Phenolic compounds versus SARS-CoV-2: An update on the main findings against COVID-19

The COVID-19 pandemic caused by SARS-CoV-2 remains an international concern. Although there are drugs to fight it, new natural alternatives such as polyphenols are essential due to their antioxidant activity and high antiviral potential. In this context, this review reports the main findings on the effect of phenolic compounds (PCs) against SARS-CoV-2 virus. First, the proven activity of PCs against different human viruses is briefly detailed, which serves as a starting point to study their anti-COVID-19 potential. SARS-CoV-2 targets (its proteins) are defined. Findings from in silico, in vitro and in vivo studies of a wide variety of phenolic compounds are shown, emphasizing their mechanism of action, which is fundamental for drug design. Furthermore, clinical trials have demonstrated the effectiveness of PCs in the prevention and as a possible therapeutic management against COVID-19. The results were complemented with information on the influence of polyphenols in strengthening/modulating the immune system. It is recommended to investigate compounds such as vitamins, minerals, alkaloids, triterpenes and fatty acids, and their synergistic use with PCs, many of which have been successful against SARS-CoV-2. Based on findings on other viruses, synergistic evaluation of PCs with accepted drugs against COVID-19 is also suggested. Other recommendations and limitations are also shown, which is useful for professionals involved in the development of efficient, safe and low-cost therapeutic strategies based on plant matrices rich in PCs. To the authors' knowledge, this manuscript is the first to evaluate the relationship between the antiviral and immunomodulatory (including anti-inflammatory and antioxidant effects) activity of PCs and their underlying mechanisms in relation to the fight against COVID-19. It is also of interest for the general population to be informed about the importance of consuming foods rich in bioactive compounds for their health benefits.


Introduction
We are currently experiencing a global health crisis due to a new coronavirus originating in Wuhan, China in 2019. First, World Health Organization (WHO) named it 2019-nCoV, but subsequently and until today, it is known as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) (Piccolella et al., 2020). This virus generates the disease COVID-19, which infects animals and humans (Mani et al., 2020).
COVID-19 infection starts out appearing to be a cold and then worsens over time. Symptoms include sore throat and headache, fatigue, fever, dry cough, conjunctivitis, lung and gastrointestinal problems (Khalil and Tazeddinova, 2020). Damage to the kidney and nervous system was also reported (Russo et al., 2020). Symptoms are aggravated if the infected person is elderly, smokes and/or consumes alcohol in excess (Mehany et al., 2021), if they suffers from hypertension, diabetes, obesity, pulmonary and cardiovascular diseases (Das et al., 2021a) and mainly if the patient has a weak immune system. 20% of infected persons present severe symptoms (Santos et al., 2021).
The global threat posed by COVID-19 makes it necessary to develop multiple alternatives for its possible therapeutic management, as existing drugs have side effects on the body. Therefore, scientists continue to strive immeasurably in the search for more efficient methods.
Medicinal plants have been used as natural drugs for many years due to their high bioactive content (Jalal et al., 2021). A wide variety of medicinal plants (leaf, steam, root, bark and fruit) have shown a high potential against various human viruses (Behl et al., 2021;Singh et al., 2021); however, their mechanism of action is still uncertain (Celik et al., 2021). In particular, natural medicine had optimal results in the treatment of people infected with SARS-CoV-1. In a study on the in vitro evaluation of extracts from more than 50 Chinese medicinal plants, Wen et al. (2011) determined that they have the necessary properties to be used as a therapy against SARS-CoV-1. Atractylodes macrocephala, Magnoliae officinalis, Angelicae dahuricae, Forsythia suspensa (Ho et al., 2020), Folium mori, Flos chrysanthemi, Astragalus membranaceus, Herba menthae, Lonicerae Japonicae Flos (Shahrajabian et al., 2020), Glycyrrhiza glabra, Cynara scolymus, Cassia occidentalis, among other medicinal plants, also showed excellent results when evaluated in vitro against SARS-CoV-1 (Patel et al., 2021). More details on the viruses studied are shown in Figure 1.
