{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T10:44:19Z","timestamp":1784371459666,"version":"3.55.0"},"reference-count":62,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,5,11]],"date-time":"2020-05-11T00:00:00Z","timestamp":1589155200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,5,11]],"date-time":"2020-05-11T00:00:00Z","timestamp":1589155200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81672052"],"award-info":[{"award-number":["81672052"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81971962"],"award-info":[{"award-number":["81971962"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81702024"],"award-info":[{"award-number":["81702024"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Zhejiang Natural Science Funds for Distinguished Young Scientists","award":["LR17H190001"],"award-info":[{"award-number":["LR17H190001"]}]},{"name":"Commonweal Technology Application Project Program of Zhejiang Province","award":["LGF20H190001"],"award-info":[{"award-number":["LGF20H190001"]}]},{"name":"Medical and Health Science and Technology Plan Project of Zhejiang Province","award":["2018KY865"],"award-info":[{"award-number":["2018KY865"]}]},{"name":"Commonweal Technology Application Project Program of Wenzhou City","award":["Y20180084"],"award-info":[{"award-number":["Y20180084"]}]},{"name":"National Undergraduate Innovation and Entrepreneurship Project of China","award":["201810343011"],"award-info":[{"award-number":["201810343011"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Parasites Vectors"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p><jats:italic>Toxoplasma gondii<\/jats:italic> is a zoonotic pathogen that causes toxoplasmosis and leads to serious public health problems in developing countries. However, current clinical therapeutic drugs have some disadvantages, such as serious side effects, a long course of treatment and the emergence of drug-resistant strains. The urgent need to identify novel anti-<jats:italic>Toxoplasma<\/jats:italic> drugs has initiated the effective strategy of repurposing well-characterized drugs. As a principled screening for the identification of effective compounds against <jats:italic>Toxoplasma gondii<\/jats:italic>, in the current study, a collection of 666 compounds were screened for their ability to significantly inhibit <jats:italic>Toxoplasma<\/jats:italic> growth.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The inhibition of parasite growth was determined using a luminescence-based \u03b2-galactosidase activity assay. Meanwhile, the effect of compounds on the viability of host cells was measured using CCK8. To assess the inhibition of the selected compounds on discrete steps of the <jats:italic>T. gondii<\/jats:italic> lytic cycle, the invasion, intracellular proliferation and egress abilities were evaluated. Finally, a murine infection model of toxoplasmosis was used to monitor the protective efficacy of drugs against acute infection of a highly virulent RH strain.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>A total of 68 compounds demonstrated more than 70% parasite growth inhibition. After excluding compounds that impaired host cell viability, we further characterized two compounds, NVP-AEW541 and GSK-J4 HCl, which had IC<jats:sub>50<\/jats:sub> values for parasite growth of 1.17\u00a0\u03bcM and 2.37\u00a0\u03bcM, respectively. In addition, both compounds showed low toxicity to the host cell. Furthermore, we demonstrated that NVP-AEW541 inhibits tachyzoite invasion, while GSK-J4 HCl inhibits intracellular tachyzoite proliferation by halting cell cycle progression from G1 to S phase. These findings prompted us to analyse the efficacy of the two compounds <jats:italic>in vivo<\/jats:italic> by using established mouse models of acute toxoplasmosis. In addition to prolonging the survival time of mice acutely infected with <jats:italic>T. gondii<\/jats:italic>, both compounds had a remarkable ability to reduce the parasite burden of tissues.