Table 1.
Antiviral activity of different polyphenols extracted from plants.
| Material | Polyphenols | Virus | Dose | Mechanism | References |
|---|---|---|---|---|---|
| mulberry (Morus alba) juice | caffeic acid, chlorogenic acid, p-coumaric acid, cyanidin-3-glucoside, cyanidin-3-rutinoside, 3,4-dihydroxybenzoic acid, gallic acid, rutin |
IAV, IBV variety (A/Brisbane/59/2007- [H1N1, BR59], A/Korea/01/2009—[H1N1, KR01], A/Brisbane/10/2007—[H3N2, BR10], B/Florida/4/2006 [FL04]) | mulberry juice at 2% and 4% exhibited 1.3 log inhibition on FL04 virus in the pretreatment and cotreatment of the virus | antiviral activity at the initial stage of the virus inhibits the attachment of viral surface protein to its cellular receptor or due to internalization of cell surface receptors from virions and prevents virus adsorption to host cells | [11] |
| black tea | theaflavin (TF1), theaflavin-3′-monogallate(TF2), theaflavin-3-3′-digallate(TF3) |
HCV | EC50—17.89 μM (10.09 μg/mL), (TF1), CC50—442.8 μM (250 μg/mL), (TF1), EC50—4.08 μM (2.92 μg/mL), (TF2), CC50—348.8 μM (250 μg/mL), (TF2), EC50—2.02 μM (1.75 μg/mL), (TF3), CC50—287.7 μM (250 μg/mL), (TF3) |
polyphenols prevent cell surface attachment or receptor binding by acting on viral particles and thus inhibiting the cell-to-cell spread | [25] |
| Euphorbia cooperi (euphorbiaceae), Morus alba (moraceae) | 1.catechin-7-gallate, 2. gallic acid, 3. kaempferol 3-O--(6′′-O-galloyl)-glucopyranoside, 4. quercetin3-O--(6′′-O-galloyl)-glucopyranoside, 5. curcumin, 6. quercetin, 7. kaempferol |
HSV-1 | CC50—[μg/mL]: 1. 43.2 ± 2.3, 2. 49.8 ± 0.4, 3. 124.1 ± 1.2, 4. 175.6 ± 0.9, 5. 49.8 ± 0.4, 6. 78.1 ± 0.8, 7. 76.1 ± 0.2 |
-the mechanism inhibits viral replication or viral genome synthesis. HSV-1 employs glycosaminoglycan (GAG) as initial attachment receptors during infection of their host cell, so polyphenols target HSV-1 glyco-proteins -this type of interaction prevents the virus from connecting with binding receptors and cell surface |
[33] |
| plant-based polyphenols | tannic acid with modified silver nanoparticles (TA-AgNPs) | HSV-2 | 5 μg/mouse TA-AgNPs sized 33 nm applied upon the mucosal tissue | -the mechanism is based on two properties of used compounds -one is connected with tannic acid that interferes with the viral adsorption mechanism - second is based on the ability of silver nanoparticles that can block the attachment of the virus and its entry -nanoparticles can also induct antiviral cytokine and chemokine production -efficiency of TA-AgNPs of the inactivation of the virus might depend on the proline content in HSV glycoproteins |
[34] |
| spice and common food colorant, turmeric | curcumin (Cur), monoacetylcurcumin (MAC) |
IAV variety (H1N1) | 30 μM in MDCK cells for single compound, 15 μM mixture of polyphenols (7.5 μM Cur and 7.5 μM MAC) |
-both polyphenols indicate the various mechanisms of inhibition. Cur and MAC reduced viral NA activity, but MAC did not block HA activity, compared to Cur -MAC dampened phosphorylation, which is essential for efficient IAV propagation -replication of IAV in cells is most likely connected with PI3K/AKT activation, which is suppressed by MAC -both polyphenols inhibit IAV separately but together give better results |
[68] |
| cranberry (Vaccinium macrocarpon aiton) extracts | A-type proanthocyanidins (A-PAC), dimers and trimers | IAV, IBV | based on the type of fraction: CC50 ≥ 200 μg/mL (1,2,5), CC50—149.7 ± 3.1 μg/mL (3), CC50—136.4 ± 2.4 μg/mL (4), IC50—50 μg/mL (1,2,5), IC50—5.02 ± 1.2 μg/mL (3 IAV), IC50—3.24 ± 1.4 μg/mL (4 IAV), IC50—6.02 ± 1.2 μg/mL (3 IBV), IC50—4.07 ±1.8 μg/mL (4 IBV) |
