Oligomeric proanthocyanidins from Rumex acetosa L. inhibit the attachment of herpes simplex virus type-1.
The polyphenole-enriched acetone-water extract R2 from the aerial parts of Rumex acetosa L. containing high amounts of oligomeric and polymeric proanthocyanidins and flavonoids was tested for antiviral activity. R2 exhibited strong antiviral activity against herpes simplex virus type-1 (HSV-1) while the replication of adenovirus 3 was not affected. By plaque reduction test and MTT assay on Vero cells, the HSV-1-specific inhibitory concentration (IC(50)) and cytotoxic concentration (CC(50)) were determined. R2 exibited an IC(50) of 0.8 μg/mL and a selectivity index (SI) (ratio of IC(50) to CC(50)) of approximately 100 when added to the virus inoculum for 1h at 37°C prior to infection. The antiviral activity was due to the presence of flavan-3-ols and oligomeric proanthocyanidins in the extract. Structure-activity analyses indicated that flavan-3-ols and proanthocyanidins with galloylation at position O-3 are highly potent compounds (SI>40), while ungalloylated compounds did not exhibit antiviral effects (SI<1). R2 and a major proanthocyanidin from R2, epicatechin-3-O-gallate-(4β→8)-epicatechin-3-O-gallate abolished virus entry into the host cell by blocking attachment to the cell surface. When added after attachment at a concentration of ≥ 12.5 μg/mL, R2 inhibited also penetration of HSV-1 into the host cell. R2 and epicatechin-3-O-gallate-(4β→8)-epicatechin-3-O-gallate were shown to directly interact with viral particles leading to the oligomerisation of envelope proteins as demonstrated for the essential viral glycoprotein gD. Using raft cultures with three-dimensional organotypic human skin equivalents it was shown that treatment of cultures with R2 after infection with HSV-1 resulted in a reduced viral spread.
Institute of Pharmaceutical Biology and Phytochemistry, University of Muenster, Hittorfstr. 56, 48149 Muenster, Germany.
Kirsten
K
Gescher
Andreas
A
Hensel
Wali
W
Hafezi
Andrea
A
Derksen
Joachim
J
Kühn
D000256:Adenoviridae / Q000187:drug effects; D000818:Animals; D000998:Antiviral Agents / Q000302:isolation & purification / Q000494:pharmacology*; D002470:Cell Survival; D002522:Chlorocebus aethiops; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D009924:Organ Culture Techniques; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology*; D044945:Proanthocyanidins / Q000302:isolation & purification / Q000494:pharmacology*; D031804:Rumex / Q000737:chemistry*; D012867:Skin / Q000821:virology; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D014709:Vero Cells; D010948:Viral Plaque Assay; D053585:Virus Attachment / Q000187:drug effects*
D000998:Antiviral Agents; D010936:Plant Extracts; D044945:Proanthocyanidins; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue