methods Programs Biomed. 2004;75:85\u201394.","journal-title":"Comput Methods Programs Biomed"}],"container-title":["Malaria Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12936-022-04171-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12936-022-04171-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12936-022-04171-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,15]],"date-time":"2022-05-15T06:18:52Z","timestamp":1652595532000},"score":1,"resource":{"primary":{"URL":"https:\/\/malariajournal.biomedcentral.com\/articles\/10.1186\/s12936-022-04171-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,15]]},"references-count":11,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["4171"],"URL":"https:\/\/doi.org\/10.1186\/s12936-022-04171-0","relation":{},"ISSN":["1475-2875"],"issn-type":[{"type":"electronic","value":"1475-2875"}],"subject":[],"published":{"date-parts":[[2022,5,15]]},"assertion":[{"value":"3 December 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 April 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 May 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was approved by the animal ethics committee of Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes (iMM, Lisboa, Portugal), and all animal experiments were performed in compliance with their guidelines and those of the Federation of European Laboratory Animal Science Associations (FELASA). Male BALB\/c mice (Charles River Laboratories), with 6\u22128 weeks of age, were kept and manipulated in iMM\u2019s animal facility. The animal experiments that were carried out at the Swiss Tropical and Public Health Institute (SwissTPH, Basel, Switzerland) adhered to local and national regulations of laboratory animal welfare in Switzerland (awarded permission no. 2693). Protocols were regularly reviewed and revised following approval by the local authority (Veterin\u00e4ramt Basel Stadt).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors read and approved the manuscript.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"AK, LB, CO, OY, WMB and TS are employed by the healthcare business of Merck KGaA, Darmstadt, Germany. JW is employed by Occams, Amstelveen, The Netherlands. All other authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"151"}}