The COVID-19 pandemic, as well as the more general global increase in viral diseases, has led researchers to look to the plant kingdom as a potential source for antiviral compounds. Since ancient times, herbal medicines have been extensively applied in the treatment and prevention of various infectious diseases in different traditional systems. The purpose of this review is to highlight the potential antiviral activity of plant compounds as effective and reliable agents against viral infections, especially by viruses from the coronavirus group.
Bronchitis is a respiratory disease caused by bacterial infections, viral infections, or irritant particles . In response to infection, the bronchial tubes become inflamed and swollen, which may eventually result in acute respiratory arrest. Nowadays, viral pneumonia is diagnosed through analyzing a sample of bronchoalveolar lavage fluid using PCR, cell cultures, and whole-genome sequencing . The virus was isolated from infected individuals and recognized as genus beta-coronavirus, placing it alongside other viruses causing Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) .
The treatment of this disease is a great challenge due to several reasons, including the rapid emergence of mutant strains, the consequent high rate of virus adaptation, and the development of resistance to antiviral medicines. Another factor is that of unwanted side effects and the high cost of synthetic antiviral drugs. The standard approach for viral infections comprises antiviral medicines that do not cause damage to the human host but can help shorten viral infection, inhibit virus expansion, and help in reducing/blocking complications . The potency of marine natural products has been confirmed to target SARS-CoV-2 main protease (Mpro) .
Medicinal plants have been identified as reliable resource against several diseases for millennia. More than 70% of the global population still depends on herbal medicines due to their relatively low cost and better compatibility with the human body compared to synthetic drugs . During the pandemic period, studies were performed using databases of scientific literature to screen and identify the potential of herbal plants to act as anti-coronavirus medication . It has been reported that water and ethanol plant extracts contain biologically active substances with antiviral activity .
A wide range of compounds identified in several plant species have demonstrated antiviral activities, including alkaloids, flavonoids, triterpenes, anthraquinones, and lignans. Interestingly, plant selection based on ethnomedical concerns provides a higher hit rate than screening plants or general synthetic products . Some known pharmacophore structures of bioactive substances may be useful in the creation of new anti-Covid-19 drugs. In addition, plants have also been introduced as a safe and reliable bioreactor for the production of recombinant virus proteins that can be used in vaccine development , e.g., nuclear transformed tomatoes and tobacco-expressing antigens have been reported to induce immunogenic responses against SARS-CoV .
The main objective of the current review is to provide the complete overview of the ethnomedicinal uses of herbs employed to treat respiratory diseases. We address questions regarding the potential of plant-derived compounds in inhibiting virus propagation, thus providing relief for viral-induced pathogenesis. We also discuss how biotechnology may help solve the challenge of rapidly obtaining pure antiviral compounds. Furthermore, this review discusses the current state of the art regarding the possible antiviral activities of herbal medicine and makes an effort to tackle the gaps in scientific knowledge that may lead to the advancement of innovative treatments for the welfare of people and against the spread of viral diseases, especially SAR-CoV.
Previous investigations have demonstrated that the development of proteases is an ideal goal to be tackled for the inhibition of CoV replication. Though the protease activity disruption causes various diseases, host proteases are considered reliable therapeutic targets. For several different viruses, protease activity represents a vital factor in replication; thus, proteases are frequently targeted as protein candidates during antiviral therapeutics studies . Lopinavir and nelfinavir are in the category of medications named protease inhibitors with a high level of cytotoxicity recommended for the treatment of cells infected with MERS, SARS, and HIV .
The use of therapeutic plants against viral infection can be traced back to the dawn of civilization; however, BOOTS Pure Drug Co., Ltd., Nottingham (England) made the first systematic effort to screen plants against influenza . Later on, the inhibitory effect of medicinal plants on the replication of viruses was studied on severe acute respiratory syndrome (SARS) virus, emerging viral infections linked with poxvirus, hepatitis B virus (HBV), HIV, and herpes simplex virus type 2 (HSV-2)  It has been demonstrated that molecular mechanisms linked to the antiviral effects of medicinal plant extracts vary among various types of viruses. Thus far, some investigations have discovered immunostimulatory properties of medicinal plant extracts possessing antiviral activity .
The phagocyte–microbe interactions in the immune system comprise a defense reaction that, under more harmful circumstances, may take part in the advancement of various immune and non-immune chronic inflammatory diseases. Agents that express a capacity to modulate and normalize pathophysiological processes are named immunomodulators . Most of the well-known immunostimulants and immunosuppressants used in clinical practice are cytotoxic drugs, which can have severe side effects. Therefore, plant-derived compounds and extracts have been studied regarding their immunomodulatory potential in humans due to their lower cytotoxicity and high bioavailability .
Some plant-derived compounds, e.g., curcumin, genistein, fisetin, quercetin, resveratrol, epigallocatechin-3-gallate, andrographolide, and colchicine, have immunomodulatory effects . These compounds can downregulate the production of proinflammatory cytokines induced by some viroidal agents . Andrographolide and other natural immunomodulators can enhance the activity of cytotoxic T cells, phagocytosis, natural killer (NK) cells, and antibody-dependent cell-mediated cytotoxicity . The use of quercetin in combination with highly active compounds such as psoralen, baccatin III, embelin, and menisdaurin increased its anti-hepatitis B activity up to 10% .