-PAC-A2 achieves the inhibitory effect of polyphenol extract against influenza viruses interacting with the ectodomain of viral HA and the formation of three hydrogen bonds Phe99, Asn210, and Trp234 of HA, which leads to extensive cross-linking of the IV glycoprotein -those properties affect the HA protein band by reducing its intensity |
[69] |
| green tea, cranberry plant | EGCG, the nutraceutical CystiCranÒ-40 (containing 40%), A-PAC, B-PAC) |
coliphage T4II (phage T4),the rotavirus strain SA-11(RTV) | mixture of 60 μg/mL (EGCG) and 100 μg/mL(C-40) or 30 μg/mL (EGCG) and 25 μg/mL (C-40) |
the combination of those polyphenols is most likely based on blocking or altering viral ligands or antigenic determinants, which reduce the binding ability of the virus | [70] |
| adlay tea | the present publication concludes two options for antiviral activity of the given extract, either the polyphenols are non-flavonoid phenols and/or the antiviral activity is elicited by other types of compounds | IAV, IBV variety (A/PR/8/34, H1N1, H3N2 and B) |
IC50—2.11–5.13 mg/mL (IAV) IC50—2.91–4.61 mg/mL (IBV) CC50 ≥ 40 mg/mL |
antiviral activity most likely manifests itself in the inhibition of virus adsorption to the cell and its replication, where tea also affects binding to cells directly | [71] |
| Arachis hypogaea (L.) skin, ethanol extract | extract most probably consist of phenolic acids (coumaric, ferulic, chlorogenic, p-hydrobenzoic acids), phenolics (catechins, A-PACB-PAC), and stilbenes (resveratrol), where resveratrol is the main compound | IAV, IBV | IC50—1.0–1.5 μg/mL, CC50—5.4–9.1l μg/mL |
-the mechanism is probably based on inhibition of replication or its early stages, where a combination of an extract with oseltamivir and amantadine prove to be more effective against the influenza virus -this phenomenon is most probably due to targeting different phases of replication | [72] |
| plant-based extract | tannic acid (TA) | IAV variety (H1N1) | HEPA filter treated with 5 mg/mL of TA for 2 h at 22 oC | linking TA molecules with HA, which are present on the influenza virus’ surface, allows their interaction and subsequent inhibition of viral proteins NA and M2 in the inner part of the virus | [73] |
| tea polyphenols found in fruits, nuts and seeds | PA2 | PRRS | EC50—2.2–3.2 μg/mL, IC50—2.5–3.2 μg/mL (Marc-145 cells), CC50—126.5 (Marc-145 cells) and 63.9 (PAM cells) μg/mL |
inhibition consists of blocking viral entry and progeny virion release, which was obtained from reducing gene expressions of cytokines (TNF-α, IFN-α, IL-1β, IL-6) | [74] |
| Ajuga iva (L.) aerial part extracts | total phenolic content (TPC) 28.3 ±1.12, flavonoids content (FC) 10.5 ± 0.83, tannins content (TC) 7.2 ± 0.31 |
coxsackie virus type B-3 (CV-B3) | IC50—0.43 ± 0.03 mg/mL, AC50—182 ± 12 μg/mL CC50—2810 ± 36 μg/mL |
- | [75] |
| Juglans regia, pellicle extract (WPE) | protocatechuic acid, gallic acid, ellagic acid, quercetin, myricetin, chlorogenic acid, kaempferolarabinoside, avicularin, (+)-procyanidin B2, rutin | HSV-1, HSV-2 | ID50—10 µg/mL (HSV-1) ID50—8 µg/mL (HSV-2) |
- | [76] |
| Cornus canadensis | 1,6-di-O-galloyl-β-D-glucopyranose, 1,2,3-tri-O-galloyl-β-D-glucopyranose, 1,2,6-tri-O-galloyl-β-D-glucopyranose, 2,3,6-tetra-O-galloyl-β-D-glucopyranos, 2,3,4,6-penta-O-galloyl-β- D-glucopyranose, tellimagrandin I, tellimagrandin II, ethyl gallate, caffeic acid, astragalin, isoquercetin, trifolin, kaempferol 3-O-β-D-xylopyranoside, reinutrin, juglanin, avicularin, juglalin, benzyl 2-O-β-glucopyranosyl-2,6-hydroxybenzoate, byzantionoside B |
