Reply To: Food For Thought: Avoiding COVID-19 Through Food Therapeutics

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Molecules. 2021 Jul; 26(13): 4099.

Published online 2021 Jul 5. doi: 10.3390/molecules26134099

PMCID: PMC8271932

PMID: 34279439

Plants and Natural Products with Activity against Various Types of Coronaviruses: A Review with Focus on SARS-CoV-2

Susana A. Llivisaca-Contreras,¹ Jaime Naranjo-Morán,² Andrea Pino-Acosta,³ Luc Pieters,⁴ Wim Vanden Berghe,^4,⁵ Patricia Manzano,^2,⁶ Jeffrey Vargas-Pérez,² Fabian León-Tamariz,^5,^7,^* and Juan M. Cevallos-Cevallos^2,^5,^6,^*

Raphaël E. Duval, Academic Editor

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271932/

Excerpts

3.2. Immune System Boosting Plants and Foods

At present, different herbal plants are being subjected to studies on their ability to strengthen the immune system and cope up with the virus and some phytocompounds have already shown potential to mitigate the incidence of infection [87]. For instance, various plant polyphenols can initiate a cellular accumulation to then trigger signaling pathways and immune responses to infection. In addition, polyphenols are potent inhibitors of the COVID-19 protease (Mpro) [87].

Natural polysaccharides and terpenoids are immunomodulatory as well as adaptogenic compounds and are also recognized for their antiviral, immunomodulatory, antitumor and anticoagulant bioactivities. Similarly, giloy herbs can stimulate IgG antibody response, macrophage activation, induction of cell-regulated immunity, and humoral immunity [87]. Moreover, several plant triterpenes such as dammaradienol, dammarenediol-II, hydroxyhopanone. dammarenolic acid, hydroxymarenone-I, ursonic acid, shoic acid, eichlerianic acid and hydroxyoleanonic lactone [87] play a vital role in the modulation of cellular metabolism [88].

Sulfated polysaccharides are a structurally multifaceted class of biomolecules with diverse physicochemical characteristics well recognized in the field of medicine and pharmaceutical sciences [29]. They have immunomodulatory properties and bioactivities [89]. Furthermore, they are selective inhibitors or suppressors of enveloped viruses, e.g., HSV, HIV, human cytomegalovirus, respiratory syncytial virus, and influenza [89].

The biomolecules hispidin, lepidine E, and folic acid from Citrus sp. inhibit the 3CL hydrolase enzyme known to counteract the host’s innate immune response [90]. Similarly, Benzene 123 Triol from Nilavembu kudineer has shown immunomodulatory activity [91] while Exocarpium Citri grandis (Flavonoids and Naringin) stimulated the antiviral immune response and showed antitussive, expectorant and helped relieve pulmonary fibrosis [89]. Moreover, Allium sativum (Allicin) stimulated the activity of immune cells and inhibited the release of pro-inflammatory cytokines dependent on Necrosis Tumoral Factor alfa (TNFα) as well as the migration of neutrophilic granulocytes, a crucial process during inflammation [46]. The plant species Acacia senegal, Laportea aestuans, and Citrus spp (Hesperidin) increased antioxidant defenses, modulated the activity of the immune system, and eliminated reactive oxygen species. In addition, Curcuma longa (Curcumin) also enhanced immunity [46].

Foods containing curcumin, allicin, papain, ginsenoside, mangoosteen, chloroquine, etc., have shown a direct effect on dendritic cells, natural killer cells (NK), lymphocytes and antibodies to protect the human body from foreign particles [89].

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4. Bioactive Compounds in the Mechanisms of the Virus–Host Interaction

Table 2 shows the plant species with activity against various coronaviruses.

4.1. Entry Inhibitors

Many plant bioactive compounds typically prevent the entrance of the viral particle into the host cell [87]. SARS-CoV entry inhibitors are divided into two categories: the first consists of molecules that bind to the ACE2 and TMPRSS2 receptors while the second comprises compounds that bind to the virus and prevent interaction with the cell receptors and membrane fusion [92]. The molecule [6] gingerol from Zingiber officinale inhibits the growth of the coronavirus by blocking the cell’s TMPRSS2 receptor [21].

