Synergistic inhibition of influenza A virus replication by a plant polyphenol-rich extract and epsilon-aminocaproic acid in vitro and in vivo.
A combined antiviral effect of a polyphenol-rich extract of the medicinal plant Geranium sanguineum L. (PC) and a protease inhibitor, epsilon-aminocaproic acid (ACA) was examined in Influenza A virus (IAV)-infected MDCK cell cultures and mice. Synergistic, antagonistic, or indifferent antiviral effects were distinguished on the basis of virus yields, namely fractional yields of individual compounds and yields of both compounds in combination. Combinations of PC and ACA in particular concentrations proved synergistic in the inhibition of virus replication in MDCK cells and in protection of mice against virus infection as determined by virus titers, lung weight, mean survival time (MST), mortality rate, and protection rate (PR). Following the application of a combination of PC and ACA to the virus-infected mice, the levels of the lung protease and protease-inhibitory activity, which were increased due to the virus infection, were brought to normal. These results demonstrate the rationale for a combined application of viral inhibitors with different modes of action to the treatment of IAV infection, in particular PC as a natural inhibitor of early viral transcription and translation and ACA as a synthetic inhibitor of cellular proteases.


BACKGROUND
Influenza A virus; antiviral effect; synergism; plant polyphenol extract; epsilon-aminocaproic acid; protease inhibitors.
Serkedjieva
J
J
Institute of Microbiology, Bulgarian Academy of Sciences, 26, Acad. Georgy Bonchev St., 1113 Sofia, Bulgaria. jserkedjieva@microbio.bas.bg
Nikolova
E
E
Kirilov
N
N
D015119:Aminocaproic Acid / Q000008:administration & dosage*; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000302:isolation & purification; D002460:Cell Line; D004357:Drug Synergism; D005419:Flavonoids / Q000008:administration & dosage* / Q000302:isolation & purification; D031315:Geranium / Q000737:chemistry; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects / Q000502:physiology; D009980:Influenza A virus / Q000187:drug effects* / Q000502:physiology; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000517:prevention & control; D010447:Peptide Hydrolases / Q000378:metabolism; D010636:Phenols / Q000008:administration & dosage* / Q000302:isolation & purification; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage / Q000302:isolation & purification; D059808:Polyphenols; D011480:Protease Inhibitors / Q000008:administration & dosage; D014779:Virus Replication / Q000187:drug effects* / Q000502:physiology
D000998:Antiviral Agents; D005419:Flavonoids; D010636:Phenols; D010936:Plant Extracts; D059808:Polyphenols; D011480:Protease Inhibitors; D010447:Peptide Hydrolases; D015119:Aminocaproic Acid