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our findings suggest that both NVP-AEW541 and GSK-J4 could be potentially repurposed as candidate drugs against <jats:italic>T. gondii<\/jats:italic> infection.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13071-020-04094-2","type":"journal-article","created":{"date-parts":[[2020,5,11]],"date-time":"2020-05-11T17:03:02Z","timestamp":1589216582000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Two old drugs, NVP-AEW541 and GSK-J4, repurposed against the Toxoplasma gondii RH strain"],"prefix":"10.1186","volume":"13","author":[{"given":"Shuxian","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mimi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Hua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daiqiang","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helin","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linyan","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinqi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,5,11]]},"reference":[{"key":"4094_CR1","doi-asserted-by":"publisher","first-page":"R770","DOI":"10.1016\/j.cub.2018.05.035","volume":"28","author":"JA Kochanowsky","year":"2018","unstructured":"Kochanowsky JA, Koshy AA. Toxoplasma gondii. Curr Biol. 2018;28:R770\u20131.","journal-title":"Curr Biol"},{"key":"4094_CR2","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1016\/j.ijpara.2009.02.004","volume":"39","author":"LM Weiss","year":"2009","unstructured":"Weiss LM, Dubey JP. Toxoplasmosis: a history of clinical observations. Int J Parasitol. 2009;39:895\u2013901.","journal-title":"Int J Parasitol"},{"key":"4094_CR3","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.jogoh.2017.12.003","volume":"47","author":"S Fallahi","year":"2018","unstructured":"Fallahi S, Rostami A, Nourollahpour SM, Behniafar H, Paktinat S. An updated literature review on maternal-fetal and reproductive disorders of Toxoplasma gondii infection. J Gynecol Obstet Hum Reprod. 2018;47:133\u201340.","journal-title":"J Gynecol Obstet Hum Reprod"},{"key":"4094_CR4","doi-asserted-by":"publisher","first-page":"1793","DOI":"10.1007\/s00436-017-5478-y","volume":"116","author":"SD Chorlton","year":"2017","unstructured":"Chorlton SD. Toxoplasma gondii and schizophrenia: a review of published RCTs. Parasitol Res. 2017;116:1793\u20139.","journal-title":"Parasitol Res"},{"key":"4094_CR5","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.17219\/acem\/61435","volume":"26","author":"AJ Fuglewicz","year":"2017","unstructured":"Fuglewicz AJ, Piotrowski P, Stodolak A. Relationship between toxoplasmosis and schizophrenia: a review. Adv Clin Exp Med. 2017;26:1031\u20136.","journal-title":"Adv Clin Exp Med"},{"key":"4094_CR6","first-page":"247","volume":"43","author":"EF Torrey","year":"2017","unstructured":"Torrey EF, Yolken RH. Schizophrenia and infections: the eyes have it. Schizophr Bull. 2017;43:247\u201352.","journal-title":"Schizophr Bull"},{"key":"4094_CR7","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.actatropica.2019.02.001","volume":"192","author":"X Chen","year":"2019","unstructured":"Chen X, Chen B, Hou X, Zheng C, Yang X, Ke J, et al. Association between Toxoplasma gondii infection and psychiatric disorders in Zhejiang, southeastern China. Acta Trop. 2019;192:82\u20136.","journal-title":"Acta Trop"},{"key":"4094_CR8","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1128\/CMR.05013-11","volume":"25","author":"F