According to the results obtained and taking into account that SARS-CoV-1 and 2 have a high similarity between their sequence identities (79.5%) (Keflie and Biesalski, 2021) and their target proteins, it is postulated that natural medicine has a high potential to address current SARS-CoV-2. Since the spread of the disease in China, based on the experiences on the use of traditional herbal medicine in patients with Middle East Respiratory Syndrome Coronavirus (MERS) and SARS-CoV, this alternative therapy also started to be used in the possible therapeutic management of patients with SARS-CoV-2 (Alam et al., 2021;Yang et al., 2021). It has been promoted to prescribe mixtures of various Chinese medicinal plants (such as qingfei paidu decoction), which have been successful in the treatment of COVID-19 (Ren et al., 2020). In general, according to Russo et al. (2020), 92% effectiveness was obtained in all stages of COVID-19 and of the 5% of patients who continued with severe symptoms, none presented sequelae upon overcoming the disease. It was determined that the herbs used had a high phytochemical potential, highlighting the phenolic compounds (PCs) (Han et al., 2021). These results are confirmed by previous studies on other viruses treated in most Asian countries (Li and Peng, 2013). The extract of Torreya nucifera leaf showed a high anti-SARS-CoV-2 potential and when evaluating its bioactive content, the presence of four flavonoids (amentoflavone, quercetin, luteolin and apigenin) was highlighted (Chojnacka et al., 2020). It was determined that the presence of cinnamtannin B1, procyanidin A2 and procyanidin B1 in Cinnamomi Cortex extract conferred a high activity against SARS-CoV-1 (Russo et al., 2020). Similarly, in the study by Chiow et al. (2015), the antiviral potential of Houttuynia cordata Thunb. extract against dengue virus and mouse coronavirus (currently used as a model of  was mainly attributed to the presence of quercetin, quercetrin and rutin. PCs are natural compounds found in a wide variety of plant materials. PCs have unique characteristics and their consumption is reported to help prevent metabolic, cardiovascular, respiratory, neurological and cancerous diseases (Behl et al., 2021;Tirado-Kulieva et al., 2021). This is due to their high antimicrobial, antioxidant and anti-inflammatory activity . PCs also modulate the immune system (de la Lastra et al., 2021;Mehany et al., 2021). Considering these characteristics and focusing on the antiviral property, Ali et al. (2022) Figure 1. Bioactive compounds activity of some medicinal plants against various human viruses. 1) Magnoliae officinalis, 2) Atractylodes macrocephala, 3) Angelicae dahuricae, 4) Forsythia suspensa, 5) Folium mori, 6) Matricaria recutita, 7) Astragalus membranaceus, 8) Herba menthae, 9) Lonicerae Japonicae Flos, 10) Glycyrrhiza glabra, 11) Cynara scolymus, 12) Cassia occidentalis, 13) Allium cepa L., 14) Nigella sativa, 15) Isatis indigotica, 16) Camellia sinensis. Design adapted from Adnan et al. (2021). V.A. Tirado-Kulieva et al. Heliyon 8 (2022) e10702 indicate that most medicinal plants contain a high polyphenolic concentration. In the study by Katalinic et al. (2006), PCs content of the extracts of 70 medicinal plants ranged from 9 to 2218 mg catechin equivalent/L. This quality can be exploited to combat COVID-19. Table 1 shows some related studies. Based on the findings reported in the literature, PCs are a suitable alternative to combat COVID-19. However, despite the importance of PCs, the field continues to grow steadily in this pandemic era. Moreover, it is difficult to fully define the relevance of PCs against SARS-CoV-2 due to the constant emergence of its new variants (such as omicron and delta). This is also a problem for vaccines, whose limits are remarkable (Snoussi et al., 2021). Therefore, it is necessary to update the data with new perspectives to support the development of appropriate therapeutic strategies by professionals related to the field. In this sense, this review will expand the knowledge on the anti-COVID-19 potential of PCs with recent evidence. First, some findings that corroborate the antiviral potential of PCs will be briefly shown, whose evidence is the basis for their study in the current context. Subsequently, the use of medicinal plants and, specifically, of more than 50 PCs isolated from different sources to counteract SARS-CoV-2 will be highlighted, defining the mechanism of action against its structural and non-structural proteins. The immunomodulatory role of PCs will also be defined, highlighting the mechanism of action. Finally, some limitations will be defined and an analysis of future trends will be carried out.

