Broad-spectrum antiviral activity of PNU-183792, a 4-oxo-dihydroquinoline, against human and animal herpesviruses.
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, IC(50) value 0.69 microM), varicella zoster virus (VZV, IC(50) value 0.37 microM) and herpes simplex virus (HSV, IC(50) value 0.58 microM) polymerases but was inactive (IC(50) value >40 microM) 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 (IC(50) ranging from 0.3 to 2.4 microM). PNU-183792 antiviral activity against both VZV (IC(50) value 0.1 microM) and HSV (IC(50) ranging from 3 to 5 microM) was analyzed using plaque reduction assays. PNU-183792 was also active (IC(50) ranging 0.1-0.7 microM) 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 (CC(50) value >100 microM). 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.
Brideau
Roger J
RJ
Pharmacia, 49001, Kalamazoo, MI, USA. roger.j.brideau@pharmacia.com
Knechtel
Mary L
ML
Huang
Audris
A
Vaillancourt
Valerie A
VA
Vera
Ellen E
EE
Oien
Nancee L
NL
Hopkins
Todd A
TA
Wieber
Janet L
JL
Wilkinson
Karen F
KF
Rush
Bob D
BD
Schwende
Francis J
FJ
Wathen
Michael W
MW
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006564:Herpesviridae / Q000187:drug effects* / Q000201:enzymology; D006566:Herpesviridae Infections / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018146:Muromegalovirus / Q000187:drug effects; D019384:Nucleic Acid Synthesis Inhibitors; D011804:Quinolines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; C455641:PNU183792; D011804:Quinolines