The TCM’s Jinchai consists of plant species such as Lonicera japonica and Bupleurum chinense among others, that prevent the coronavirus entry into cells and inhibit general viral replication as well as the specific 3CLpro-mediated replication [29]. One of the main active components of Jinchai is baicalin which inhibited antiviral activity with an Effective Concentration (EC₅₀) of 12-50 µg/mL in SARS-CoV-infected fetal rhesus monkey kidney cell line (fRHK4) and EC₅₀ of 100 µg/mL in Vero-E6 cells [93].

Flavonoids stand out among the blockers of the ACE2 receptor, but they have also shown anti-replication activities. Similarly, compounds such as baicalin, epigallocatechin gallate, gallocatechin gallate, derivatives of kaempferol, myricetin, quercetin and scutellarein are other major constituents of TCM used to treat SARS by inhibiting the entry and replication of the virus [64].

The flavonoid hesperetin has the potential to inhibit ACE2 and block SARS-CoV-2 infection by binding to viralS protein, helicase, and protease sites of the ACE2 receptor [29].

Alternatively, computational analysis revealed that hesperidin, baicalin and kaempferol 3-O-rutinoside can block SARS-CoV-2 infection by weakening the adsorption of virus to cells [19,46]. Similarly, procyanidins and the butanol extract of Cinnamomi Cortex (bark of Cinnamomum verum) have shown antiviral effects at the RNA level, in addition to inhibiting SARS-CoV infection with an IC₅₀ of 29.9 ± 3.3 μM (Table 2 and Table 3) [30]. Additionally, cinnamon extract inhibited wild-type SARS-CoV infection in vitro with an IC₅₀ of 43 μM and blockage of the virus entry to the cell was suggested as the possible mechanism of action [32]. The polyphenol epigallocatechin gallate (EGCG) from Camellia sinensis (green tea) inhibited the spread of the bovine coronavirus and interfered with the viral adsorption to bovine kidney cells [94].

Among the virus-binding molecules, lectins have emerged as a new class of antivirals thanks to their ability to bind to the glycosylated molecules found on the surface of viruses such as the SARS-CoV spike glycoprotein [24]. One of the most potent molecules reported against SARS-CoV is the mannose-binding lectin isolated from leek (Allium porrum L.), with an EC₅₀ of 0.45 μg/mL and a selectivity index >222 (Table 2 and Table 3) [29]. Specific N-acetylglucosamine lectins obtained from tobacco (Nicotiana tabacum L.) and stinging nettle (Urtica dioica L.) were also active against SARS-CoV with selectivity indexes of >77 and >59, respectively [24]. Additionally, the mannose-specific lectin from Hippeastrum striatum (Lam.) has the potential to inhibit the final step of the virus infection cycle [24,87]. Similarly, triterpenoids such as glycyrrhizin from the licorice plant, Glycyrrhiza glabra L., have been reported to have in vitro anti-SARS effects with an EC₅₀ of 300 µg/mL [51]. These natural compounds interfere with virus–host fusion steps through the envelope of the predominant heptad repeat 2 domains in viral envelopes [89].

Emodin is a natural anthraquinone derivative and an active ingredient of medicinal plants such as rhubarb (Genus Rheum) (Table 2 and Table 3), Polygonum cuspidatum, Aloe vera, Senna obtusifolia [59] and Cassia tora L [28]. Emodin blocked SARS-CoV entry to host cells by binding to the S proteins and interfering with the 3CLpro activity of the virus, thus preventing the formation of the Nsp required for replication [27]. In trials involving SARS-CoV and OC43, emodin significantly blocked, in a dose-dependent manner, the interaction between SARS-CoV S protein and ACE2, inhibited the ion channel 3a and interrupted the release of new coronaviruses [22]. Similarly, terpenoids from medicinal plants exhibit general antiviral effects in vitro against SARS-CoV [29]. Oleanane-type saikosaponins found in medicinal plants such as Bupleurum spp. and Heteromorpha spp. prevented the entry of SARS-CoV into the cell [46].