Methods
The bibliographic search was performed in the Scopus database in April 2022. After several attempts and discussion among the authors of this study, the methodology of Jalali et al. (2021) was adapted, presenting the main findings in three sections: A. First, the findings on the antiviral activity of PCs and plant matrices rich in PCs were determined. The following search string was used: ("phenolic compounds" OR phenols OR polyphenols) AND (antiviral OR viruses). An amount of 5742 documents were found. All types of articles (mainly reviews) published since 2020 and presenting results of in silico, in vitro and in vivo studies were included. The information presented was brief and the purpose was to determine the high antiviral potential of PCs. 13 articles were selected for this section. B. Specifically, this section focused on the potential of PCs and plant matrices rich in PCs as prevention and possible therapeutic management against COVID-19 and the underlying mechanisms. The first search string was modified: ("phenolic compounds" OR phenols OR polyphenols) AND (coronavirus OR COVID-19 OR SARS-CoV-2). An amount of 587 documents were found. In vitro and in silico studies and clinical trials were included. No in vivo studies on the effect of PCs on SARS-CoV-2 targets were found. 47 articles were selected for this section. During the writing of the manuscript, the snowballing technique was used to include other studies relevant to the topic (from any period) from the references of the selected articles. Since the targets of SARS-CoV 1 and 2 are very similar, results on activity against SARS-CoV were also shown, as suggested by Gligorijevic et al. (2021). C. To complement the anti-COVID-19 potential of PCs, a brief explanation was made on their immunomodulatory/anti-inflammatory/ antioxidant effect, which strengthens the body's defenses to prevent COVID-19 or resist its impact in case of infection. The same search string was used as in section B, but only 7 articles on in vitro and in vivo studies were included. The snowballing technique was also carried out. Some findings on this biological activity of PCs were also found in the selected articles on clinical trials in Section B.

Antiviral potential of polyphenols
PCs are plant secondary metabolites whose function is to defend plants against stressful situations, pathogens and environmental factors (Annunziata et al., 2020;Russo et al., 2020). They are composed of aromatic rings (phenyl) linked to hydroxyl groups (OH) and are classified into flavonoids (the most numerous group), tannins, xanthones, phenolic acids, lignans, among others. Further information on the classification and metabolism of PCs, the polyphenolic composition of foods and the effect of processing can be found at http://phenol-explorer.eu, a specialized database on the topic. PCs have demonstrated broad antiviral spectrum against herpes simplex virus type 1 (HSV-1), hepatitis A (HAV), hepatitis B (HBV) and hepatitis C virus (HCV), influenza A (H1N1) virus and human immunodeficiency virus (HIV) (Paraiso et al., 2020). Studies on the use PCs to combat enterovirus (EV) (Annunziata et al., 2020), respiratory syncytial virus (RSV) (Iddir et al., 2020), chandipura virus (CHPV), japanese encephalitis virus (JEV) and SARS-CoV-2 was reported in the literature (Das et al., 2021a). According to Mehany et al. (2021), although the effect of PCs is concentration-dependent, the proportions used are low.

