Broad-spectrum antiviral activity of PNU-183792, a 4-oxo-dihydroquinoline, against human and animal herpesviruses

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• 作者：Brideau ; Roger J. ; Knechtel ; Mary L. ; Huang ; Audris ; Vaillancourt ; Valerie A. ; Vera ; Ellen E. ; et. al.
• 关键词：Herpesviruses ; DNA polymerases ; Antiviral activity ; Dihydroquinoline ; PNU-183792
• 刊名：Antiviral Research
• 出版年：2002
• 出版时间：April, 2002
• 年：2002
• 卷：54
• 期：1
• 页码：19-28
• 全文大小：133 K

文摘

We identified a novel class of 4-oxo-dihydroquinolines represented by PNU-183792 which specifically inhibit herpesvirus polymerases. PNU-183792 was highly active against human cytomegalovirus (HCMV, IC₅₀ value 0.69 μM), varicella zoster virus (VZV, IC₅₀ value 0.37 μM) and herpes simplex virus (HSV, IC₅₀ value 0.58 μM) polymerases but was inactive (IC₅₀ value >40 μM) against human alpha (α), gamma (γ), or delta (δ) polymerases. In vitro antiviral activity against HCMV was determined using cytopathic effect, plaque reduction and virus yield reduction assays (IC₅₀ ranging from 0.3 to 2.4 μM). PNU-183792 antiviral activity against both VZV (IC₅₀ value 0.1 μM) and HSV (IC₅₀ ranging from 3 to 5 μM) was analyzed using plaque reduction assays. PNU-183792 was also active (IC₅₀ ranging 0.1–0.7 μM) in cell culture assays against simian varicella virus (SVV), murine cytomegalovirus (MCMV) and rat cytomegalovirus (RCMV). Cell culture activity was compared with the appropriate licensed drugs ganciclovir (GCV), cidofovir (CDV) and acyclovir (ACV). PNU-183792 was also active against both GCV-resistant and CDV-resistant HCMV and against ACV-resistant HSV. Toxicity assays using four different species of proliferating mammalian cells indicated PNU-183792 was not cytotoxic at relevant drug concentrations (CC₅₀ value >100 μM). PNU-183792 was inactive against unrelated DNA and RNA viruses indicating specificity for herpesviruses. In animals, PNU-183792 was orally bioavailable and was efficacious in a model of lethal MCMV infection.