title: Hexadecyloxypropyl-cidofovir (CMX001) suppresses JC virus replication in human fetal brain SVG cell cultures.
abstract: JC virus (JCV) is a polyomavirus that infects human oligodendrocytes, leading to development of progressive multifocal leukoencephalopathy (PML), an often fatal demyelinating disease occurring in immunocompromised individuals. Currently there are no effective therapies for the treatment of PML that result in clearance of JCV from the brain. Cidofovir (CDV) is an acyclic nucleoside phosphonate that inhibits DNA polymerases and has been used for the treatment of PML. However, CDV demonstrated little efficacy as a treatment for PML and causes substantial side effects to patients. To improve efficacy and reduce the toxicity of CDV, a lipid-ester derivative, CMX001, was generated by Chimerix and is currently in multicenter phase II clinical trials for the prevention or control of cytomegalovirus infection in hematopoietic stem cell transplant recipients and of BK virus in the urine of stem cell or renal allograft recipients. CMX001 caused minimal cytotoxic effects in human fetal brain SVG cells when used at concentrations between 0.01 μM and 0.1 μM. CMX001 resulted in a dose-dependent decrease in the number of JCV-infected cells during initial infection and nearly eliminated JCV-infected cells during an established infection. In addition, CMX001 treatment resulted in a 60% reduction in JCV DNA copy number during initial infection, which suggests that suppression of JCV infection by CMX001 is likely due to inhibition of virus DNA replication. This study demonstrates that CMX001 suppresses JCV infection at concentrations that have limited toxicity to human brain cells, indicating its potential use to limit JCV replication in infected patients.
authors.affiliation: Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke/NIH, 10 Center Drive, Bethesda, MD 20892-1296, USA.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Jiang
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Cohen
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Marshall
authors.forename: Eugene O
authors.initials: EO
authors.lastname: Major
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000166:cytology* / Q000196:embryology*; D002460:Cell Line; D003596:Cytosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005333:Fetus / Q000166:cytology*; D006801:Humans; D017403:In Situ Hybridization; D007577:JC Virus / Q000187:drug effects*; D008858:Microscopy, Phase-Contrast; D015394:Molecular Structure; D063065:Organophosphonates / Q000737:chemistry / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; C525733:brincidofovir; D003596:Cytosine
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