In silico and in vitro evidence
The high mutation and recombination of SARS-CoV-2 is a serious problem for drugs that act on the aforementioned proteins (Keflie and Biesalski, 2021). In this context, PCs also target viral receptors such as angiotensin-converting enzyme 2 (ACE2) (Paraiso et al., 2020), which is immediately recognized by the virus due to the S protein. This usually generates the S protein-ACE2 complex, 20-fold more likely compared to the S protein of SARS-CoV-1 (Das, 2020). Curcumin modulates ACE2 levels, preventing the alteration in the organism of infected people (Paraiso et al., 2020). Thymol from thyme essential oil and oregano essential oil was also reported to be efficient in inhibiting the activity of S protein (Kulkarni et al., 2020). Emodin from Rheum officinale roots interfered at the S protein-ACE2 interface, the reason for which was competition at the recognition binding domain (RBD) of the S protein . Curcumin from Curcuma longa, epigallocatechin gallate from tea, herbacetin from Rhodiola spp., PCs from Citrus spp., piceatannol and resveratrol from berries also showed a strong interaction with S protein, interfering with its binding to ACE2 (Yamamoto et al., 2016;Das et al., 2021aDas et al., , 2021bTallei et al., 2020;Singh et al., 2021).
Specific areas of proteins are also investigated such as the protease domain (PD) of ACE2, the RBD (which binds to PD) of S protein (Albohy et al., 2020), S1 (contains the RBD) and S2 (responsible for membrane fusion subsequent to the role of S1) subunit protein (Harisna et al., 2021;Verma et al., 2020), and the protease enzyme 6LU7, which is the crystal structure of the 3CLpro (Sherif et al., 2021). Arokiyaraj et al. (2020) determined that kaempferol, kaempferol 7-o-rhamnoside, quercetin, kaempferitrin, geraniin, corilagin, protocatechuic acid, gallic acid and ellagic acid are compounds with the potential to inhibit the RBD activity of S protein of the SARS-CoV-2. A large number of flavonoid glycosides, ellagitannins and stilbenoids showed a strong interaction with the human transmembrane serine protease (TMPRSS2), preventing its role in viral and host cell membrane fusion by cleaving at the S1/S2 and S'2 sites (Puttaswamy et al., 2020).
PLpro influences virus replication and infection. In addition, its inhibition would prevent the production of other proteins such as nsP1, nsP2 and nsP3, agents that also act in viral replication (Verma et al., 2020). Fortunately, many isolated PCs such as baicalein, hesperidin, quercetin, luteolin, gallocatechin, epigallocatechin gallate, kaempferol, and isoliquiritigenin have shown efficiency in its inhibition (Paraiso et al., 2020;de la Lastra et al., 2021). For example, xanthoangelol E from Angelica keiskei, PCs from Psoralea corylifolia seeds and PCs from Broussonetia papyrifera showed an IC50 value of de 1,2, 15 g/L y 3,7 μM, respectively against SARS-CoV PLpro (Gligorijevic et al., 2021). When evaluating the potential of myricetin from Scutellaria baicalensis against nsP13 helicase of SARS-CoV, the IC50 value was 2.71 μM. With this result, the authors determined that the entry of the virus into the cell was blocked (Llivisaca-contreras et al., 2021). The same value showed myricetin from Chondropetalum mucronatum (Verma et al., 2020).
Others targets of interest are the non-structural protein such as nsP13 (Zia et al., 2021), nsP16 (Albohy et al., 2020) and RNA-dependent RNA polymerase (RdRp) (Verma et al., 2020). Inhibition of RdRp is necessary because its role is to catalyze virus RNA replication (Verma et al., 2020). Resveratrol, epigallocatechin, quercetagetin, and myricetin showed strong affinity for RdRp, successfully interfering with virus replication (Paraiso et al., 2020) and slowing the progression of COVID-19 in patients, regardless of the severity of the infection. Selvaraj et al. (2021) analyzed the affinity of 30 phytochemicals from Plectranthus amboinicus against the RdRp of SARS-CoV-2. The best results were obtained with some PCs such as rutin, luteolin, rosmarinic acid and salvianolic acid. Similarly, the effect of 12 PCs of honey and propolis against the RdRp of SARS-CoV-2 was evaluated. Quercetin, kaempferol, ellagic acid and p-coumaric acid had the highest affinity/inhibition (Shaldam et al., 2021). Quercetin, myricetin, apigenin, chrysin, chlorogenic acid and ellagic acid from Moringa oleifera showed high inhibition potential V.A. Tirado-Kulieva et al.
