title: β-l-1-[5-(E-2-bromovinyl)-2-(hydroxymethyl)-1,3-(dioxolan-4-yl)] uracil (l-BHDU) prevents varicella-zoster virus replication in a SCID-Hu mouse model and does not interfere with 5-fluorouracil catabolism.
abstract: The alphaherpesvirus varicella-zoster virus (VZV) causes chickenpox and shingles. Current treatments are acyclovir (ACV) and its derivatives, foscarnet and brivudine (BVdU). Additional antiviral compounds with increased potency and specificity are needed to treat VZV, especially to treat post-herpetic neuralgia. We evaluated β-l-1-[5-(E-2-bromovinyl)-2-(hydroxymethyl)-1,3-(dioxolan-4-yl)] uracil (l-BHDU, 1) and 5'-O-valyl-l-BHDU (2) in three models of VZV replication: primary human foreskin fibroblasts (HFFs), skin organ culture (SOC) and in SCID-Hu mice with skin xenografts. The efficacy of l-BHDU in vivo and its drug-drug interactions were previously not known. In HFFs, 200μM l-BHDU was noncytotoxic over 3days, and l-BHDU treatment reduced VZV genome copy number and cell to cell spread. The EC50 in HFFs for l-BHDU and valyl-l-BHDU were 0.22 and 0.03μM, respectively. However, l-BHDU antagonized the activity of ACV, BVdU and foscarnet in cultured cells. Given its similar structure to BVdU, we asked if l-BHDU, like BVdU, inhibits 5-fluorouracil catabolism. BALB/c mice were treated with 5-FU alone or in combination with l-BHDU or BVdU. l-BHDU did not interfere with 5-FU catabolism. In SCID-Hu mice implanted with human skin xenografts, l-BHDU and valyl-l-BHDU were superior to ACV and valacyclovir. The maximum concentration (Cmax) levels of l-BHDU were determined in mouse and human tissues at 2h after dosing, and comparison of concentration ratios of tissue to plasma indicated saturation of uptake at the highest dose. For the first time, an l-nucleoside analog, l-BHDU, was found to be effective and well tolerated in mice.
authors: Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY, USA. Electronic address: dec@upstate.edu.
authors: Chandrav
authors: C
authors: De
authors: Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY, USA. Electronic address: liud@upstate.edu.
authors: Dongmei
authors: D
authors: Liu
authors: Department of Pharmaceutics, College of Pharmacy, State University of New York at Buffalo, Buffalo, NY, USA. Electronic address: bozheng@buffalo.edu.
authors: Bo
authors: B
authors: Zheng
authors: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA, USA. Electronic address: ussingh@rx.uga.edu.
authors: Uma S
authors: US
authors: Singh
authors: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA, USA. Electronic address: schavre@rx.uga.edu.
authors: Satish
authors: S
authors: Chavre
authors: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA, USA. Electronic address: cwhite@rx.uga.edu.
authors: Catherine
authors: C
authors: White
authors: Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA. Electronic address: rda0007@auburn.edu.
authors: Robert D
authors: RD
authors: Arnold
authors: Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY, USA. Electronic address: fred_hagen@urmc.rochester.edu.
authors: Fred K
authors: FK
authors: Hagen
authors: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA, USA. Electronic address: dchu@mail.rx.uga.edu.
authors: Chung K
authors: CK
authors: Chu
authors: Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY, USA. Electronic address: moffatj@upstate.edu.
authors: Jennifer F
authors: JF
authors: Moffat
mesh_terms: D000212:Acyclovir / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002460:Cell Line; D002644:Chickenpox / Q000188:drug therapy; D004148:Dioxolanes / Q000009:adverse effects / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D005472:Fluorouracil / Q000378:metabolism*; D017245:Foscarnet / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006562:Herpes Zoster / Q000188:drug therapy; D014645:Herpesvirus 3, Human / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009705:Nucleosides / Q000494:pharmacology*; D009924:Organ Culture Techniques; D012867:Skin / Q000821:virology; D014498:Uracil / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: C000598561:1-(5-(2-bromovinyl)-2-(hydroxymethyl)-1,3-(dioxolan-4-yl))uracil; D000998:Antiviral Agents; D004148:Dioxolanes; D009705:Nucleosides; C020235:brivudine; D017245:Foscarnet; D014498:Uracil; D001973:Bromodeoxyuridine; D005472:Fluorouracil; D000212:Acyclovir
keywords: 5-Fluorouracil; Antiviral; Nucleoside analog; SCID-Hu mouse; Skin organ culture; Varicella-zoster virus