{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:44:27Z","timestamp":1791308667712,"version":"4.3.1"},"reference-count":61,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2009,5,1]],"date-time":"2009-05-01T00:00:00Z","timestamp":1241136000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2009,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Progressive multifocal leukoencephalopathy (PML) is a rare but frequently fatal disease caused by the uncontrolled replication of JC virus (JCV), a polyomavirus, in the brains of some immunocompromised individuals. Currently, no effective antiviral treatment for this disease has been identified. As a first step in the identification of such therapy, we screened the Spectrum collection of 2,000 approved drugs and biologically active molecules for their anti-JCV activities in an in vitro infection assay. We identified a number of different drugs and compounds that had significant anti-JCV activities at micromolar concentrations and lacked cellular toxicity. Of the compounds with anti-JCV activities, only mefloquine, an antimalarial agent, has been reported to show sufficiently high penetration into the central nervous system such that it would be predicted to achieve efficacious concentrations in the brain. Additional in vitro experiments demonstrated that mefloquine inhibits the viral infection rates of three different JCV isolates, JCV(Mad1), JCV(Mad4), and JCV(M1\/SVE\u0394), and does so in three different cell types, transformed human glial (SVG-A) cells, primary human fetal glial cells, and primary human astrocytes. Using quantitative PCR to quantify the number of viral copies in cultured cells, we have also shown that mefloquine inhibits viral DNA replication. Finally, we demonstrated that mefloquine does not block viral cell entry; rather, it inhibits viral replication in cells after viral entry. Although no suitable animal model of PML or JCV infection is available for the testing of mefloquine in vivo, our in vitro results, combined with biodistribution data published in the literature, suggest that mefloquine could be an effective therapy for PML.<\/jats:p>","DOI":"10.1128\/aac.01614-08","type":"journal-article","created":{"date-parts":[[2009,3,3]],"date-time":"2009-03-03T02:54:31Z","timestamp":1236048871000},"page":"1840-1849","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":192,"title":["Identification and Characterization of Mefloquine Efficacy against JC Virus In Vitro"],"prefix":"10.1128","volume":"53","author":[{"given":"Margot","family":"Brickelmaier","sequence":"first","affiliation":[{"name":"Biogen IDEC Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey","family":"Lugovskoy","sequence":"additional","affiliation":[{"name":"Biogen IDEC Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramya","family":"Kartikeyan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta M.","family":"Reviriego-Mendoza","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norm","family":"Allaire","sequence":"additional","affiliation":[{"name":"Biogen IDEC Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Simon","sequence":"additional","affiliation":[{"name":"Biogen IDEC Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Frisque","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonid","family":"Gorelik","sequence":"additional","affiliation":[{"name":"Biogen IDEC Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1080\/13550280152537292","volume":"7","year":"2001","unstructured":"Aksamit, A. J. 2001. Treatment of non-AIDS progressive multifocal leukoencephalopathy with cytosine arabinoside. J. Neurovirol.7:386-390.","journal-title":"J. Neurovirol."},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.41.3.587"},{"key":"e_1_3_2_4_2","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1080\/13550280152537157","volume":"7","year":"2001","unstructured":"Atwood, W. J. 2001. A combination of low-dose chlorpromazine and neutralizing antibodies inhibits the spread of JC virus (JCV) in a tissue culture model: implications for prophylactic and therapeutic treatment of progressive multifocal leukencephalopathy. J. Neurovirol.7:307-310.","journal-title":"J. Neurovirol."