In in vitro studies, the IC50 value is useful for determining the concentration of PCs required to inhibit 50% of the activity of SARS-CoV-1 and 2 targets (Table 2). In addition, most studies are performed in silico, i.e. by simulation or computational analysis. Molecular docking is the most widely used technique as it helps to predict the relationship between a protein and compounds based on affinity or binding energy (Vardhan and Sahoo, 2021). In this case, the impact/affinity of PCs on the active region of SARS-CoV-2 proteins is evaluated. Lower binding energy means higher efficiency (Xu and Chang, 2007). The advantages of conducting research using simulation processes based on existing data are that it is less time consuming and significantly reduces costs. For example, Das et al. (2021b) rapidly evaluated the effect of 4 commercial drugs, 17 natural compounds, 2 antifungal drugs, 4 antiviral drugs, and 6 antinematodal and antiprotozoal drugs on the 3CLpro activity of SARS-Cov-2. It was concluded that rutin (À9.55 kcal/mol) had the highest docking score. Table 3 presents the main in silico findings, classifying PCs as promising compounds to combat the current pandemic.

Specific mechanisms of action
Based on PCs from algal, a general mechanism of action was described. First, PCs prevent the attachment and subsequent entry of the virus into host cells. If the virus manages to enter the organism, PCs inhibit the activity of its proteins (Al-khafaji et al., 2021). This prevents the recognition, multiplication and release of the virus (Wink, 2020). In addition, PCs such as flavonoids were reported to induce death in infected host cells (Wang et al., 2022).
Specifically, PCs interact with amino acid residues through hydrogen, electrostatic, and polar bonds, among others interactions (Table 3). The activity of the PCs depends on their structure. For example, phenolic acids from Vitis amurensis had a strong interaction with SARS-CoV-2 target residues due to their hydroxyl and carbonyl groups (Souid et al., 2022). Furthermore, the high biological activity of stilbenes is due to their two phenyl groups linked by a transethane bond; the biological activity of ellagic acid is due to its lipophilic domain (four phenolic groups) and mainly to its hydrophilic domain (four rings and two lactones); the anti-3CLpro potential of sotetsuflavone from Dacrydium balansae Brongn. & Gray is attributed to the position and number of the methyl groups (Puttaswamy et al., 2020).
A slight structural change is enough to affect the activity of the PCs. In vitro, Nguyen et al. (2021) determined that the greater the number of OH groups on the B-ring of flavonols, the greater the anti-COVID-19 activity: myricetin (three OH groups) > quercetin (two OH groups) > kaempferol (one OH group). It was also reported that glycosylation of quercetin and the OH group at position 7 of the A-ring of quercetagenin decreased their effect. In flavanones, the activity against 3CLpro of naringenin and hesperidin was attributed to glycosylation at position 7 of their A-ring. Hesperidin had less effect due to the methoxy group at position 5 of its B-ring. In flavan-3-ols and flavones, antiviral activity was also directly proportional to the OH groups in the B-ring. It was also determined that the presence of galloyl moiety at position 3 of the C-ring increased the effect of epigallocatechin, gallocatechin, epicatechin gallate and catechin gallate. In the case of flavones and isoflavones, biological activity was enhanced by glycosylation at position 8 of the A-ring. Finally, it was determined that the activity of diarylheptanoids on 3CLpro depends on the presence of methoxy groups: curcumin (two methoxy groups) > bisdemethoxycurcumin (no methoxy group) (Nguyen et al., 2021).

Clinical trials
These drugs have had adverse effects, and their development and evaluation can take many years. National and international entities related to the field have joined forces with scientists and industry for the development of new and natural drugs (Tavakoli et al., 2022).
