Identification and characterization of mefloquine efficacy against JC virus in vitro

Margot Brickelmaier, Alexey Lugovskoy, Ramya Kartikeyan, Marta M. Reviriego-Mendoza, Norm Allaire, Kenneth Simon, Richard J. Frisque, Leonid Gorelik

Research output: Contribution to journalArticle

166 Citations (Scopus)

Abstract

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/SVEΔ), 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.

Original languageEnglish (US)
Pages (from-to)1840-1849
Number of pages10
JournalAntimicrobial agents and chemotherapy
Volume53
Issue number5
DOIs
StatePublished - May 1 2009

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JC Virus
Mefloquine
Progressive Multifocal Leukoencephalopathy
Virus Diseases
Neuroglia
In Vitro Techniques
Polyomavirus
Viral DNA
Antimalarials
Brain
DNA Replication
Astrocytes
Pharmaceutical Preparations
Antiviral Agents
Cultured Cells
Central Nervous System
Animal Models
Polymerase Chain Reaction

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Brickelmaier, M., Lugovskoy, A., Kartikeyan, R., Reviriego-Mendoza, M. M., Allaire, N., Simon, K., ... Gorelik, L. (2009). Identification and characterization of mefloquine efficacy against JC virus in vitro. Antimicrobial agents and chemotherapy, 53(5), 1840-1849. https://doi.org/10.1128/AAC.01614-08
Brickelmaier, Margot ; Lugovskoy, Alexey ; Kartikeyan, Ramya ; Reviriego-Mendoza, Marta M. ; Allaire, Norm ; Simon, Kenneth ; Frisque, Richard J. ; Gorelik, Leonid. / Identification and characterization of mefloquine efficacy against JC virus in vitro. In: Antimicrobial agents and chemotherapy. 2009 ; Vol. 53, No. 5. pp. 1840-1849.
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Brickelmaier, M, Lugovskoy, A, Kartikeyan, R, Reviriego-Mendoza, MM, Allaire, N, Simon, K, Frisque, RJ & Gorelik, L 2009, 'Identification and characterization of mefloquine efficacy against JC virus in vitro', Antimicrobial agents and chemotherapy, vol. 53, no. 5, pp. 1840-1849. https://doi.org/10.1128/AAC.01614-08

Identification and characterization of mefloquine efficacy against JC virus in vitro. / Brickelmaier, Margot; Lugovskoy, Alexey; Kartikeyan, Ramya; Reviriego-Mendoza, Marta M.; Allaire, Norm; Simon, Kenneth; Frisque, Richard J.; Gorelik, Leonid.

In: Antimicrobial agents and chemotherapy, Vol. 53, No. 5, 01.05.2009, p. 1840-1849.

Research output: Contribution to journalArticle

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AU - Brickelmaier, Margot

AU - Lugovskoy, Alexey

AU - Kartikeyan, Ramya

AU - Reviriego-Mendoza, Marta M.

AU - Allaire, Norm

AU - Simon, Kenneth

AU - Frisque, Richard J.

AU - Gorelik, Leonid

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Brickelmaier M, Lugovskoy A, Kartikeyan R, Reviriego-Mendoza MM, Allaire N, Simon K et al. Identification and characterization of mefloquine efficacy against JC virus in vitro. Antimicrobial agents and chemotherapy. 2009 May 1;53(5):1840-1849. https://doi.org/10.1128/AAC.01614-08