4.2. Protease Inhibitors

Proteases are key players in the pathogenesis caused by SARS-CoV and SARS-CoV-2 as they are involved in the S protein activation and viral replication. Therefore, protease inhibitors can aid the COVID-19 treatment. Because of the good binding affinity for Mpro and S protein of eugenol and curcumin, these compounds can be considered promising anti-SARS-CoV agents [22,95]. Curcumin inhibited SARS-CoV 3CLpro with an IC₅₀ value of 23.5 μM [22,92]. Similarly, various phenolic tea constituents, such as tannic acid, 3-isotheaflavin-3-gallate and theaflavin-3,3-digallate (Table 2 and Table 3) also inhibit SARS-CoV 3CLpro with IC₅₀ values between 3, 7 and 9.5 μM, respectively [37]. Similarly, a cell-based study showed that sinigrin significantly blocked the cleavage process of 3CLpro with an IC₅₀ of 752 μM. Sinigrin is a glucosinolate found in some plants of the Brassicaceae family, such as Brussels sprouts, broccoli, and black mustard seeds [29] (Table 2 and Table 3).

Scutellaria baicalensis polysaccharides, polyphenols and polyglycans can inhibit immune regulation and have shown antioxidant and antiviral activity [57]. The flavonoids scutellarein and baicalin from the same species inhibited SARS-CoV Nsp13 helicase [56], while myricetin reached an IC₅₀ of 2.71 μM against the virus [61]. These two compounds potently inhibited Nsp13 in vitro by affecting the ATPase activity of SARS-CoV [57].

4.3. Replication Inhibitors

Inhibitors of viral replication are amongst the key molecules to fight coronavirus diseases. The phenolic compounds from Melia azedarach (cinamomo or chinaberry tree) and Camellia sinensis (green tea) have shown antiviral activity due to the inhibition of RNA polymerase or the RNA-dependent proteases involved in the replication of the coronavirus RNA [29]. Additionally, tea extracts can also affect the virus assembly and release [96]. Similarly, the consecutive application of stilbene derivatives such as resveratrol at 62.5 μM partially mitigated MERS-CoV-induced cell death and reduced the replication of infectious MERS-CoV by 10-fold [63]. Similarly, concentrations below 0.5 mg/mL of stilbene derivatives like resveratrol inhibited the replication of SARS-CoV in vitro [62]. These compounds are found in different plants, including the Vitis vinifera L. grape and berries of the genus Vaccinium (Table 2 and Table 3) [30]. Compounds in berries have been suggested to block the virus entry to cells through endocytosis [97].

In general, natural flavonoids such as quercetin, catechin, naringenin and hesperetin are the most abundant polyphenols in the human diet, as they are found in fruits and vegetables as glycosides or acylglycosides [95]. Naringenin exhibited a partial inhibition of SARS-CoV-2 replication observed at 24 h post-infection (hpi) in cells upon Two-pore channel 2 (TPC2) silencing while stronger inhibition was observed at 48 and 72 hpi [36].

The standardized extract of Pelargonium sidoides (EPS 7630), mainly containing polyphenolic compounds such as prodelphinidin, gallocatechin and its stereoisomer epigallocatechin [53,98], is an approved treatment for acute bronchitis in Germany and other countries [53]. Concentrations up to 100 μg/mL of EPS 7630 interfered with the replication of human coronavirus as well as the seasonal influenza A virus Hemagglutinin Type 1 and Neuraminidase Type 1 (H1N1, H3N2), respiratory syncytial virus, parainfluenza virus and coxsackie virus [52] and inhibited the entry and replication of 229E with EC₅₀ of 44.50 ± 15.84 μg/mL [99].