Supplementation with PCs has been successful as a method of COVID-19 prevention. 76 outpatients (18-80 years, 60.5% male) received two doses of 200 mg quercetin daily for 30 days. Among the findings, a) the number of patients hospitalized (9.2 vs 28.9%) was lower and for less time (1.6 vs 6.8 days) than in the control group (cg); b) the need for oxygen therapy was lower than in the cg (1,3 vs 19,7%); c) symptoms were not aggravated in any patient compared to the cg (10,5%) (Di Pierro et al., 2021a). Similarly, 120 outpatients (20-60 years, 52.5% male) received two doses of 250 mg quercetin daily for three months. The number of patients hospitalized (1,67 vs 6,67%) was lower than in the cg (Rondanelli et al., 2022). 53 outpatients (45-84 years, 45.3% male) received fourth doses of 500 mg resveratrol daily for 7-15 days. The number of hospitalized patients (2 vs 6%), visits to the emergency room (8 vs 14%) and the incidence of pneumonia (8 vs 16%) was lower than in the cg. There was also incidence of pulmonary embolism in the same proportion of patients in each group (2%) (Pawar et al., 2021).
To fully define the anti-COVID-19 potential of PCs, properly designed clinical trials are needed to ensure that the treatment is safe and effective (Nile and Kai, 2021). For example, Takdehghan et al. (2021) ruled out the toxicity of the extract of Phoenix dactylifera L. leaf (rich in PCs) by in vitro and in vivo assays in Wistar rats. Subsequently, they evaluated the effect of its intake in patients with COVID-19, obtaining optimal results. Likewise, frequent follow-ups should be carried out to detect possible side effects. Karimi et al. (2021) evaluated the effect of ingesting a polyherbal decoction rich in PCs. Promising results were obtained and at each visit any adverse effects were recorded and ruled out. Further findings on these clinical trials are shown in Table 4.

Effect of COVID-19 infection on the organism
For a good quality of life, it is essential to have an immune system in optimal condition. The immune system is related to physiological   Patients recovered in less time (7 (lower dose) and 6 (higher dose) vs. 12 days) than in the cg. Decrease in acute kidney injury with higher dose.
Takdehghan et al. processes and defenses against microbial infections and other internal and external problems. A deficient immune system can lead to different diseases such as being more susceptible to contracting COVID-19 and presenting severe symptoms. Innate immunity is activated when the organism is attacked by foreign agents. Since SARS-CoV-2 is extremely dangerous, the defense is so excessive that it causes overactivation of the NLRP3 inflammasome. This generates a severe storm of cytokines such as interferon-γ (IFN-γ), C-C chemokine ligand Motif 2 (CCL-2), CCL-3, tumor necrosis factor (TNF) and various interleukins (IL) (Cena and Chieppa, 2020). These cytokines act not only in the infected parts of the body, but also in healthy areas, causing irreparable damage to various organs (Ghati et al., 2021).

Fundamentals of the immunomodulatory activity of PCs
To stop the cytokine storm and avoid its lethality, the body must be kept in good condition and in a natural way. The necessary intake of certain dietary compounds helps modulate the immune system (Banik et al., 2021). PCs also have high immunomodulatory, anti-inflammatory and antioxidant activity, ideal for preventing damage to the immune system, maintaining homeostasis in the body and regulating energy metabolism to promote the absorption of nutrition (Wang et al., 2022).
PCs influence immune cells such as dendritic cells, lymphocytes, macrophages and leukocytes (Neyestani, 2008). Harisna et al. (2021) indicate that due to the phenolic potential of propolis, its consumption helps to increase the performance of macrophages. Specifically, kaempferitin, curcumin and quercetin are considered a potent immunostimulators as it acts on macrophages, splenocytes, natural killer (NK) cells and peripheral blood mononuclear cells (PBMC), which play a key role in immune function (Llivisaca-contreras et al., 2021;Ali et al., 2022). These cells play a role in the expression of cytokine genes. PCs influence the increase of anti-inflammatory cytokines (AICs) and the reduction of proinflammatory cytokines (PICs). For example, according to in vitro studies, curcumin has the potential to inhibit and/or control the production of PICs (Celik et al., 2021). Curcumin administration improved the condition of virus-infected mice, which was associated with suppression of cytokine storm (Roy et al., 2020).

