Flavonoids as Antiviral Agents for Enterovirus A71 (EV-A71)

Abstract

Flavonoids are natural biomolecules that are known to be effective antivirals. These biomolecules can act at different stages of viral infection, particularly at the molecular level to inhibit viral growth. Enterovirus A71 (EV-A71), a non-enveloped RNA virus, is one of the causative agents of hand, foot and mouth disease (HFMD), which is prevalent in Asia. Despite much effort, no clinically approved antiviral treatment is available for children suffering from HFMD. Flavonoids from plants serve as a vast reservoir of therapeutically active constituents that have been explored as potential antiviral candidates against RNA and DNA viruses. Here, we reviewed flavonoids as evidence-based natural sources of antivirals against non-picornaviruses and picornaviruses. The detailed molecular mechanisms involved in the inhibition of EV-A71 infections are discussed.

Keywords: Enterovirus 71 (EV-A71); antivirals; flavonoids; hand, foot and mouth disease (HFMD); infectious childhood disease; viruses.

Figure 1

The antiviral activity of flavonoids in the life cycle of EV-A71. Flavonoids are reported to exhibit antiviral activity against EV-A71 and they are categorized according to the mechanism of inhibition at different stages of the virus life cycle. NR: not reported (Flavonoids that affect uncoating, assembly and release of EV-A71 are not reported). HnRNP = heterogeneous nuclear ribonucleoproteins, IRES = internal ribosome entry site, IFN = interferon, JAK = janus kinase, TYK = tyrosine kinase, and STAT = signal transducer and activator of transcription proteins.

Figure 2

Inhibition of molecular signaling pathways involved in EV-A71 infection by flavonoids. Flavonoids are classified according to their ability at the molecular level to inhibit signaling pathways involved in EV-A71-induced apoptosis, inflammation and infection associated cytokine production. GDP = guanosine diphosphate, GTP = guanosine triphosphate, RAF = rapidly accelerated fibrosarcoma, MEK/MAPK = mitogen-activated protein kinase, ERK = extracellular signal-regulated kinase, SRSF/MnK2a = serine/threonine-protein kinase. JNK = c-Jun N-terminal kinase, ASK = apoptosis signal-regulating kinase, PEG = prostaglandins, COX = cyclooxygenase, and FasL = Fas ligand.

Figure 3

General chemical structure of flavone nucleus.