Robert-Gangneux","year":"2012","unstructured":"Robert-Gangneux F, Dard\u00e9 ML. Epidemiology of and diagnostic strategies for toxoplasmosis. Clin Microbiol Rev. 2012;25:264\u201396.","journal-title":"Clin Microbiol Rev"},{"key":"4094_CR9","doi-asserted-by":"publisher","first-page":"e1001920","DOI":"10.1371\/journal.pmed.1001920","volume":"12","author":"PR Torgerson","year":"2015","unstructured":"Torgerson PR, Devleesschauwer B, Praet N, Speybroeck N, Willingham AL, Kasuga F, et al. World Health Organization estimates of the global and regional disease burden of 11 foodborne parasitic diseases, 2010: a data synthesis. PLoS Med. 2015;12:e1001920.","journal-title":"PLoS Med"},{"key":"4094_CR10","doi-asserted-by":"publisher","first-page":"7161","DOI":"10.1128\/AAC.02009-15","volume":"59","author":"AJ Neville","year":"2015","unstructured":"Neville AJ, Zach SJ, Wang X, Larson JJ, Judge AK, Davis LA, et al. Clinically available medicines demonstrating anti-Toxoplasma activity. Antimicrob Agents Chemother. 2015;59:7161\u20139.","journal-title":"Antimicrob Agents Chemother"},{"key":"4094_CR11","doi-asserted-by":"publisher","first-page":"111711","DOI":"10.1016\/j.ejmech.2019.111711","volume":"183","author":"Y Deng","year":"2019","unstructured":"Deng Y, Wu T, Zhai SQ, Li CH. Recent progress on anti-Toxoplasma drugs discovery: design, synthesis and screening. Eur J Med Chem. 2019;183:111711.","journal-title":"Eur J Med Chem"},{"key":"4094_CR12","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1038\/nature09022","volume":"465","author":"S Lourido","year":"2010","unstructured":"Lourido S, Shuman J, Zhang C, Shokat KM, Hui R, Sibley LD. Calcium dependent protein kinase 1 is an essential regulator of exocytosis in Toxoplasma. Nature. 2010;465:359\u201362.","journal-title":"Nature"},{"key":"4094_CR13","doi-asserted-by":"publisher","first-page":"15936","DOI":"10.1073\/pnas.1208069109","volume":"109","author":"JS Doggett","year":"2012","unstructured":"Doggett JS, Nilsen A, Forquer I, Wegmann KW, Jones-Brando L, Yolken RH, et al. Endochin-like quinolones are highly efficacious against acute and latent experimental toxoplasmosis. Proc Natl Acad Sci USA. 2012;109:15936\u201341.","journal-title":"Proc Natl Acad Sci USA"},{"key":"4094_CR14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ijpddr.2014.12.001","volume":"5","author":"T Sugi","year":"2015","unstructured":"Sugi T, Kawazu S, Horimoto T, Kato K. A single mutation in the gatekeeper residue in TgMAPKL-1 restores the inhibitory effect of a bumped kinase inhibitor on the cell cycle. Int J Parasitol Drugs Drug Resist. 2015;5:1\u20138.","journal-title":"Int J Parasitol Drugs Drug Resist"},{"key":"4094_CR15","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1093\/jac\/dkn451","volume":"63","author":"JG D\u2019Angelo","year":"2009","unstructured":"D\u2019Angelo JG, Bord\u00f3n C, Posner GH, Yolken R, Jones-Brando L. Artemisinin derivatives inhibit Toxoplasma gondii in vitro at multiple steps in the lytic cycle. J Antimicrob Chemother. 2009;63:146\u201350.","journal-title":"J Antimicrob Chemother"},{"key":"4094_CR16","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.actatropica.2011.10.018","volume":"121","author":"Y Carlier","year":"2012","unstructured":"Carlier Y, Truyens C, Deloron P, Peyron F. Congenital parasitic infections: a review. Acta Trop. 2012;121:55\u201370.","journal-title":"Acta Trop"},{"key":"4094_CR17","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1007\/s40268-017-0206-8","volume":"17","author":"RR Ben-Harari","year":"2017","unstructured":"Ben-Harari RR, Goodwin E, Casoy J. Adverse event profile of pyrimethamine-based therapy in toxoplasmosis: a systematic review. Drugs R D. 2017;17:523\u201344.","journal-title":"Drugs R D"},{"key":"4094_CR18","doi-asserted-by":"publisher","first-page":"2587","DOI":"10.3389\/fmicb.2018.02587","volume":"9","author":"M Montazeri","year":"2018","unstructured":"Montazeri M, Mehrzadi S, Sharif M, Sarvi S, Tanzifi A, Aghayan SA, et al. Drug resistance in Toxoplasma gondii. Front Microbiol. 