title: CMX001 (1-O-hexadecyloxypropyl-cidofovir) inhibits polyomavirus JC replication in human brain progenitor-derived astrocytes.
abstract: Polyomavirus JC (JCV) replication causes progressive multifocal leukoencephalopathy (PML), a frequently fatal brain disease in immunodeficient patients, yet antiviral drugs are lacking. We characterized the lipid conjugate 1-O-hexadecyloxypropyl-cidofovir (CMX001) regarding JCV (Mad-4) replication in human brain progenitor-derived astrocytes (PDA) and the simian virus 40 (SV40) large-T-antigen-expressing COS-7 cells up to 7 days postinfection (dpi). We examined JCV loads by PCR, the infection rate by immunofluorescence, and host cell toxicity by WST-1 and BrdU incorporation assays. Supernatants from CMX001-treated PDA demonstrated a drug concentration-dependent decrease in JCV loads and infectivity. CMX001 had only a modest effect on host cell metabolism but reduced overall BrdU incorporation. In PDA at 7 dpi, the CMX001 50% effective concentration (EC50) was 5.55 nM, the 50% cytotoxic concentration (CC50) was 184.6 nM, and the 50% selectivity index (SI50) was 33.3. The EC90 was 19.7 nM, the CC90 was 5,054 nM, and the SI90 was 256.1. In COS-7 cells, JCV replication was faster and the EC50 and EC90 were 18- and 37-fold higher than those in PDA, i.e., 0.1 μM and 0.74 μM (CC50, 0.67 μM; SI50, 6.7; CC90, 12.2 μM; SI90, 16.5) at 5 dpi. We conclude that CMX001 inhibits JCV replication at concentrations in vitro that can be attained by oral administration without significant side effects in clinical studies.
authors.affiliation: Transplantation Virology, Institute for Medical Microbiology, Department of Biomedicine, University of Basel, and Infectious Diseases & Hospital Epidemiology, University Hospital Basel, Petersplatz 10, CH-4003 Basel, Switzerland.
authors.forename: Rainer
authors.initials: R
authors.lastname: Gosert
authors.forename: Christine Hanssen
authors.initials: CH
authors.lastname: Rinaldo
authors.forename: Marion
authors.initials: M
authors.lastname: Wernli
authors.forename: Eugene O
authors.initials: EO
authors.lastname: Major
authors.forename: Hans H
authors.initials: HH
authors.lastname: Hirsch
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000821:virology*; D001921:Brain / Q000166:cytology*; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D006801:Humans; D007577:JC Virus / Q000187:drug effects*; D063065:Organophosphonates / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D063065:Organophosphonates; C525733:brincidofovir; D003596:Cytosine