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

• Published in: Antiviral research Vol. 110; pp. 10 - 19
• Main Authors: DE, Chandrav, DONGMEI LIU, BO ZHENG, SINGH, Uma S, CHAVRE, Satish, WHITE, Catherine, ARNOLD, Robert D, HAGEN, Fred K, CHU, Chung K, MOFFAT, Jennifer F
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier 01.10.2014
• Subjects: Acyclovir - antagonists & inhibitors; Acyclovir - pharmacology; Alphaherpesvirus; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - antagonists & inhibitors; Antiviral Agents - pharmacology; Biological and medical sciences; Bromodeoxyuridine - analogs & derivatives; Bromodeoxyuridine - antagonists & inhibitors; Bromodeoxyuridine - pharmacology; Cell Line; Chickenpox - drug therapy; Dioxolanes - adverse effects; Dioxolanes - pharmacology; Drug Therapy, Combination; Fluorouracil - metabolism; Foscarnet - antagonists & inhibitors; Foscarnet - pharmacology; Herpes Zoster - drug therapy; Herpesvirus 3, Human - drug effects; Humans; Medical sciences; Mice; Mice, Inbred BALB C; Mice, SCID; Nucleosides - pharmacology; Organ Culture Techniques; Pharmacology. Drug treatments; Skin - virology; Uracil - adverse effects; Uracil - analogs & derivatives; Uracil - pharmacology; Varicella-zoster virus; Virus Replication - drug effects; Antineoplastic agent; Animal model; SCID-Hu mouse; 5-Fluorouracil; Alphaherpesvirinae; Prevention; Skin organ culture; Nucleoside analog; Antiviral; Varicella-zoster virus; Fluorouracil; Varicella zoster virus; Enzyme; Fluoropyrimidine derivatives; Herpesviridae; Transferases; Rodentia; Enzyme inhibitor; Thymidylate synthase; In vitro; Virus; Vertebrata; Mammalia; Antimetabolic; Methyltransferases; Mouse; Animal; Pyrimidine derivatives; Replication; Catabolism; Skin; Combined immune deficiency
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2014.07.007

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.