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, 200 μM L-BHDU was noncytotoxic over 3 days, 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 0.03 μM, 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 2 h 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.

H84T BanLec has broad spectrum antiviral activity against human herpesviruses in cells, skin, and mice

“…Compounds were evaluated for antiviral activity against VZV, HCMV, and HSV-1 using previously established dose response assays 59 . Briefly, cells were seeded in tissue culture treated 24-well plates 1–3 d prior to infection.…”

DNA Encapsidation and Capsid Assembly Are Underexploited Antiviral Targets for the Treatment of Herpesviruses

“…Below, we provide the first in vivo evidence that a small molecule compound targeting a viral portal is a viable drug candidate. The host of range of VZV is limited to humans, therefor the in vivo efficacy of a thiourea analog was tested in a previously described SCID-Hu VZV infection model (Rowe et al, 2010;De et al, 2014). The results presented here are the first for any compound targeting a viral portal in an animal model.…”

Highlights of the 30th International Conference on Antiviral Research

“…In an effort to identify an alternative to BVDU (a D-nucleoside) that would not block 5-FU catabolism, David and his colleagues synthesized and tested a series of L-analogs of BVDU in VZV- infected primary human foreskin fibroblasts and in skin organ culture (Choi et al, 2000;De et al, 2014). They identified b-L-1-[5-(E-2-bromovinyl)-2-(hydroxymethyl)-1,3-(dioxolan-4-yl)] uracil (L-BHDU) as an especially promising compound, with minimal cytotoxicity and 50% effective concentration (EC 50 ) values against VZV significantly lower than those of acyclovir or foscarnet.…”