HSV-1 | direct mode EC50—11–17 μg/mL (extract) EC50—2.6 ± 0.1 μM (tellimagrandin I) EC50—7 ± 4 μM (2,3,6-tetra-O-gal-loyl-β-D-glucopyranose) EC50—10 ± 2 μM (2,3,4,6-penta-O-galloyl-β-D-glucopyranose) EC50—7 ± 1 μM (tellimagrandin II) absorption mode EC50—9 μg/mL (extract) EC50—5.0 ± 0.2μM (tellimagrandin I) EC50—11 ± 3 μM (2,3,6-tetra-O-gal-loyl-β-D-glucopyranose) EC50—12 ± 4 μM (2,3,4,6-penta-O-galloyl-β-D-glucopyranose) EC50—11 ± 3 μM (tellimagrandin II) |
- | [77] |
| magnolia officinalis | honokiol, magnolol |
murine norovirus (MNV-1), feline Calicivirus |
5 mg/mL added to food products such as milk or plum, orange, apple juice | - | [78] |
| pomegranate peel extract | ellagic acid, punicalin, gallic acid, punicalagin | SARS-CoV-2 | - | -polyphenols combined with the amino acids contained in S-glycoprotein, ACE2, furin, TMPRSS2 using mainly hydrogen bonds -in punicalagin and punicalin, there are 3-4 hydrogen bonds, and also Pi-alkyl, Pi-Pi bonds are present, which stabilizes the complex |
[79] |
| blueberry | B-PAC | aichi virus | 5 mg/mL | various mechanisms are considered in the treatment of host cells with B-PAC, including binding: -host cells receptors -virus particles and blocking attachment -host cell and preventing host cell entry connected to blocking/damaging the above host cell or viral receptor, which prevents viral entry |
[80] |
| extracted plants | type of the flavonoids | dengue virus (DENV) | - | -inhibition of this virus is caused by the disruption of the NS2B-NS3 protein complex, which has a negative effect on replication -each of the present flavonoids interacts with different amino acids of viral protein, which changes the process mechanism: |
[81] |
| Euphorbia lunulate | quercetin 3-O-(2′′,3′′-digalloyl)-β-D-galactopyranoside | Gly 87, Val 146, Asn 167, within the active site | |||
| Sedum sarmentosum | quercetin 3-O-α-(6′′-caffeoylglucosyl-β-1,2-rhamnoside) | Lys 74, Ile 165 within the inactive site | |||
| Pas siflora tripartite | schaftoside | an arene–arene link with amino acid Trp 83 | |||
| Myrica rubra | myricetin | Trp 83 Gly 87 and Val 146 | |||
| Anethum graveolens | quercetin 3-sulfate | an arene cationic link with Lys 74 | |||
| Citrus lumia, Cyclopia, Subternata | eriocitrin | Lys 74 | |||
| Richilia catigua | catiguanin B | a cationic arene interaction with Lys 74 and a hydrogen bond donation with Trp 83 | |||
| Lepisorus contortus | 4′,5,7-trihydroxy-3-methoxyflavone-7-O-α-L-arabinofuranosyl(1→6)-β-D-glucopyranoside | Asn 167, Val 147, Trp 89 | |||
| Scutellaria baicalensis | wogonin 7-O-β-D-glucuronide | Gly 87, Trp 83 | |||
| Silybum marianum | silychristin | a cationic arene link with Lys 74 and a hydrogen bond with Trp 83 | |||
| plant-based polyphenols | catechin, procyanidin B2 (PB2) | felinecalici virus (FCV F9), MNV-1 | 0.5 and 1 mg/mL for both compounds, where time was the main factor deciding about inhibition of the viruses | -inhibition is achieved by PB2 that changes the structure of the P domain of VLPs -PB2 binds the P domain, where electrostatic interactions play a dominant role while PB2 significantly alters tertiary but not secondary structures of VLPs |
[82] |
| grapefruit mesocarp extract | hesperidin | HCV genotype 3a | IC50—23.32 µmol/L | the mechanism is based on HCV NS3 protease fused with co-factor NS4A, which then binds hesperidin with the catalytic site residues of the NS4A-NS3 protease domain | [83] |
| almond skin extracts | EC, eriodictyol quercetin, catechin protocatechuic acid, kaempferol p-hydroxybenzoic acid chlorogenic acid vanillic acid isorhamnetin naringenin trans-p-coumaric acid eryodictiol-7-O-glucoside isorhamnetin-3-O-glucoside isorhamnetin-3-O-rutinoside naringenin-7-O-glucoside kaempferol-3-O-glucoside kaempferol-3-O-rutinoside quercetin-3-O-glucoside quercetin-3-O-galactoside quercetin-3-O-rutinoside |