The essential oils of Laurus nobilis and Salvia officinalis have also shown significant anti-replication activity against SARS-CoV with an Inhibitory Concentration (IC₅₀) value of 120 μg/mL [58]. Similarly, the essential oils from Thuja orientalis (β-ocimene, 1,8-cineole, α-pinene and β-pinene) also inhibited SARS-CoV replication [58] and the aescin isolated from the horse chestnut tree also inhibited SARS-CoV replication at non-toxic concentrations [22,100].

4.4. Virucidal Activity

The inactivation of the viral particles is another strategy to combat respiratory diseases. Echinacea purpurea extracts available as the commercial product Echinaforce^® showed dose-dependent inhibition of 229E infectivity in respiratory epithelial cells and this extract irreversibly inactivated the virus with an IC₅₀ of 3.2 μg/mL [101] and 9 ± 3 μg/mL in another study [76]. The multicomponent extract non-specifically and irreversibly interfered with viral docking receptors to block the infectivity of pathogens [102]. Similarly, inhibition for MERS-CoV was observed with 10 μg/mL of Echinaforce^®, reducing viral infectivity by 99.9% at 50 μg/mL [41]. Combining E. purpurea with vitamin D, vitamin C, and zinc has been suggested to reduce the risk of infection and death from SARS-CoV-2 [103]. A scientific review concluded that along with vitamin D, vitamin C and zinc, Echinacea extracts are pivotal in terms of prevention and treatment (shortening the duration and/or lessening the severity of symptoms) of common colds [104].

4.5. Immunomodulatory Agents

Generally, the viral loads observed in patients correlate with the severity of symptoms and mortality. The multisystem inflammatory syndrome, known as cytokine storm, occurring in many COVID-19 patients, is caused by an uncontrolled replication of the virus resulting in an over-activation of the immune system, including high levels of pro-inflammatory cytokines, i.e., interleukin-1β (IL-1β) and TNFα [105]. The geranylated flavonoid tomentin E from Paulownia tomentosa inhibited SARS-CoV (PLpro) in a dose-dependent manner with an IC₅₀ between 5.0 and 14.4 μM and reduced the concentration of the pro-inflammatory cytokines IL-1β and TNFα [51]. Similarly, one study observed that chlorogenic acid, luteoloside, quercetin, and other compounds in L. japonica, exhibited anti-inflammatory, antiviral, antibacterial, and antioxidant activity and enhanced immune response. It is known that one of the main possible anti-SARS mechanisms is decreasing the expression of inflammatory mediators such as the transforming growth factor-beta (TNF-β) and IL-1β [49].

Anthocyanins are found in red to violet fruits such as berries of the genus Vaccinium, blackberry, among others (Table 2 and Table 3) [106]. Anthocyanin metabolites, such as the protocatechuic acid, were shown to weakly inhibit Nitric Oxide (NO) production and TNF-α secretion in Lipopolysaccharide-Gamma interferon-induced macrophages (LPS-INF-γ) [107]. Additionally, gallic acid decreased the secretion of the inflammatory mediators monocyte chemoattractant protein 1 (MCP-1), intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) in endothelial cells [83]. However, the anthocyanins concentrations used for the anti-inflammatory activity tests cannot be achieved physiologically [107]. Similarly, Echinacea has also been proposed as a suppressor of the immunoinflammatory cascades observed in COVID-19, thanks to the plant’s ability to activate the anti-inflammatory cannabinoid-2 (CB2) receptors and peroxisome proliferator-activated receptors gamma (PPARγ) [102].

4.6. Regulators of RAAS

Table 3 summarizes medicinal plants and purified bioactives with potential benefits against SARS-CoV-2, especially those that modulate the RAAS. For example, the ethanolic extract of Thymus vulgaris (thyme), among other plants has shown the inhibitory capacity of AT1R [34].