In vitro e in vivo studies
PCs such as catechins, resveratrol, genistein and vanillic acid induce the activation/deactivation of signaling pathways related to inflammation such as nuclear factor kappa B (NF-κB), Nuclear factor-erythroid factor 2-related factor (Nrf2), and Signal transducer and activator of transcription 1/3 (STAT1/3). This reduces PICs, chemokines, inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX) (Khalil and Tazeddinova, 2020;Neyestani, 2008). Xanthohumol consumption reduced plasma IL-6 levels in mice by 80% through Nrf2 signaling (Miranda et al., 2016). Resveratrol increased the messenger RNA expression of AICs such as IL-10, and reduced that of PICs such as TNF-α, IL-2 and IFN-γ in mice by inhibiting MEK/ERK signaling pathway . Kaempferol helps decrease IL-1β and TNF-α expression by preventing NF-κB translocation (Khalil and Tazeddinova, 2020). Theaflavin from black tea and resveratrol also modulates the immune system by inducing the proper functioning of Mitogen activated protein kinase (MAPK) (Annunziata et al., 2020;Iddir et al., 2020). Chlorogenic acid significantly reduces NF-κB expression. This caused the reduction of PICs such as IL-12 and the increase of AICs such as IL-10 and IL-22, the latter also considered as PIC (Abaidullah et al., 2021). In mice, catechin ingestion induced inhibition of PI3K/AKT/mTOR signaling and increased T lymphocytes. This meant improvement in adaptive immunity and, in general, in attenuation of induced acute lung injury and oxidative stress . Naringin ingestion inhibited lipopolysaccharide-induced IL-1β, IL-6, iNOS and COX-2 production in a mouse model by inhibiting the expression of high mobility group box 1 . Naringenin prevented the production of PICs in a murine model by inhibiting NF-κB translocation and MAPK phosphorylation (de la Lastra et al., 2021). Quercetin, kaempferol, myricetin, luteolin, baicalein and apigenin modulate the immune system by deactivating the NLRP3 inflammasome (Mckee et al., 2020). Similarly, quercetin reduced NLRP3 inflammasome activation in animal models (Ricordi et al., 2021).
The production of reactive oxygen species (ROS) is common in viral infections, and SARS-CoV-2 infection is no exception. PCs also prevent oxidative damage and amplification of the inflammatory response by ROS (Khan et al., 2019), helping to keep the immune system strong (Abedi et al., 2021). This is achieved by inhibiting ROS-producing enzymes and also by increasing the activity of antioxidant enzymes (El-Missiry et al., 2021). In this pandemic context, PCs such as lutein were reported to have high anti-inflammatory activity. de la Lastra et al.
(2021) emphasize that luteolin can treat lung inflammatory disorders because it inhibits PICs and inflammatory enzymes. In addition, it prevents ROS production by suppressing signaling pathways such as NF-κB.
In summary, when the immune system is in good condition, viral infection would be stopped in the first phase (incubation stage). In this case, infected patients would present only mild symptoms (Khalil and Tazeddinova, 2020). Otherwise, if the person has a weak immune system, the infection will progress to the second stage and patients may experience severe symptoms. Likewise, although the mechanism of action of each specific polyphenol has not yet been defined, Figure 3 shows the anti-COVID-19 mechanisms of action of polyphenols in general.
Synergistic use should also be evaluated. In vitro, Angelis et al. (2021) determined the activity of a mixture of ellagic acid, polydatin, honokiol, pterostilbene, selenium zinc and chromium against influenza A virus and SARS-CoV-2. For comparison purposes, the authors also evaluated the effect of polydatin alone. Polydatin (20 mg/L) inhibited the expression of hemagglutinin and nucleoprotein of influenza A virus by 28 and 35%, respectively, while the lower dose compound mixture (5 mg/L) had greater inhibition for both (%45 and %40%, respectively). Regarding SARS-CoV-2, polydatin had no effect when used before or after infection; however, the mixture reduced the virus concentration by 1.8 and 2 logs at the different times, respectively. Biancatelli et al. (2020) determined that the combined use of quercetin and vitamin C, as opposed to their separate use, offers greater antiviral efficiency with a high potential for the current pandemic context.