},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.3109\/13550289509111009"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1992.tb04081.x"},{"key":"e_1_3_2_7_2","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1111\/j.2042-7158.1997.tb06047.x","volume":"49","year":"1997","unstructured":"Baudry, S., Y. T. Pham, B. Baune, S. Vidrequin, C. Crevoisier, F. Gimenez, and R. Farinotti. 1997. Stereoselective passage of mefloquine through the blood-brain barrier in the rat. J. Pharm. Pharmacol.49:1086-1090.","journal-title":"J. Pharm. Pharmacol."},{"key":"e_1_3_2_8_2","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1007\/s11940-000-0053-7","volume":"2","year":"2000","unstructured":"Berger, J. R. 2000. Progressive multifocal leukoencephalopathy. Curr. Treat. Options Neurol.2:361-368.","journal-title":"Curr. Treat. Options Neurol."},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-2008-1040837"},{"key":"e_1_3_2_10_2","first-page":"195","volume":"34","year":"1996","unstructured":"Bianchetti, G., S. Billy, V. Ascalone, S. Saivin, G. Houin, and P. Rosenzweig. 1996. Multicenter studies on the pharmacokinetic profile of sustained-release oral diltiazem (300 mg) after once a day repeated administration: influence of age. Int. J. Clin. Pharmacol. Ther.34:195-201.","journal-title":"Int. J. Clin. Pharmacol. Ther."},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1086\/427698"},{"key":"e_1_3_2_12_2","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/s002280050100","volume":"50","year":"1996","unstructured":"Bourahla, A., C. Martin, F. Gimenez, V. Singhasivanon, P. Attanath, A. Sabchearon, T. Chongsuphajaisiddhi, and R. Farinotti. 1996. Stereoselective pharmacokinetics of mefloquine in young children. Eur. J. Clin. Pharmacol.50:241-244.","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"e_1_3_2_13_2","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1080\/00498250050119871","volume":"30","year":"2000","unstructured":"Bregante, M. A., J. J. Aramayona, L. J. Fraile, M. A. Garcia, and C. Solans. 2000. Diltiazem blood pharmacokinetics in the pregnant and non-pregnant rabbit: maternal and foetal tissue levels. Xenobiotica30:831-841.","journal-title":"Xenobiotica"},{"key":"e_1_3_2_14_2","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.2165\/00003088-200342150-00004","volume":"42","year":"2003","unstructured":"Brocks, D. R., and R. Mehvar. 2003. Stereoselectivity in the pharmacodynamics and pharmacokinetics of the chiral antimalarial drugs. Clin. Pharmacokinet.42:1359-1382.","journal-title":"Clin. Pharmacokinet."},{"key":"e_1_3_2_15_2","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/S0733-8619(18)31105-8","volume":"2","year":"1984","unstructured":"Brooks, B. R., and D. L. Walker. 1984. Progressive multifocal leukoencephalopathy. Neurol. Clin.2:299-313.","journal-title":"Neurol. Clin."},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2007.02.018"},{"key":"e_1_3_2_17_2","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1080\/13550280390195351","volume":"9","year":"2003","unstructured":"Cinque, P., S. Bossolasco, A. M. Brambilla, A. Boschini, C. Mussini, C. Pierotti, A. Campi, S. Casari, D. Bertelli, M. Mena, and A. Lazzarin. 2003. The effect of highly active antiretroviral therapy-induced immune reconstitution on development and outcome of progressive multifocal leukoencephalopathy: study of 43 cases with review of the literature. J. Neurovirol.9(Suppl. 1):73-80.","journal-title":"J. Neurovirol."},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1080\/13550280390195298"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.52.3.623"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.41.2.709-709.1982"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-6143.2005.00800.x"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0b013e32830a5043"},{"key":"e_1_3_2_23_2","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1006\/taap.1997.8220","volume":"146","year":"1997","unstructured":"Eckhoff, C., and C. C. Willhite. 