2018;9:2587.","journal-title":"Front Microbiol"},{"key":"4094_CR19","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00057-17","author":"IR Dunay","year":"2018","unstructured":"Dunay IR, Gajurel K, Dhakal R, Liesenfeld O, Montoya JG. Treatment of toxoplasmosis: historical perspective, animal models, and current clinical practice. Clin Microbiol Rev. 2018. https:\/\/doi.org\/10.1128\/CMR.00057-17.","journal-title":"Clin Microbiol Rev."},{"key":"4094_CR20","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1093\/jlb\/lsw008","volume":"3","author":"NP Tallapragada","year":"2016","unstructured":"Tallapragada NP. Off-patent drugs at brand-name prices: a puzzle for policymakers. J Law Biosci. 2016;3:238\u201347.","journal-title":"J Law Biosci"},{"key":"4094_CR21","doi-asserted-by":"publisher","first-page":"h6922","DOI":"10.1136\/bmj.h6922","volume":"357","author":"O Dyer","year":"2015","unstructured":"Dyer O. Senate committee inquiry into drug price hikes will continue despite arrest of hedge fund manager Shkreli. BMJ. 2015;357:h6922.","journal-title":"BMJ"},{"key":"4094_CR22","doi-asserted-by":"publisher","first-page":"5581","DOI":"10.1128\/AAC.00868-12","volume":"56","author":"ET Kamau","year":"2012","unstructured":"Kamau ET, Srinivasan AR, Brown MJ, Fair MG, Caraher EJ, Boyle JP. A focused small-molecule screen identifies 14 compounds with distinct effects on Toxoplasma gondii. Antimicrob Agents Chemother. 2012;56:5581\u201390.","journal-title":"Antimicrob Agents Chemother"},{"key":"4094_CR23","doi-asserted-by":"publisher","first-page":"e0178203","DOI":"10.1371\/journal.pone.0178203","volume":"12","author":"Y Murata","year":"2017","unstructured":"Murata Y, Sugi T, Weiss LM, Kato K. Identification of compounds that suppress Toxoplasma gondii tachyzoites and bradyzoites. PLoS ONE. 2017;12:e0178203.","journal-title":"PLoS ONE"},{"key":"4094_CR24","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1007\/s00436-017-5698-1","volume":"117","author":"OS Adeyemi","year":"2018","unstructured":"Adeyemi OS, Sugi T, Han Y, Kato K. Screening of chemical compound libraries identified new anti-Toxoplasma gondii agents. Parasitol Res. 2018;117:355\u201363.","journal-title":"Parasitol Res"},{"key":"4094_CR25","doi-asserted-by":"publisher","first-page":"e2973","DOI":"10.1371\/journal.pntd.0002973","volume":"8","author":"RM Andrade","year":"2014","unstructured":"Andrade RM, Chaparro JD, Capparelli E, Reed SL. Auranofin is highly efficacious against Toxoplasma gondii in vitro and in an in vivo experimental model of acute toxoplasmosis. PLoS Negl Trop Dis. 2014;8:e2973.","journal-title":"PLoS Negl Trop Dis"},{"key":"4094_CR26","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1007\/s40268-015-0083-y","volume":"15","author":"C Roder","year":"2015","unstructured":"Roder C, Thomson MJ. Auranofin: repurposing an old drug for a golden new age. Drugs R D. 2015;15:13\u201320.","journal-title":"Drugs R D"},{"key":"4094_CR27","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.ijpddr.2018.12.004","volume":"9","author":"JL Zhang","year":"2019","unstructured":"Zhang JL, Si HF, Shang XF, Zhang XK, Li B, Zhou XZ, et al. New life for an old drug: in vitro and in vivo effects of the anthelmintic drug niclosamide against Toxoplasma gondii RH strain. Int J Parasitol Drugs Drug Resist. 2019;9:27\u201334.","journal-title":"Int J Parasitol Drugs Drug Resist"},{"key":"4094_CR28","doi-asserted-by":"publisher","first-page":"e00042-15","DOI":"10.1128\/mSphere.00042-15","volume":"1","author":"AJ Dittmar","year":"2016","unstructured":"Dittmar AJ, Drozda AA, Blader IJ. Drug repurposing screening identifies novel compounds that effectively inhibit Toxoplasma gondii growth. mSphere. 2016;1:e00042-15.","journal-title":"mSphere"},{"key":"4094_CR29","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1186\/gm326","volume":"4","author":"YY Li","year":"2012","unstructured":"Li YY, Jones SJ. Drug repositioning for personalized medicine. Genome Med. 2012;4:27.","journal-title":"Genome Med"},{"key":"4094_CR30","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1038\/nrd1468","volume":"3","author":"TT Ashburn","year":"2004","unstructured":"Ashburn TT, Thor KB. Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov. 2004;3:673\u201383.","journal-title":"Nat Rev Drug Discov"},{"key":"4094_CR31","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/S0920-9964(02)00357-2","volume":"62","author":"L Jones-Brando","year":"2003","unstructured":"Jones-Brando L, Torrey EF, Yolken R. Drugs used in the treatment of schizophrenia and bipolar disorder inhibit the replication of Toxoplasma gondii. Schizophr Res. 2003;62:237\u201344.","journal-title":"Schizophr Res"},{"key":"4094_CR32","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/0378-1119(95)00786-5","volume":"169","author":"F Seeber","year":"1996","unstructured":"Seeber F, Boothroyd JC. Escherichia coli beta-galactosidase as an in vitro and in vivo reporter enzyme and stable transfection marker in the intracellular protozoan parasite Toxoplasma gondii. Gene. 1996;169:39\u201345.","journal-title":"Gene"},{"key":"4094_CR33","doi-asserted-by":"publisher","first-page":"1680","DOI":"10.1128\/EC.00079-10","volume":"9","author":"KR Sweeney","year":"2010","unstructured":"Sweeney KR, Morrissette NS, LaChapelle S, Blader IJ. Host cell invasion by Toxoplasma gondii is temporally regulated by the host microtubule cytoskeleton. Eukaryot Cell. 2010;9:1680\u20139.","journal-title":"Eukaryot Cell"},{"key":"4094_CR34","doi-asserted-by":"publisher","first-page":"e1002416","DOI":"10.1371\/journal.ppat.1002416","volume":"7","author":"S Besteiro","year":"2011","unstructured":"Besteiro S, Brooks CF, Striepen B, Dubremetz JF. Autophagy protein Atg3 is essential for maintaining mitochondrial integrity and for normal intracellular development of Toxoplasma gondii tachyzoites. PLoS Pathog. 2011;7:e1002416.","journal-title":"PLoS Pathog"},{"key":"4094_CR35","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.molbiopara.2007.09.003","volume":"157","author":"DFM Conde","year":"2008","unstructured":"Conde DFM, Lehmann MM, Jerome ME, White MW. Inhibition of Toxoplasma gondii growth by pyrrolidine dithiocarbamate is cell cycle specific and leads to population synchronization. Mol Biochem Parasitol. 2008;157:22\u201331.","journal-title":"Mol Biochem Parasitol"},{"key":"4094_CR36","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1006\/expr.2001.4636","volume":"98","author":"M Camps","year":"2001","unstructured":"Camps M, Boothroyd JC. Toxoplasma gondii: selective killing of extracellular parasites by oxidation using pyrrolidine dithiocarbamate. Exp Parasitol. 2001;98:206\u201314.","journal-title":"Exp Parasitol"},{"key":"4094_CR37","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/S0166-6851(01)00284-5","volume":"115","author":"JR Radke","year":"2001","unstructured":"Radke JR, Striepen B, Guerini MN, Jerome ME, Roos DS, White MW. Defining the cell cycle for the tachyzoite stage of Toxoplasma gondii. Mol Biochem Parasitol. 