Human cytomegalovirus-inhibitory flavonoids: Studies on antiviral activity and mechanism of action

Abstract

We report antiviral activity against human cytomegalovirus for certain dietary flavonoids and their likely biochemical mechanisms of action. Nine out of ten evaluated flavonoids blocked HCMV replication at concentrations that were significantly lower than those producing cytotoxicity against growing or stationary phase host cells. Baicalein was the most potent inhibitor in this series (IC(50)=0.4-1.2 microM), including positive control ganciclovir. Baicalein and genistein were chosen as model compounds to study the antiviral mechanism(s) of action for this series. Both flavonoids significantly reduced the levels of HCMV early and late proteins, as well as viral DNA synthesis. Baicalein reduced the levels of HCMV immediate-early proteins to nearly background levels while genistein did not. The antiviral effects of genistein, but not baicalein, were fully reversible in cell culture. Pre-incubation of concentrated virus stocks with either flavonoid did not inhibit HCMV replication, suggesting that baicalein did not directly inactivate virus particles. Baicalein functionally blocked epidermal growth factor receptor tyrosine kinase activity and HCMV nuclear translocation, while genistein did not. At 24h post infection HCMV-infected cells treated with genistein continued to express immediate-early proteins and efficiently phosphorylate IE1-72. However, HCMV induction of NF-kappaB and increases in the levels of cell cycle regulatory proteins--events that are associated with immediate-early protein functioning--were absent. The data suggested that the primary mechanism of action for baicalein may be to block HCMV infection at entry while the primary mechanism of action for genistein may be to block HCMV immediate-early protein functioning.

Cytotoxicity, antiviral and antimicrobial activities of alkaloids, flavonoids, and phenolic acids

“…In many cases, antimicrobial effects of various plant extracts have been attributed to their flavonoid contents (Tsao et al, 1982;Cafarchia et al, 1999). Flavonoid derivatives have also been reported to possess antiviral activity against a wide range of viruses such as HSV, HIV, Coxsackie B virus, coronavirus, cytomegalovirus, poliomyelitis virus, rhinovirus, rotavirus, poliovirus, sindbis virus, and rabies virus (De Bruyne et al, 1999;Evers et al, 2005;Chávez et al, 2006;Nowakowska, 2007). In a study by Chiang et al (2002), Plantago major, which has been used in the treatment of viral hepatitis in Chinese traditional medicine, showed a strong anti-herpes activity against HSV-1 and antiviral activity of the aqueous extract of this species mainly attributed to its rich phenolic content, caffeic acid, in particular, which is consistent with our data (Table 1).…”

Hepatic Metabolism and Disposition of Baicalein via the Coupling of Conjugation Enzymes and Transporters—In Vitro and In Vivo Evidences

“…1) is a bioactive flavonoid present in Scutellariae radix, a traditional Chinese medicinal herb derived from the root of Scutellaria baicalensis Georgi (1). Ba has been demonstrated to have diverse pharmacological activities including anti-inflammatory (2,3), anti-allergic (4), antioxidative activities (5), antiviral (6,7), etc. In recent years, the anticancer activities of Baicalein have received great attention (8)(9)(10).…”

Inhibitory Effects of Baicalein on the Influenza Virus in Vivo Is Determined by Baicalin in the Serum

“…It also significantly reduces the levels of early and late proteins of HCMV, as well as viral DNA synthesis. 4) Influenza, one of the major pandemic diseases worldwide, represents a grave threat to human health. At present, only two types of chemical drug are used clinically in the treatment of influenza.…”