1997. Embryonic delivered dose of isotretinoin (13-cis-retinoic acid) and its metabolites in hamsters. Toxicol. Appl. Pharmacol.146:79-87.","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1103492"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.51.2.458-469.1984"},{"key":"e_1_3_2_26_2","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/S0166-0934(96)02117-9","volume":"63","year":"1997","unstructured":"Frye, S., C. Trebst, U. Dittmer, H. Petry, M. Bodemer, G. Hunsmann, T. Weber, and W. Luke. 1997. Efficient production of JC virus in SVG cells and the use of purified viral antigens for analysis of specific humoral and cellular immune response. J. Virol. Methods63:81-92.","journal-title":"J. Virol. Methods"},{"key":"e_1_3_2_27_2","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1254\/jphs.FP0040752","volume":"97","year":"2005","unstructured":"Fukuda, M., K. Kitaichi, F. Abe, Y. Fujimoto, K. Takagi, K. Takagi, T. Morishima, and T. Hasegawa. 2005. Altered brain penetration of diclofenac and mefenamic acid, but not acetaminophen, in Shiga-like toxin II-treated mice. J. Pharmacol. Sci.97:525-532.","journal-title":"J. Pharmacol. Sci."},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1080\/13550280152537274"},{"key":"e_1_3_2_29_2","doi-asserted-by":"crossref","first-page":"421","DOI":"10.3109\/13550289909029483","volume":"5","year":"1999","unstructured":"Gasnault, J., Y. Taoufik, C. Goujard, P. Kousignian, K. Abbed, F. Boue, E. Dussaix, and J. F. Delfraissy. 1999. Prolonged survival without neurological improvement in patients with AIDS-related progressive multifocal leukoencephalopathy on potent combined antiretroviral therapy. J. Neurovirol.5:421-429.","journal-title":"J. Neurovirol."},{"key":"e_1_3_2_30_2","first-page":"23","year":"1966","unstructured":"Glazko, A. J. 1966. Experimental observations on flufenamic, mefenamic and meclofenamic acids. 3. Metabolic disposition. Ann. Phys. Med. (Suppl.):23-36.","journal-title":"Ann. Phys. Med. (Suppl.)"},{"key":"e_1_3_2_31_2","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/S0006-8993(99)02089-2","volume":"856","year":"2000","unstructured":"Groothuis, D. R., H. Benalcazar, C. V. Allen, R. M. Wise, C. Dills, C. Dobrescu, V. Rothholtz, and R. M. Levy. 2000. Comparison of cytosine arabinoside delivery to rat brain by intravenous, intrathecal, intraventricular and intraparenchymal routes of administration. Brain Res.856:281-290.","journal-title":"Brain Res."},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199805073381903"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1007\/0-387-32957-9_11"},{"key":"e_1_3_2_34_2","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/0379-0738(94)90376-X","volume":"68","year":"1994","unstructured":"Jones, R., G. Kunsman, B. Levine, M. Smith, and C. Stahl. 1994. Mefloquine distribution in postmortem cases. Forensic Sci. Int.68:29-32.","journal-title":"Forensic Sci. Int."},{"key":"e_1_3_2_35_2","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1007\/s002800050535","volume":"39","year":"1996","unstructured":"Khan, A. A., J. G. Villablanca, C. P. Reynolds, and V. I. Avramis. 1996. Pharmacokinetic studies of 13-cis-retinoic acid in pediatric patients with neuroblastoma following bone marrow transplantation. Cancer Chemother. Pharmacol.39:34-41.","journal-title":"Cancer Chemother. Pharmacol."},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1007\/0-387-32957-9_2"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.3109\/13550289809113481"},{"key":"e_1_3_2_38_2","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/BF02228887","volume":"3","year":"1985","unstructured":"Lopez, J. A., E. Nassif, P. Vannicola, J. G. Krikorian, and R. P. Agarwal. 1985. Central nervous system pharmacokinetics of high-dose cytosine arabinoside. J. Neurooncol.3:119-124.","journal-title":"J. Neurooncol."},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.82.4.1257"},{"key":"e_1_3_2_40_2","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1097\/00002030-200209060-00012","volume":"16","year":"2002","unstructured":"Marra, C. M., N. Rajicic, D. E. Barker, B. A. Cohen, D. Clifford, M. J. Donovan Post, A. Ruiz, B. C. Bowen, M. L. Huang, J. Queen-Baker, J. Andersen, S. Kelly, and S. Shriver. 2002. A pilot study of cidofovir for progressive multifocal leukoencephalopathy in AIDS. AIDS16:1791-1797.","journal-title":"AIDS"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01405176"},{"key":"e_1_3_2_42_2","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/S0090-9556(25)05714-9","volume":"3","year":"1975","unstructured":"Mu, J. Y., Z. H. Israili, and P. G. Dayton. 