The antiviral agent 5-chloro-1,3-dihydroxyacridone interferes with assembly and maturation of herpes simplex virus.
Antiviral drug screening and exploratory mechanistic work identified 5-chloro-1,3-dihydroxyacridone as a lead inhibitor of herpes simplex virus (HSV) replication, one without a primary effect on either HSV DNA or late viral protein synthesis (Antivir. Res. 45 (2000) 123). In this report, drug effects on viral DNA cleavage and packaging, HSV capsid production and virion morphogenesis in infected Vero cells were studied systematically in order to better localize the sensitive stage of the replication cycle. Maturation of replicating HSV DNA and virion production at late times were inhibited in the same dose-dependent fashion, suggesting that the drug might directly inhibit the cleavage and packaging processes. Based on density centrifugation analysis however, this possibility appears unlikely because overproduction of neither A- or B-capsids occurred upon drug treatment. Interestingly, similar studies coupled with either Western immunoblot or ultrastructural analysis showed that B-capsids with apparent normal protein composition accumulated at reduced levels (maximally about two- to three-fold) in drug-treated cells. Limited attempts to isolate drug-resistant viral mutants using standard approaches proved unsuccessful. In summery, 5-chloro-1,3-dihydroxyacridone inhibits one or more steps of HSV assembly since treatment results in reduced levels of capsids (particularly B-type) and reduced levels of encapsidated DNA. The action of the acridone derivative is an unusual one, with distinctive features when compared to a recently reported class of HSV encapsidation inhibitor and to the late replication defects of relevant viral mutants.
Akanitapichat
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Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina at Chapel Hill, CB# 7630, Chapel Hill, NC 27599, USA.
Bastow
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KF
D000166:Acridines / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002213:Capsid / Q000187:drug effects; D002522:Chlorocebus aethiops; D004279:DNA, Viral / Q000378:metabolism; D006561:Herpes Simplex / Q000821:virology; D006801:Humans; D018139:Simplexvirus / Q000187:drug effects* / Q000502:physiology* / Q000648:ultrastructure; D014709:Vero Cells; D019065:Virus Assembly / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
C411209:5-chloro-1,3-dihydroxyacridone; D000166:Acridines; D000998:Antiviral Agents; D004279:DNA, Viral