Phenolic acids

Phenolic compounds are known to have antiviral activity against many viruses such as HCV and HIV, through their phenol rings interaction with viral proteins and/or RNA, or via its regulating MAP kinase signaling in host cell defense [1].
The molecular docking the profound binding affinity of 14 selected phenolics against the main protease (Mpro) and RNA-dependent RNA polymerase (RdRp) enzymes of the novel SARS-CoV-2 virus. Of these compounds, p-coumaric acid, ellagic acid, kaempferol, and quercetin have the strongest interaction with the SARS-CoV-2 target enzymes, and it may be considered an effective COVID-19 inhibitor.

P-coumaric acid, ellagic acid, kaempferol, and quercetin are the most promising compounds on COVID-19 active sites (RdRb and Mpro). These bioactive compounds were also found to have potential antiviral activity against the common cold human rhinovirus which is RNA virus like SARS-CoV-2 [2].

Another study tested phenolic acids against the COVID-19 polymerase (ARG 555, ARG 555, LYS 545). Gallic acid and quercetin exhibited high binding affinity than ribavirin toward COVID-19 polymerase and expressed good drug likeness and pharmacokinetic properties. Therefore, gallic acid and quercetin may represent a potential treatment option for COVID-19. Additionally, resveratrol, naringenin, benzoic and ellagic acid seem to have the best potential to act as COVID-19 polymerase inhibitors.
Conclusion: The obtained data in the present study revealed that, gallic acid and quercetin have high binding affinity to COVID–19 polymerase with expected good drug likeness and pharmacokinetic properties, and resveratrol, naringenin, benzoic and ellagic acid come next [1].

1. Inhibition of COVID-19 RNA-Dependent RNA Polymerase by Natural Bioactive Compounds: Molecular Docking Analysis. Research Square, 30 Apr, 2020 DOI: https://doi.org/10.21203/rs.3.rs-25850/v1
2. In silico screening of potent bioactive compounds from honeybee products against COVID-19 target enzymes. Environ Sci Pollut Res (2021). https://doi.org/10.1007/s11356-021-14195-9

Luteolin

Luteolin is a flavone which can be isolated from medicinal plant Ocimum basilicum, Spinacia oleracea and Capsicum annuum and have in vitro antiviral activity against a wide range of viruses including HIV-1, EBV, EV71, SARS-CoV, influenza virus and JEV (Zakaryan et al. 2017). Luteolin displays antiviral activity by inhibiting RNA replication [1].
In this study, the molecular docking studies of Luteolin with six important protein receptors (spike, main protease and nucleocapsid protein) which are encoded by SARS-CoV–2 were studied. The docking results (binding energy) were compared with remdesivir, an FDA-approved drug against COVID–19. Luteolin showed excellent inhibitory action against papain-like proteinase, a main protease of SARS-CoV-2. The results revealed that Luteolin exhibited higher dock score than remdesivir against the proteins of SARS-CoV–2. In addition, Luteolin is also known to have pharmacological properties which of particular relevance in respiratory illnesses. Therefore, based on the promising docking results and the medicinal importance of Luteolin, we propose that the Luteolin should be further studied to determine its viability as pharmacological agent against COVID–19 [2].
This study reviewed Out of the forty-three flavonoids, luteolin was found to develop successful docked complex within the binding sites of target proteins in SARS-CoV-2 in terms of lowest binding free energy and inhibition constant. They proposes that luteolin and might act as potential therapeutic candidates for SARS-CoV-2 infection [3].

1. Flavonoids: promising natural compounds against viral infections. Arch Virol 162(9):2539–2551
2. Luteolin: A Dietary Molecule as Potential Anti-COVID-19 Agent. Research Square, 16 Jun, 2020 DOI: https://doi.org/10.21203/rs.3.rs-35368/v1
3. Luteolin and abyssinone II as potential inhibitors of SARS-CoV-2: an in silico molecular modeling approach in battling the COVID-19 outbreak. Bull Natl Res Cent 45, 27 (2021). https://doi.org/10.1186/s42269-020-00479-6

Naringenin

Studies verified a direct role of Naringenin (NAR) in abrogating viral replication in human cells, before and after infection [1, 2]. In SARS-CoV2, in silico analysis demonstrated that NAR has the potential to inhibit SARS-CoV-2 3CLpro and consequently inhibit viral replication (91), which still needs to be further verified experimentally [3].
The consumption of NAR via supplementation can rapidly increase circulating levels of NAR and increase intracellular levels of NAR [4]. In addition, in vitro models have also demonstrated a long-term anti-viral benefit, even after discontinuation of supplementation with NAR, although there is little evidence of in vivo antiviral activity [4, 5].
Coronavirus disease 2019 can also lead to cytokine storm, progress to septic shock, and cause death [6]. Modulating the cytokine storm is thus a vital process for treating COVID-19. Naringenin has been used in experimental models to regulate the production of IL-6 and TNF, cytokines that are increased in COVID-19 and further increased in severe cases [7-9]. Also in an animal model of septic shock, the consumption of NAR has been demonstrated to reduce kidney damage via an increase in antioxidant enzymes [10].

Figure. Outline of the putative role of naringenin in COVID-19 pulmonary pathophysiology. (A) Established effects of naringenin on different pulmonary diseases. (B) Naringenin may reduce inflammatory cytokines and tissue damage, and it may directly bind to SARS-CoV-2. Abbreviations: Interferon gamma (IFN-γ), glucocorticoid receptor expression (GCR), and cluster differentiation (CD) [11].