2001;115:165\u201375.","journal-title":"Mol Biochem Parasitol"},{"key":"4094_CR38","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02628-16","author":"ZH Li","year":"2017","unstructured":"Li ZH, Li C, Szajnman SH, Rodriguez JB, Moreno SNJ. Synergistic activity between statins and bisphosphonates against acute experimental toxoplasmosis. Antimicrob Agents Chemother. 2017. https:\/\/doi.org\/10.1128\/AAC.02628-16.","journal-title":"Antimicrob Agents Chemother"},{"key":"4094_CR39","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1016\/j.ijpara.2017.12.006","volume":"48","author":"E Moine","year":"2018","unstructured":"Moine E, Moir\u00e9 N, Dimier-Poisson I, Brunet K, Couet W, Colas C, et al. Imidazo[1,2-b]pyridazines targeting Toxoplasma gondii calcium-dependent protein kinase 1 decrease the parasite burden in mice with acute toxoplasmosis. Int J Parasitol. 2018;48:561\u20138.","journal-title":"Int J Parasitol"},{"key":"4094_CR40","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1016\/j.parint.2008.03.001","volume":"57","author":"C Pina-Vazquez","year":"2008","unstructured":"Pina-Vazquez C, Saavedra R, Herion P. A quantitative competitive PCR method to determine the parasite load in the brain of Toxoplasma gondii-infected mice. Parasitol Int. 2008;57:347\u201353.","journal-title":"Parasitol Int"},{"key":"4094_CR41","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1590\/S0036-46652013000100012","volume":"55","author":"L Monzote","year":"2013","unstructured":"Monzote L, Rodriguez M, Alfonso Y, Cox R. Antiretroviral activity of protease inhibitors against Toxoplasma gondii. Rev Inst Med Trop Sao Paulo. 2013;55:65\u20137.","journal-title":"Rev Inst Med Trop Sao Paulo"},{"key":"4094_CR42","doi-asserted-by":"publisher","first-page":"2393","DOI":"10.1128\/AAC.46.8.2393-2399.2002","volume":"46","author":"T Asai","year":"2002","unstructured":"Asai T, Takeuchi T, Diffenderfer J, Sibley LD. Identification of small-molecule inhibitors of nucleoside triphosphate hydrolase in Toxoplasma gondii. Antimicrob Agents Chemother. 2002;46:2393\u20139.","journal-title":"Antimicrob Agents Chemother"},{"key":"4094_CR43","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1517\/17460441.2012.729036","volume":"7","author":"S Kortagere","year":"2012","unstructured":"Kortagere S. Screening for small molecule inhibitors of Toxoplasma gondii. Expert Opin Drug Discov. 2012;7:1193\u2013206.","journal-title":"Expert Opin Drug Discov"},{"key":"4094_CR44","doi-asserted-by":"publisher","first-page":"3068","DOI":"10.1021\/jm4001314","volume":"56","author":"S Lourido","year":"2013","unstructured":"Lourido S, Zhang C, Lopez M, Tang K, Barks J, Wang Q, et al. Optimizing small molecule inhibitors of calcium-dependent protein kinase 1 to prevent infection by Toxoplasma gondii. J Med Chem. 2013;56:3068\u201377.","journal-title":"J Med Chem"},{"key":"4094_CR45","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/S1535-6108(04)00051-0","volume":"5","author":"C Garcia-Echeverria","year":"2004","unstructured":"Garcia-Echeverria C, Pearson MA, Marti A, Meyer T, Mestan J, Zimmermann J, et al. In vivo antitumor activity of NVP-AEW541\u2014a novel, potent, and selective inhibitor of the IGF-IR kinase. Cancer Cell. 2004;5:231\u20139.","journal-title":"Cancer Cell"},{"key":"4094_CR46","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.mib.2006.06.017","volume":"10","author":"V Carruthers","year":"2007","unstructured":"Carruthers V, Boothroyd JC. Pulling together: an integrated model of Toxoplasma cell invasion. Curr Opin Microbiol. 2007;10:83\u20139.","journal-title":"Curr Opin Microbiol"},{"key":"4094_CR47","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1016\/S1535-6108(04)00050-9","volume":"5","author":"CS Mitsiades","year":"2004","unstructured":"Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Akiyama M, et al. Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. Cancer Cell. 2004;5:221\u201330.","journal-title":"Cancer Cell"},{"key":"4094_CR48","doi-asserted-by":"publisher","first-page":"3868","DOI":"10.1158\/0008-5472.CAN-04-3192","volume":"65","author":"K Scotlandi","year":"2005","unstructured":"Scotlandi K, Manara MC, Nicoletti G, Lollini PL, Lukas S, Benini S, et al. Antitumor activity of the insulin-like growth factor-I receptor kinase inhibitor NVP-AEW541 in musculoskeletal tumors. Cancer Res. 2005;65:3868\u201376.","journal-title":"Cancer Res"},{"key":"4094_CR49","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1016\/j.bcp.2010.05.011","volume":"80","author":"MB Gariboldi","year":"2010","unstructured":"Gariboldi MB, Ravizza R, Monti E. The IGFR1 inhibitor NVP-AEW541 disrupts a pro-survival and pro-angiogenic IGF-STAT3-HIF1 pathway in human glioblastoma cells. Biochem Pharmacol. 2010;80:455\u201362.","journal-title":"Biochem Pharmacol"},{"key":"4094_CR50","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1038\/nature11262","volume":"488","author":"L Kruidenier","year":"2012","unstructured":"Kruidenier L, Chung CW, Cheng Z, Liddle J, Che K, Joberty G, et al. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature. 2012;488:404\u20138.","journal-title":"Nature"},{"key":"4094_CR51","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/nrclinonc.2010.9-c1","volume":"7","author":"AJ Ferreri","year":"2010","unstructured":"Ferreri AJ, Illerhaus G, Zucca E, Cavalli F. Flows and flaws in primary central nervous system lymphoma. Nat Rev Clin Oncol. 2010;7:1\u20132.","journal-title":"Nat Rev Clin Oncol"},{"key":"4094_CR52","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1530\/REP-15-0338","volume":"151","author":"B Xie","year":"2016","unstructured":"Xie B, Zhang H, Wei R, Li Q, Weng X, Kong Q, et al. Histone H3 lysine 27 trimethylation acts as an epigenetic barrier in porcine nuclear reprogramming. Reproduction. 2016;151:9\u201316.","journal-title":"Reproduction"},{"key":"4094_CR53","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1093\/jmcb\/mjv022","volume":"7","author":"Z Liu","year":"2015","unstructured":"Liu Z, Cao W, Xu L, Chen X, Zhan Y, Yang Q, et al. The histone H3 lysine-27 demethylase Jmjd3 plays a critical role in specific regulation of Th17 cell differentiation. J Mol Cell Biol. 2015;7:505\u201316.","journal-title":"J Mol Cell Biol"},{"key":"4094_CR54","doi-asserted-by":"publisher","first-page":"6083","DOI":"10.21873\/anticanres.11198","volume":"36","author":"H Watarai","year":"2016","unstructured":"Watarai H, Okada M, Kuramoto K, Takeda H, Sakaki H, Suzuki S, et al. Impact of H3K27 demethylase inhibitor GSKJ4 on NSCLC cells alone and in combination with metformin. Anticancer Res. 2016;36:6083\u201392.","journal-title":"Anticancer Res"},{"key":"4094_CR55","doi-asserted-by":"publisher","first-page":"1394","DOI":"10.1038\/nm.3716","volume":"20","author":"R Hashizume","year":"2014","unstructured":"Hashizume R, Andor N, Ihara Y, Lerner R, Gan H, Chen X, et al. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat Med. 2014;20:1394\u20136.","journal-title":"Nat Med"},{"key":"4094_CR56","doi-asserted-by":"publisher","first-page":"373","DOI":"10.3324\/haematol.2016.144964","volume":"102","author":"R Mathur","year":"2017","unstructured":"Mathur R, Sehgal L, Havranek O, Kohrer S, Khashab T, Jain N, et al. Inhibition of demethylase KDM6B sensitizes diffuse large B-cell lymphoma to chemotherapeutic drugs. Haematologica. 