Anti-COVID-19 therapy based on natural compounds should complement the drugs accepted and indicated by the health entities concerned. It is often a mistake to believe that natural compounds are sufficient, considering that this may be the case, but in, for example, for prevention or in cases of mild infection. Yildirim et al. (2016) analyzed the effect of propolis, acyclovir (drug), and their combined use against HSV-1 and HSV-2. HSV-1 replication was %4 Â 10 7 , 2 Â 10 7 and 1.5 Â 10 7 , when using propolis, acyclovir and propolis þ acyclovir, respectively. Likewise, HSV-2 replication was 4.5 Â 10 7 , 2 Â 10 7 and 1.5 Â 10 7 , when using propolis, acyclovir and propolis þ acyclovir, respectively, at 24 h. Further studies are needed to evaluate the synergy between various agents with confirmed properties of interest. To find out which compounds are under constant investigation, it is recommended to explore https://sbnb.irbbarcelona.org/covid19/. This platform is constantly updated and provides information on more than 1 million bioactive compounds with proven efficiency against COVID-19.
Another key point is that, it must be ensured that drugs are directed to different targets, which is often a limitation (Liu et al., 2022). PCs act against multiple SARS-CoV-2 targets in parallel and rapidly. Isoliquiritigenin and kaempferol from Broussonetia papyrifera showed a significant effect against 3CLpro and PLpro (Paraiso et al., 2020). PCs from propolis, green tea, garlic, turmeric, soybean and echinacea disrupted the function of S protein, ACE2, 3CLpro and RdRp (Keflie and Biesalski, 2021). Chrysin from honey has the potential to bind to ACE2 and to inhibit in parallel the activity of S protein (Abedi et al., 2021). Caffeic acid inhibited the activity of E and N protein of SARS-CoV-2 (Ali et al., 2022). Likewise, isoliquiritigenin and kaempferol from Broussonetia papyrifera inhibited 3CLpro and PLpro activity (Paraiso et al., 2020).
On the other hand, the use of plant matrices in particular (i.e., when isolated compounds are not used) is recommended because, in addition to polyphenols, they also contain other substances with biological activity. Therefore, synergistically, antiviral, antioxidant, antiinflammatory and immunomodulatory effects would be enhanced (Chojnacka et al., 2020). However, Chapman and Andurkar (2022) mention that this is a double-edged sword. The argument is that the mixture of compounds can also have an antagonistic effect on each other. Another option is the use of isolated compounds, but the process of identification, separation and purification is complex. Moreover, at this last point, the compounds may partially or even totally lose their biological activity. Studies are suggested to help explore this field in depth in order to solve the aforementioned problem.
There is still much to be explored with respect to the evaluation of efficient compounds against COVID-19. More clinical trials are needed to provide information on other PCs and plant matrices rich in PCs that have not yet been explored. Although the current outlook is discouraging, the challenges create an opportunity to improve the natural medicine system (Wakeman et al., 2020). When this crisis is overcome, there will be a wide range of options to counteract not only viral diseases, but also other diseases of global concern.

Conclusion
The use of bioactive compounds is being extensively investigated, highlighting PCs to deal with COVID-19 due to its known high antiviral activity. According to the studies evaluated, polyphenols have shown an efficient activity against SARS-CoV-2. This is because PCs act on proteins of the virus, interfering in its different mechanisms of infection. In addition, PCs consumption helps modulate the immune system through several mechanisms of action, which significantly influences the prevention against COVID-19, mainly avoiding the appearance of severe symptoms. In silico, in vitro and in vivo studies have allowed us to determine the anti-COVID-19 potential and mechanism of action of PCs. Clinical trials have demonstrated the effectiveness of PCs in the prevention and as a possible therapeutic management against COVID-19, ruling out adverse effects. It is also recommended to explore new compounds and drugs with proven antiviral activity to test their individual and synergistic efficacy with PCs against SARS-CoV-2.

Author contribution statement
All authors listed have significantly contributed to the development and the writing of this article.

Funding statement
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability statement
Data included in article/supp. material/referenced in article.