1. Naringenin inhibits the assembly and long-term production of infectious hepatitis C virus particles through a PPAR-mediated mechanism. J Hepatol. (2011) 55:963–71. 10.1016/j.jhep.2011.02.011
2. Inhibitors of alphavirus entry and replication identified with a stable Chikungunya replicon cell line and virus-based assays. PLoS One. (2011) 6:e28923. doi: 10.1371/journal.pone.0028923
3. Potential inhibitor of COVID-19 main protease (M pro) from several medicinal plant compounds by molecular docking study. Preprints. (2020): 10.20944/preprints202003.0226.v1
4. The citrus-derived flavonoid naringenin exerts uterotrophic effects in female mice at human relevant doses. Basic Clin Pharmacol Toxicol. (2008) 94:30–6. 10.1111/j.1742-7843.2004.pto_940106.x
5. The therapeutic potential of naringenin: a review of clinical trials. Pharmaceuticals. (2019) 12:11. 10.3390/ph12010011
6. Cytokine storm and sepsis disease pathogenesis. Semin Immunopathol. (2017) 39:517–28. 10.1007/s00281-017-0639-8
7. Naringenin ameliorates acute inflammation by regulating intracellular cytokine degradation. J Immunol. (2017) 199:3466–77. 10.4049/jimmunol.1602016
8. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy Eur J Allergy Clin Immunol. (2020) 75:1730–41. 10.1111/all.14238
9. Clinical and immunologic features in severe and moderate forms of Coronavirus disease 2019. medRxiv [Preprint] (2020). 10.1101/2020.02.16.20023903
10. Mu L, Hu G, Liu J, Chen Y, Cui W, Qiao L. Protective effects of naringenin in a rat model of sepsis-triggered acute kidney injury via activation of antioxidant enzymes and reduction in urinary angiotensinogen. Med Sci Monit. (2019) 25:5986–91. 10.12659/MSM.916400
11. Perspective: The Potential Effects of Naringenin in COVID-19. Front Immunol. 2020;11:570919. Published 2020 Sep 25. doi:10.3389/fimmu.2020.570919

EGCG

EGCG may impede SARS-CoV-2 infection by activating Nrf2 which downregulates ACE2 and TMPRSS2. EGCG may suppress SARS-CoV-2 replication via inhibiting SARS-CoV-2 main protease, mitochondrial ROS and ER-resident GRP78. EGCG may protect against ROS burst inflicted by SARS-CoV-2 induced neutrophil extracellular traps. EGCG may decrease SARS-CoV-2 triggered cytokine storm, sepsis, thrombosis and lung fibrosis. EGCG may prevent diabetes comorbidity risk in COVID-19 patients [1].

Another study showed the inhibition effects of EGCG on SARS-CoV-2 occur through its actions on the ACE2 receptor, the main protease (Mpro, a 3C-like protease) and RdRp (RNA-dependent RNA polymerase). Molecular docking experiments revealed that EGCG had a higher atomic contact energy value, binding energy, Ki value, ligand efficiency and surface area than hydroxychloroquine (HCQ) during binding with the spike protein. There were three binding sites on the spike protein. EGCG can bind with all of the three sites, while HCQ binds only with site III, based on the fact that sites I and sites II are in closer contact with open state location and viral–host contact area. These suggest that EGCG has a stronger ability to inhibit the infection of SARS-CoV-2 to the host cells than HCQ [2]. 

Molecular docking test on various plant polyphenol compounds showed that EGCG had the highest binding affinity with SARS-COV-2 spike proteins among the 11 tested plant polyphenols [3].

Conclusion: EGCG is shown to be able to bind strongly with many molecules in viruses, especially protease and protein; therefore, it influences their functional activities. Through attaching with virion surface or the receptors on the host cell membrane, EGCG disturbs the interaction between viral and host cells. EGCG suppresses viral genome replication and viral protein expression, inactivating viral activity and inhibiting pro-inflammatory factor promotion. Besides, EGCG exhibits synergistic effects on several antiviral-specific drugs via reducing toxicity and enhancing the efficacy of drugs, increasing the resistance of cells to drugs [4].

Figure. Schematic diagram of SARS-CoV-2 life cycle and the inhibition effects of EGCG.

The inhibition effects of EGCG on SARS-CoV-2 occur through its actions on the ACE2 receptor, the main protease (Mpro, a 3C-like protease) and RdRp (RNA-dependent RNA polymerase). [4].

1. Potential protective mechanisms of green tea polyphenol EGCG against COVID-19. Trends in Food Science & Technology, Volume 114, August 2021, Pages 11-24 https://doi.org/10.1016/j.tifs.2021.05.023

2. Epigallocatechin gallate and theaflavin gallate interaction in SARS-CoV-2 spike protein central channel with reference to the hydroxychloroquine interaction: Bioinformatics and molecular docking study. Drug Dev. Res. 2020

3. In silico molecular docking analysis targeting SARS-CoV-2 spike protein and selected herbal constituents. J. Pure Appl. Microbiol. 2020, 14, 989–998.

4. Antiviral Effects of Green Tea EGCG and Its Potential Application against COVID-19. Molecules 2021, 26(13), 3962; https://doi.org/10.3390/molecules26133962