Scientific Paper / May 2020

By J. Cannillo, F. Tuzi

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Among the plants most studied for their antiviral properties, Scutellaria baicalensis stands out for its complex biochemical profile.

Used for centuries in Traditional Chinese Medicine, an invaluable source for the discovery and development of molecules, S. baicalensis contains more than 200 identified compounds with over 40 flavonoids. Six important bioactive flavonoids are baicalin, baicalein, wogonin, wogonoside, oroxylin, and oroxylin A-7-glucuronide; minor bioactive flavonoids include chrysin, chrysin-6,8-di-C-glucoside, apigenin, and apigenin-6-C-glucose-8-C-arabinose.

In particular, baicalin is the main metabolite of baicalein (5,6,7-trihydroxyflavone). This flavonoid exhibits a wide range of pharmacological activities, including antiviral activity, as well as protective effects on the nervous, immune, and vascular systems, along with antibacterial, anti-inflammatory, antioxidant, antiproliferative, and antitumor effects.

Both the chemical composition of S. baicalensis and its pharmacological effects have been and continue to be the subject of numerous studies.

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Antiviral Action

ACE2 is essential for the virus’s entry into the host cell. Some research has shown that baicalin can inhibit ACE2, a functional receptor also for the SARS-coronavirus (SARS-CoV), against which baicalin’s antiviral activity had already been successfully tested. Indeed, SARS-CoV-2 has been shown to share 79.5% of the genomic sequence with SARS-CoV.

Using structural modeling of its S (spike) protein, scientists suggest a strong interaction of human ACE2 molecules with SARS-CoV-2. It is a type I integral membrane protein with an active site domain on the extracellular surface. It has been found that the SARS-CoV-2 receptor binding domain is able to enter cells expressing human ACE2, but not others with different receptors.

By applying molecular docking (Figure 1), to verify the possibility of baicalin binding to the ACE2 receptor and therefore blocking SARS-CoV entry, it was highlighted that baicalin can indeed have a strong bond with the enzyme.

Characterization studies of RNA virus genomes have shown that coronaviruses share key genomic elements for replication and suppression. These include a chymotrypsin-like cysteine protease (3CLpro), along with a papain-like protease (PLpro), required for the transformation of polyproteins into mature nonstructural proteins such as RNA-dependent RNA polymerases and helicases, making it essential for viral transcription and replication.

The substrate specificity of 3CLpro, also known as the major protease (Mpro), is highly conserved among coronaviruses and similar to that of picornaviruses, making it an ideal antiviral target.

Enzyme assays combined with X-ray crystallography, ITC, and ESI-MS studies have shown that baicalin and baicalein act as noncovalent, nonpeptidomimetic inhibitors of 3CLpro (Figure 2). Together with favorable clinical safety data, these bioactive components exhibit high ligand-binding efficiency. The crystal structure demonstrates a unique protein-ligand interaction mode used to block the proteolytic activity of SARS-CoV-2 3CLpro.

Scutellaria baicalensis extracts have broad-spectrum antiviral activity against:

    •    HIV (Human Immunodeficiency Virus)

    •    Influenza virus

    •    DENV (Dengue Virus)

    •    HBV (Hepatitis B Virus)

    •    HTLV-I (Human T-cell Leukemia Virus type I)

    •    HSV-1 (Herpes Simplex Virus-1)

Among the mechanisms highlighted, S. baicalensis extracts act on innate antiviral immunity by regulating cytokines including IFN-γ and IFN-β and promoting resistance of human leukocytes by stimulating TNF-γ, IL-12, and IL-10 production.

It has shown antiviral activity against:

    •    CVB3 (Coxsackievirus B3) via inhibition of AKT and p38 gene expression

    •    EV71 (Enterovirus 71), correlated with blockade of EV71/3D mRNA and polymerase

    •    In hand-foot-and-mouth disease, rapid reduction of fever, oral lesions, skin rashes, and improved nervous system involvement

Baicalin also inhibits apoptosis of EV71-infected cells by activating Fas/FasL signaling pathways and blocking NF-κB signaling.

Baicalein has been shown to inhibit reverse transcriptase and interfere with HIV RNA replication by inducing apoptosis in infected cells in vitro. It is also a potent inhibitor of HCMV (Human Cytomegalovirus), reducing early and late proteins and viral DNA synthesis.

In mice infected with H1N1, baicalin demonstrated antiviral effects comparable to lamivudine. The proposed mechanism is inhibition of neuraminidase (NA) and immune modulation. Baicalein and baicalin bind with high affinity to NA1, NA2, and NA9 (Figure 3).

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Action on the Immune System

Studies demonstrate that S. baicalensis has a significant inhibitory effect on allergic inflammation, both in vivo and in vitro.

Mechanisms include:

    •    Downregulation of inflammatory mediators

    •    Reduced inflammatory cytokine production

    •    MAPK activation suppression

Wogonin reduces ovalbumin-induced Th2 immune response, inhibits IL-5 production, and indirectly reduces IgE levels without reducing cell viability.

Scutellaria baicalensis may offer preventive and therapeutic effects in Th2 or mast cell-mediated allergic asthma, likely associated with regulation of Th1/Th2 imbalance and histamine release.

Investigations of viral vesicular stomatitis revealed modulation of cytokine production in human peripheral blood leukocytes, increasing host cell resistance to infection.

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Anti-inflammatory Action

In inflammatory models, S. baicalensis reduces NO production through downregulation of IKK (IκB kinase) and activation of NF-κB via suppression of c-Raf-1 phosphorylation, MEK1/2, and MAPK pathways.

Baicalein inhibits production of NO, cytokines, chemokines, and growth factors in macrophages induced by double-stranded RNA. It also reduces inflammation by selectively binding chemokine ligands on CD4 and leukocytes.

Wogonoside reduces inflammatory mediators such as NO and PGE2 and inhibits release of pro-inflammatory cytokines including TNF-γ and IL-6.

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Antioxidant Action

S. baicalensis protects lung tissue from lipid peroxidation after free radical injury.

Baicalein, baicalin, and wogonin:

    •    Scavenge ONOO⁻

    •    Inhibit nitrotyrosine formation

    •    Block inducible NO synthase (iNOS)

    •    Inhibit COX-2

    •    Suppress MAPK phosphorylation

Extracts protect against oxidative damage to human plasma proteins and lipids induced by hydroxyl radicals. They chelate and oxidize Fe²⁺ ions and eliminate free radicals during formation.

Baicalein and baicalin inhibit mitochondrial lipid peroxidation in rat cortex and protect cells from H₂O₂-induced damage in human neuroblastoma.

Due to antioxidant properties, S. baicalensis may help prevent diseases related to oxidative stress, including inflammatory, cardiovascular, and cancer diseases.

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