Anti-herpesvirus activity of citrusinine-I, a new acridone alkaloid, and related compounds.
Citrusinine-I, a new acridone alkaloid isolated from the root bark of the citrus plant (Rutaceae), exhibited potent activity against herpes simplex virus (HSV) type 1 and type 2 at low concentrations relative to their cytotoxicity; 50% effective concentrations (ED50) of citrusinine-I were 0.56 micrograms/ml and 0.74 micrograms/ml against HSV-1 and HSV-2, respectively. Inhibitory action was also demonstrated against cytomegalovirus (CMV) and thymidine kinase-deficient or DNA polymerase mutants of HSV-2. The compound markedly suppressed HSV-2 and CMV DNA synthesis at concentrations which did not inhibit the synthesis of virus-induced early polypeptides. However, citrusinine-I had no inhibitory activity against HSV and CMV DNA polymerases in cell-free extracts. Although the target of this inhibitor remains to be elucidated, the most plausible candidate is a virus-coded ribonucleotide reductase. Citrusinine-1, when combined with acyclovir or ganciclovir, synergistically potentiated the antiherpetic activity of these agents. Based on a comparative study of the antiherpetic activity of citrusinine-1 and 28 related compounds, a structure-activity relationship could be established.
Yamamoto
N
N
Laboratory of Virology, Nagoya University School of Medicine, Japan.
Furukawa
H
H
Ito
Y
Y
Yoshida
S
S
Maeno
K
K
Nishiyama
Y
Y
D000166:Acridines / Q000378:metabolism; D054831:Acridones; D000470:Alkaloids / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000187:drug effects / Q000201:enzymology; D004279:DNA, Viral / Q000096:biosynthesis / Q000187:drug effects; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D006801:Humans; D009154:Mutation; D018139:Simplexvirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000096:biosynthesis; D014779:Virus Replication / Q000187:drug effects
D000166:Acridines; D054831:Acridones; D000470:Alkaloids; D000998:Antiviral Agents; D004279:DNA, Viral; D014764:Viral Proteins; C041300:acridone; C062044:citrusinine I; D004259:DNA-Directed DNA Polymerase