HSV-1 | 0.4 mg/mL extracts concentration (90% decrease of viral titer) | NS acts on the HSV-1 lytic cycle in that it blocks virion entry into the cells, i.e., the polyphenols bind to cell receptors of the virus, preventing them from entering the cell | [84] |
| 141 diverse plant and fungal species belonging to 66 different families, with asteraceae (10%), lamiaceae (10%), apiaceae (6%), and fabaceae (4%) | 1. rutamari, 2. piperine, 3. piperylin, 4. 1-[(2E,4E,8E)-9-(1,3-benzodioxol-5-yl)-1-oxo-2,4,8-nona-trienyl]-pyrrolidine, 5. piperoleine A, 6. dehydropipernonaline, 7. pipernonaline, 8. chabamide, 9. ganoderol B |
Hong Kong/68 (HK/68), rhinovirus RV-A2, CV-B3 | extracts: IC50—50 μg/mL (HK/68) IC50—20 μg/mL (CV-B3) IC50—11 μg/mL (RV-A2) pure compound: 1. CC50—4.7 μM (MDCK cells) and 4.6 μM (HeLa cells), 2. CC50—50 μM (HeLa cells), 3. CC50 ≥ 100 μM (HeLa cells), 4. CC50 ≥ 100 μM (HeLa cells), 5. CC50—25 μM (HeLa cells), 6. CC50—34 μM (HeLa cells), 7. CC50—21 μM (HeLa cells), 8. CC50—11 μM (HeLa cells), 9. CC50 ≥ 100 μM (MDCK cells) and >100 μM (HeLa cells), 1. IC50—2.7 μM (HK/68 in MDCK cells) and 5.1 μM (CV-B3 in HeLa cells), 2. IC50—41 μM (RV-A2 in HeLa cells), 3. IC50—51 μM (CV-B3 in HeLa cells) and 79 μM (RV-A2 in HeLa cells), 4. IC50—61 μM (CV-B3 in HeLa cells), 5. IC50—22 μM (CV-B3 in HeLa cells), 6. IC50—24 μM (CV-B3 in HeLa cells), 7. IC50—32 μM (CV-B3 in HeLa cells), 8. IC50—9.1 μM (CV-B3 in HeLa cells), 9. IC50—17 μM (HK/68 in MDCK cells) and 65—μM (RV-A2 in HeLa cells), |
the paper indicates the properties of ganoderol B to inhibit RV coat protein, which is connected to its antiviral activity | [85] |
| Canarium album | isocorilagin | IAV variety (H1N1) | IC50—9.19 ± 1.99 µM A/Puerto Rico/8/34 (H1N1) IC50—23.72 ± 2.51 µM A/Aichi/2/68 (H3N2) IC50—4.64 ± 3.01 µM for NA-H274Y (H1N1) |
isocorilagin inhibiting NA activity in a dose-dependent manner via residues Arg118, Glu119, Arg156, and Glu276. Interaction with NA mainly through hydrogen bonds and van der Waals forces | [86] |
| rhoeo discolor leaves and their methanol extract | luteolin-7-glucoside 15% kaempferol 75% isoquercetin 5% quercetin 2% rutin 3% |
IAV variety (H1N1) | CC50—0.90 ± 0.01 μg/mL IC50—0.30 ± 0.02 μg/mL |
-the inhibition of the influenza virus is accomplished through the suppression of the HA - MF1 fraction acts at the HA level and thus prevents the virus from binding to the cell surface receptors |
[87] |
| flos caryophylli | rhamnetin-3-O-b-D-glucuronide-600-methyl ester, rhamnazin-3-O-b-D-glucuronide- 600-methyl ester, kaempferol-3-O-b-D-glucuronide-600-methyl ester, isorhamnetin-3-O-b-D-glucuronide-600-methyl ester, rhamnetin-3-O-b-D-glucopyranoside, quercetin 3-O-b-D-glucuronide-600-methyl ester, quercetin 3-O-b-D-glucuronide, isoquercitrin, isorhamnetin-3-O-b-D-glucopyranoside, rhamnazin-3-O-b-D-glucopyranoside, 1,2,3-tri-O-galloylglucose, casuarinin, tellimagrandins I, 1,3-Di-O-galloyl-4,6-HHDP-glucose, casuarictin, eugeniin, 1,2,3,6-tetra-O-galloylglucose, isobiflori, biflori |
IAV variety (H1N1) | IC50—8.4 to 94.1 μM EC50—1.5–84.7 μM CC50—374.3–1266.9 μM |
inhibition of the key surface proteins of the virus, which is NA, is affected by a group of polyphenols | [88] |
| Vaccinium oldhamii ethanol extracts | procyanidin B2,O-hexosides, quercetin-3-O-rhamnosidequercetin-O-pentoside-O rhamnoside | IAV, IBV | IC50—38 µg/mL (30% extract) IC50—22 µg/mL (40% extract) IC50—65 µg/mL (50% extract) CC50—251 µg/mL (30% extract) CC50—160 µg/mL (40% extract) CC50—78 µg/mL (50% extract) |
