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

被引：62

作者：

Brideau, RJ ^{[1
]}

Knechtel, ML ^{[1
]}

Huang, A ^{[1
]}

Vaillancourt, VA ^{[1
]}

Vera, EE ^{[1
]}

Oien, NL ^{[1
]}

Hopkins, TA ^{[1
]}

Wieber, JL ^{[1
]}

Wilkinson, KF ^{[1
]}

Rush, BD ^{[1
]}

Schwende, FJ ^{[1
]}

Wathen, MW ^{[1
]}

机构：

[1] Pharmacia & Upjohn Inc, Kalamazoo, MI 49001 USA

来源：

ANTIVIRAL RESEARCH | 2002年 / 54卷 / 01期

关键词：

herpesviruses; DNA polymerases; antiviral activity; dihydroquinoline; PNU-183792;

D O I：

10.1016/S0166-3542(01)00208-X

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

We identified a novel class of 4-oxo-dihydroquino lines represented by PNU-183792 which specifically inhibit herpesvirus polymerases. PNU-183792 was highly active against human cytomegalovirus (HCMV, IC50 value 0.69 muM). varicella zoster virus (VZV, IC50 value 0.37 muM) and herpes simplex virus (HSV, IC50 value 0.58 muM) polymerases but was inactive (IC50 value > 40 muM) against human alpha (alpha), gamma (gamma), or delta (delta) 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 muM). PNU-183792 antiviral activity against both VZV (IC50 value 0.1 muM) and HSV (IC50 ranging from 3 to 5 muM) was analyzed using plaque reduction assays. PNU-183792 was also active (IC50 ranging 0.1-0.7 muM) 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 muM). 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. (C) 2002 Elsevier Science B.V. All rights reserved.

引用

页码：19 / 28

页数：10

共 18 条

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