The onions tunic extract, rich in flavonols like quercetin, has been shown to be a competitive inhibitor of ACE, comparable to pure quercetin (IC₅₀: 0.36 ± 0.04 and 0.34 ± 0.03 μg/mL respectively). This same extract further revealed competitive ACE inhibition with the substrate, N-[3-(2-furyl) acryloyl]-L-phenylalanylglycylglycine [26]. Agrawal and collegeus reported that quercetin can interfere with various stages of the coronavirus entry and replication cycle, such as PLpro, 3CLpro and nucleoside-triphosphatase (NTPase)/helicase, showing pleiotropic activities and lack of systemic toxicity [25]. Similarly, EGCG also inhibited ACE and blocked the AII binding to AT1R in vitro, showing the potential to control the symptoms of various diseases, especially those of a respiratory nature [108]. Further research is needed to assess the potential of EGCG for the treatment of symptoms caused by coronaviruses.

4.7. Unknown Mechanisms of Action

The lycorine purified from Lycoris spp. was identified as a promising anti-SARS-CoV bioactive compound with an EC₅₀ value of 34.5 ± 2.6 μg/mL, by poorly understood mechanisms [50]. Flavonoids, benzofurans, stilbene, polyhydroxylated alkaloids, and kuwanons from Morus spp. have shown a large variety of pharmacological activities including antiviral activity but the mechanism is also unclear [68,109]. The same is through for the compounds from Ginkgo biloba (ginkgolide, terpenic lactones, flavonoids, polyphenols, oleic acid, among others) [110]. Therefore, further research is needed to resolve their antiviral mechanism(s) of action.

Recently, two naturally occurring alkaloid-derived compounds (homoharringtonine and emetine), effectively inhibited the SARS-CoV-2 in Vero E6 cells with an estimated EC50 of 2.55 μM and 0.46 μM, respectively [111]. Similarly, emetine has been reported as an inhibitor of hCoV-OC43, hCoV-NL43, SARS-CoV MERS-CoV and MHV-A59 in vitro with EC50 at the low micromolar range. However, the study did not disclose the mechanisms by which both compounds induced anti-SARS-CoV-2 activity [112]. Emetine is a natural alkaloid isolated from Psychotria ipecacuanha and belongs to the methine class of alkaloids [113]. Similarly, homoharringtonine is a natural alkaloid derived from some species of the genus Cephalotaxus. This drug is a protein synthesis inhibitor and has been approved by the Food and Drug Administration (FDA) to treat chronic myeloid leukemia [112].

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5. Risks Associated with the Incorrect Use of Natural Products

Although many of the plant species hold promise to reduce or mitigate COVID-19 symptoms, it is necessary to further validate their potential health benefits with clinical trials as well as to identify potential side effects. Despite the reported health benefits, high doses of ginkgo (Ginkgo biloba) [Table 2] can cause an increase in cerebral blood flow, and affect people with peptic ulcer and coagulation disorders [114,115].

Although no adverse effects have been reported in the consumption of ginger ([6]-gingerol) (Table 2), irritation of the gastric mucosa has sometimes been mentioned. Similarly, turmeric should not be used in case of infections or inflammation of the hepato-bile duct or jaundice [115] and only the stem of rhubarb (Table 3) can be ingested as the leaves contain a large amount of oxalic acid that causes kidney stones [30]. Moreover, the excessive use of Aloe species (Table 2) can cause damage to the epithelium and the intestinal mucosa, hemorrhagic diarrhea, and kidney damage. Doses greater than 1 g/day are not recommended for pregnant women, women during menstruating periods or people suffering from kidney disease [115]. Consequently, medical observation is recommended for people who have never consumed any of the plants mentioned in this work. People must be properly informed of the contraindications before combining medicinal plants with any treatment against the symptoms of COVID-19 [116] in order to avoid a counterproductive effect.

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6. Conclusions

Scientific evidence of medicinal plants and foods that can help to mitigate the symptoms of COVID-19 has been growing since the start of the pandemic. Therefore, it is important to promote the consumption of natural products under the supervision of experts in the medical, nutritional and pharmaceutical areas as well as encouraging the generation of scientific information that promotes the manufacture of plant-based products that help to better protect the people against the SARS-CoV2.