ferulic acid and its derivatives bind NA and inhibit the initial stage of IFV infection, where quercetin and rhamnoside suppress IFV replication in cells | [89] |
|
Solieria filiformis, Ecklonia arborea |
solieria filiformis: kaempferide, kaempferol-3-O-rutinoside, quercetin 3-O-malonylglucoside, demethoxycentaureidin7-O-rutinoside, quercetin 3-(6-O-acetyl-beta-glucoside) ecklonia arborea: phlorofucofuroeckol-B, formononetin, apigenin 7-O-glucoside |
measles virus | solieria filiformis: CC50 ≥ 1500 μg/mL IC50 -0.4 ± 0.11 μg/mL ecklonia arborea: CC50 ≥ 1500 μg/mL IC50—2.6 ± 0.28 μg/mL |
inhibition is based on the deactivation of the virus virion, which prevents it from absorbing and penetrating the host cell | [90] |
| blueberry | B-PAC | MNV-1, FCV-F9 |
5 mg/mL in simulated intestinal fluid | -in used nutritional models, milk has decreased antiviral activity because of the presence of complex matrices containing lipids -the publication clarifies that the presence of proteolytic enzymes did not affect the inhibition of those viruses |
[91] |
| plant based polyphenols | EGCG, TF1, theaflavin -3′-O-gallate (TF2a), theaflavin-3′-gallate (TF2b), TF3, hesperidin, quercetagetin, myricetin |
SARS-CoV-2 | maximum tolerated dose for humanEGCG—0.441 (log mg/kg/day) TF3—0.438 (log mg/kg/day) TF2b—0.438 (log mg/kg/day) TF2a—0.439 (log mg/kg/day) |
the complex is formed by van der Waals bonds, electrostatic interactions, nonpolar solvation free energy, where polyphenols bind to the virus through RNA-dependent RNA polymerase (RdRp) | [92] |
| Cassia alata | alatains A and B | tobacco mosaic virus (TMV) | IC50—18.8 µM (A type) IC50—11.4 µM (B type) |
the presence of C-14—C-5 linkage between a chromone moiety and an isocoumarin moiety in the studied polyphenols | [93] |
| eucalyptus bark extract | benzoic acid, quinol, salicylic acid, myricetin, rutin | TMV | 100 μg/mL | the direct inhibition of virus replication as well as by simultaneous activation of the host innate immune response and inducing SAR against the virus | [94] |
| plant-based polyphenol | resveratrol | vaccinia virus (VACV), monkeypox virus (MPXV) | CC50—176.88 ± 17.44 μM (VACV HFF cells),IC50 -3.51 ± 1.22 μM (VACV HFF cells), CC50—157.75 ± 23.66 μM (VACV Hela cells), IC50—4.72 ± 2.34 μM (VACV Hela cells), IC50—12.41 μM (MPXV-WA), IC50—15.23 μM (MPXV-ROC) |
polyphenol affects genome replication as well as post-replicative gene expression, where resveratrol affects the cellular function of VACV | [95] |
| plants and natural products based on polyphenols | delphinidin (D), EGCG | west Nile virus (WNV), zika virus (ZIKV), DENV | antiviral activity is dose-dependent with values ranging from 1–10 μM, the best results were obtained with 10 μM | inhibition mechanism is based around entry steps of the virus life cycle, where polyphenols contain trihydroxyphenyl group at R2, which may interact with the function of proteins at multiple binding sites | [96] |
| fruits and vegetables (plant-based polyphenols) | isoquercitrin (quercetin-3-O-glucoside or Q3G) | ZIKV | IC50—15.5 ± 2.3 μM (A549), CC50—551.2 ± 43.2 μM (A549), IC50—14.0 ± 3.8 μM (Huh-7), CC50—326.8 ± 45.7 μM (Huh-7), IC50—9.7 ± 1.2 μM (SH-SY5Y), CC50—582.2 ± 41.4 μM (SH-SY5Y), |
polyphenol prevents the internalization of virus particles into the host cell, most likely by clathrin-mediated endocytosis pathway involving Axl/Gas6 as entry factors | [97] |
| honey, tea, red wine | pinocembrin | ZIKV | IC50—17.4 µM | polyphenol inhibits the replication cycle of the virus as well as RNA production and envelope protein synthesis, where those actions happen in the post-entry stages of the infection | [98] |
CC-cytotoxic concentration, EC—effective concentration, ID50-infective dose.