2017;102:373\u201380.","journal-title":"Haematologica"},{"key":"4094_CR57","doi-asserted-by":"publisher","first-page":"62131","DOI":"10.18632\/oncotarget.19100","volume":"8","author":"VM Morozov","year":"2017","unstructured":"Morozov VM, Li Y, Clowers MM, Ishov AM. Inhibitor of H3K27 demethylase JMJD3\/UTX GSK-J4 is a potential therapeutic option for castration resistant prostate cancer. Oncotarget. 2017;8:62131\u201342.","journal-title":"Oncotarget"},{"key":"4094_CR58","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1038\/nature13605","volume":"514","author":"P Ntziachristos","year":"2014","unstructured":"Ntziachristos P, Tsirigos A, Welstead GG, Trimarchi T, Bakogianni S, Xu L, et al. Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. Nature. 2014;514:513\u20137.","journal-title":"Nature"},{"key":"4094_CR59","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.mce.2017.07.001","volume":"460","author":"MB Backe","year":"2018","unstructured":"Backe MB, Andersson JL, Bacos K, Christensen DP, Hansen JB, Dorosz JJ, et al. Lysine demethylase inhibition protects pancreatic beta cells from apoptosis and improves beta-cell function. Mol Cell Endocrinol. 2018;460:47\u201356.","journal-title":"Mol Cell Endocrinol"},{"key":"4094_CR60","doi-asserted-by":"publisher","first-page":"E1","DOI":"10.1038\/nature13688","volume":"514","author":"B Heinemann","year":"2014","unstructured":"Heinemann B, Nielsen JM, Hudlebusch HR, Lees MJ, Larsen DV, Boesen T, et al. Inhibition of demethylases by GSK-J1\/J4. Nature. 2014;514:E1\u20132.","journal-title":"Nature"},{"key":"4094_CR61","doi-asserted-by":"publisher","first-page":"6772","DOI":"10.1158\/1078-0432.CCR-06-1479","volume":"12","author":"B Tanno","year":"2006","unstructured":"Tanno B, Mancini C, Vitali R, Mancuso M, McDowell HP, Dominici C, et al. Down-regulation of insulin-like growth factor I receptor activity by NVP-AEW541 has an antitumor effect on neuroblastoma cells in vitro and in vivo. Clin Cancer Res. 2006;12:6772\u201380.","journal-title":"Clin Cancer Res"},{"key":"4094_CR62","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1007\/s00432-018-2631-7","volume":"144","author":"Y Li","year":"2018","unstructured":"Li Y, Zhang M, Sheng M, Zhang P, Chen Z, Xing W, et al. Therapeutic potential of GSK-J4, a histone demethylase KDM6B\/JMJD3 inhibitor, for acute myeloid leukemia. J Cancer Res Clin Oncol. 2018;144:1065\u201377.","journal-title":"J Cancer Res Clin Oncol"}],"container-title":["Parasites &amp; Vectors"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13071-020-04094-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13071-020-04094-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13071-020-04094-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,11]],"date-time":"2021-05-11T00:23:11Z","timestamp":1620692591000},"score":1,"resource":{"primary":{"URL":"https:\/\/parasitesandvectors.biomedcentral.com\/articles\/10.1186\/s13071-020-04094-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,11]]},"references-count":62,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["4094"],"URL":"https:\/\/doi.org\/10.1186\/s13071-020-04094-2","relation":{},"ISSN":["1756-3305"],"issn-type":[{"value":"1756-3305","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,11]]},"assertion":[{"value":"24 January 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 April 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 May 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Mice were maintained in strict accordance with the Good Animal Practice requirements of the Animal Ethics Procedures and Guidelines of China. All murine protocols were reviewed and approved by the Laboratory Animal Ethics Committee of Wenzhou Medical University (Permit number #wydw 2016-0177).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"242"}}