Comparison of the Selectivity of Anti‐Varicella‐Zoster Virus Nucleoside Analogues

Abstract

We compared the selectivity of six anti‐varicella‐zoster virus (VZV) drugs, which are clinically available or of which clinical efficacy for the treatment of VZV infections has been reported. Sorivudine (BV‐araU) had the most potent anti‐VZV effect in the plaque inhibition assay, followed by brivudine (BVDU) and 5‐propynyl‐arabinofuranosyluracil (Pry‐araU). All test compounds, except vidarabine (AraA), had only a very weak effect on human embryonic lung cell growth. The selectivity indexes (ID50 for cell growth/ED50 for VZV plaque inhibition) of BV‐araU, BVDU, and Pry‐araU were > 1,000,000, 20,000, and > 10,000, respectively, while those of acyclovir and penciclovir ranged from 600 to 800. AraA was much less selective than any of the other drugs tested. We measured the amount of pH] thymidine incorporated into the acid‐insoluble fraction of VZV‐infected cells to determine the ability of these drugs to selectively inhibit viral DNA synthesis. [3H]Thymidine incorporation was markedly inhibited by all anti‐VZV compounds, except BVDU. Treatment of infected cells with drugs from 32 to 38 hr after infection inhibited the DNA synthesis to the same extent as VZV plaque formation, except that AraA inhibited the DNA synthesis at a lower dose than for VZV plaque formation. DNA synthesis in non‐infected growing cells was inhibited to the same extent as cell growth. A particularly high selectivity index for the inhibition of DNA synthesis was noted for BV‐araU, which was defined as the ratio of inhibitions of DNA synthesis in VZV‐infected and non‐infected. The highest selectivity indexes were recorded for BV‐araU > Pry‐araU > acyclovir ≥ penciclovir > AraA.

Antiviral effects of Glycyrrhiza species

“…In human embryonic fibroblast cells inoculated with five strains of the virus, glycyrrhizin produced an inhibitory effect on viral proliferation with an IC 50 (inhibitory concentration reducing activity to 50% of controls) of 0.71 mM. The selectivity index, defined as the ratio of IC 50 for host-cell DNA synthesis to IC 50 for virus replication, was estimated to be 30 (this value is not as high as for the most commonly used antiviral drugs, the selectivity index for acyclovir is close to 600 [Machida et al, 1995]). Pretreatment of cells with the drug 24 h before inoculation was able to inhibit replication of the virus.…”

“…Cell cultures References Gotoh et al, 1987Mori et al, 1989Ito et al, 1987Baba et al, 1988Tochikura et al, 1989Harada, 2005Harada et al, 1998Sasaki et al, 2002De Clercq 2000Thyagarajan et al, 2002Wang et al, 1998Utsonomiya et al, 1997Abe et al, 1982Pompei et al, 1983Ko et al, 2006Cinatl et al, 2003Hoever et al, 2005Baba and Sigeta, 1987Lampi et al, 2001Lin, 2003Numazaki et al, 1994Machida et al, 1995Pompei et al, 1979Sekizawa et al, 2001Pompei et al, 1979Pompei et al, 1979Pompei et al, 1979Ohtsuki and Iahida, 1988Crance et al, 2003Wang et al, 2006Curreli et al, 2005Cohen, 2005 ANTIVIRAL EFFECTS OF GLYCYRRHIZA SPECIES…”

Identification of Small Molecule Compounds That Selectively Inhibit Varicella-Zoster Virus Replication

“…They are subsequently phosphorylated by cellular kinases, and the activated compounds inhibit the viral DNA polymerase. Sorivudine and brivudine are also potent inhibitors of VZV, and although they represent a different class of nucleoside analogues from ACV, they also require phosphorylation by the viral thymidine kinase for activation (18,31). While thymidine kinase-deficient VZV can be treated with foscarnet, a direct inhibitor of the viral DNA polymerase (25), this drug requires intravenous administration and has a marked potential for nephrotoxicity.…”

Enzymatic Synthesis of 2′-O-acyl Prodrugs of 1-(β-D-arabinofuranosyl)-5(E)-(2-bromovinyl)uracil and of 2′-O-acyl-araU, -araC and -araA

“…Among the drugs clinically tested for the treatment ofvaricella-zoster virus (VZV) infections, 1-~-D-arabinofurano syl-5-[(E)-(2-bromovinyl)]uracil (1; sorivudine; BV-araU; for review see Alrabiah & Sacks, 1996) shows the most potent anti-VZV activity in plaque reduction assays (Machida et al, 1995). One serious drawback has been observed when administering BV-araU to patients receiving 5-fluorouracil (5-FU) therapy: as a consequence of inhibition of dihydropyrimidine dehydrogenase (DPD), efficacy but also toxicity of 5-FU are greatly potentiated (Machida et al, 1995).…”

“…One serious drawback has been observed when administering BV-araU to patients receiving 5-fluorouracil (5-FU) therapy: as a consequence of inhibition of dihydropyrimidine dehydrogenase (DPD), efficacy but also toxicity of 5-FU are greatly potentiated (Machida et al, 1995). This occurrence has been attributed to' enzymatic cleavage of the N-glycosylic bond with release of the corresponding BV-uracil, which strongly inhibits DPD (De Clercq, 1995).…”