1975. Studies of the disposition and metabolism of mefloquine HCl (WR 142,490), a quinolinemethanol antimalarial, in the rat. Limited studies with an analog, WR 30,090. Drug Metab. Dispos.3:198-210.","journal-title":"Drug Metab. Dispos."},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)82087-7"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virusres.2007.11.002"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.15.2.656-662.1977"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(71)91777-6"},{"key":"e_1_3_2_47_2","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1093\/infdis\/133.6.686","volume":"133","year":"1976","unstructured":"Padgett, B. L., D. L. Walker, G. M. ZuRhein, A. E. Hodach, and S. M. Chou. 1976. JC papovavirus in progressive multifocal leukoencephalopathy. J. Infect. Dis.133:686-690.","journal-title":"J. Infect. Dis."},{"key":"e_1_3_2_48_2","first-page":"58","volume":"37","year":"1999","unstructured":"Pham, Y. T., F. Nosten, R. Farinotti, N. J. White, and F. Gimenez. 1999. Cerebral uptake of mefloquine enantiomers in fatal cerebral malaria. Int. J. Clin. Pharmacol. Ther.37:58-61.","journal-title":"Int. J. Clin. Pharmacol. Ther."},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.74.5.2288-2292.2000"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1097\/00007890-200105150-00020"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-2952(96)00556-4"},{"key":"e_1_3_2_52_2","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1046\/j.1460-9592.2001.00660.x","volume":"11","year":"2001","unstructured":"Romsing, J., D. Ostergaard, T. Senderovitz, D. Drozdziewicz, J. Sonne, and G. Ravn. 2001. Pharmacokinetics of oral diclofenac and acetaminophen in children after surgery. Paediatr. Anaesth.11:205-213.","journal-title":"Paediatr. Anaesth."},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm040163o"},{"key":"e_1_3_2_54_2","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1007\/s12031-007-0055-y","volume":"33","year":"2007","unstructured":"Seelig, A. 2007. The role of size and charge for blood-brain barrier permeation of drugs and fatty acids. J. Mol. Neurosci.33:32-41.","journal-title":"J. Mol. Neurosci."},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1053-2498(02)00804-5"},{"key":"e_1_3_2_56_2","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1177\/0091270002042001006","volume":"42","year":"2002","unstructured":"Stevens, R. E., J. Konsil, S. S. Verrill, P. Roy, P. B. Desai, D. H. Upmalis, and F. L. Cone. 2002. Bioavailability study of a 1200 mg miconazole nitrate vaginal ovule in healthy female adults. J. Clin. Pharmacol.42:52-60.","journal-title":"J. Clin. Pharmacol."},{"key":"e_1_3_2_57_2","doi-asserted-by":"crossref","first-page":"S23","DOI":"10.1016\/S0924-8579(98)00071-5","volume":"12","year":"1999","unstructured":"Turnidge, J. 1999. Fusidic acid pharmacology, pharmacokinetics and pharmacodynamics. Int. J. Antimicrob. Agents12(Suppl. 2):S23-S34.","journal-title":"Int. J. Antimicrob. Agents"},{"key":"e_1_3_2_58_2","unstructured":"USP dictionary of USAN and international drug names. 2005"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/0042-6822(89)90425-X"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000095581.20961.7D"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.66.2.804-815.1992"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1177\/108705719900400206"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.01614-08","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.01614-08","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T23:37:47Z","timestamp":1738971467000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.01614-08"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,5]]},"references-count":61,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2009,5]]}},"alternative-id":["10.1128\/AAC.01614-08"],"URL":"https:\/\/doi.org\/10.1128\/aac.01614-08","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,5]]},"assertion":[{"value":"2008-12-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2009-02-20","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2009-05-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}