At the same time, analyses of other medicinal plant extracts with antiviral properties have shown thatGymnema sylvestre,Stephania tetrandraS , andVitex trifoliaextracts  possess immunomodulating activity.  found immunomodulation potential and antiviral activities against acute common cold in leaf extracts ofThuja occidentalis. The anti-SARS and immunomodulatory activity of water extracts ofHouttuynia cordatahave been reported via the stimulation of lymphocyte proliferation together with enhancing the proportion of CD4+and CD8+Tcells  (Table 1).
|Plant Species and
|Active Compounds||Coumarins||Extract||Model Organism||Mode of Action/Activity||Ref|
Luteolin and its derivatives
|n/a||Trans-resveratrol||n/a||Ethanol||Vero cell cultures||High antiviral activity|||
|n/a||n/a||n/a||Ethanol||Vero cell cultures||High antiviral activity and
|Sandosaponin B and its derivativesSoyasaponin I Soyasaponin VI||Homoorientin
|n/a||n/a||Ethanol||Vero cell cultures||High antiviral activity|||
(whole plant, flowers)
|Do not produce purine alkaloids||n/a||n/a||Ethanol||Vero cells (African green monkey kidney cell line; ATCC CCR-81)||High antiviral activity on PEDV corona virus
Inhibitory effects on key gene and protein synthesis during PEDV replication
|Ethanol||Vero cells (African green monkey kidney cell line; ATCC CCR-81)||High antiviral activity on PEDV corona virus|||
|Quercus ilex L.
|kaempferol glycosides (juglanin, kaempferol-3-O-α-L-arabinofuranoside, and afzelin, kaempferol-3-O-α-L-rhamnoside||n/a||n/a||n/a||DMSO||Xenopus oocytes||Inhibits 3a channel protein of coronavirus|||
|n/a||n/a||n/a||DMSO||Human fetal lung fibroblasts (MRC-5; ATCC CCL-171)||Saikosaponins attenuate viral attachment and penetration|||
|n/a||n/a||Water||BALB/c mice||Decreases the viral SARS-3CLpro activity
Stops viral t RNA polymerase activity (RdRp)
Increases the secretion of interleukin (IL)-2 and (IL)-10
|Sinigrin||n/a||Water||Vero cells||Cleavage of the activity of SARS-3CLpro enzyme decreased|||
|n/a||Ethanol||Vero E6 cells||Exhibits anti-SARS-CoV activity|||
|3-Oxotrirucalla-7,24-dien-21-oic acid||Herbacetin Rhoifolin
Pectolinarin Quercetin Epigallocatechin gallate Gallocatechin gallate
|n/a||n/a||n/a||Water||On model with SARS-CoV 3CLpro||Inhibits SARS-3CLpro activity|||
|Stephania tetrandra S Moore
|n/a||n/a||Tetrandrine Fangchinoline, Cepharanthine||n/a||n/a||DMSO||Human cell line MRC-5 cells||Inhibits the expression of HCoV-OC43 spike and nucleocapsid protein.
|n/a||n/a||n/a||DMSO||Model with SARS-CoV helicase, and nsP13||Inhibits nsP13 by affecting the ATPase activity|||
α-pinene Terpinolene Limonene
|n/a||n/a||Aquaporin||Chicken embryos||Inhibitory effects on avian coronavirus|||
Glycosides of quercetin
|Artamarin Artamaridin, Artamaridinin, Artamarinin QuebrachitolArtemitin||n/a||n/a||Water||Delayed brain tumor cells||Reduces coronavirus replication|||
|n/a||n/a||Umbelliferone||n/a||Protein-molecular docking with network pharmacology analysis||Inhibits the replication, 3CLpro|||
|n/a||Quercetin||n/a||n/a||n/a||n/a||protein-molecular docking with network pharmacology analysis||PLpro and 3CLpro|||
Plant sources of polyphenolic compounds with anti-protease activity.
The mode of action against viruses and methods of active compound extraction from medicinal plants.
Lectins are a special type of natural proteins (split into seven different classes of evolutionarily- and structurally-related proteins) found in higher plants that bind to the sugar moieties of a wide range of glycoproteins . Plant lectins can inhibit virus replication by preventing the adsorption and fusion of HIV in lymphocyte cell cultures . Furthermore, the antiviral effect of agglutinins specific for N-acetylglucosamine and mannose on HIV has been reported. The inhibitory effect of these plant lectins has been shown in vitro on infection with influenza A virus, respiratory syncytial virus, and cytomegalovirus .
During the digestion of food, quercetin and its conjugated metabolites can be converted into a range of metabolites (phenolic acids) by enteric enzymes and bacteria in intestinal mucosal epithelial cells (IMECs) . Additionally, several studies have shown the protective function of this flavonol against inflammation in human umbilical vein endothelial cells (HUVECs), as well as mediation via the downregulation of vascular cell adhesion molecule 1 (VCAM-1) and CD80 expression . Quercetin considerably induces the production of derived interferon (IFN) and T helper type 1 (Th-1), and it consequently downregulates Th-2-derived interleukin 4 (IL-4) by normal peripheral blood mononuclear cells. Investigations into influenza mechanisms have shown the positive interactions between the viral HA2 subunit (a mark for antiviral vaccines) and quercetin.
It has been reported that the osteoblast supporting transcription factor Runx2 is essential for the long-term perseverance of antiviral CD8+memory T cells . An addition, SFN-rich broccoli homogenate attenuated granzyme B production in NK cells that was induced by influenza virus and granzyme B production in NK cells, and granzyme B levels appeared to have negatively interacted with influenza RNA levels in nasal lavage fluid cells . Nasal influenza infection can induce complex cascades of changes in peripheral blood NK cell activation. SFN increases as a result of virus-induced peripheral blood NK cell granzyme B production, which may enhance antiviral defense mechanisms .
Resveratrol is a natural polyphenol found in grapes, mulberry, and peanuts. It is known to have antiviral properties against a variety of viral pathogens in vitro and in vivo . Studies have shown that indomethacin and resveratrol can act as adjuncts for SARS developed the hairy root lines fromArachis hypogaea(peanut) for the sustained and reproducible production of resveratrol and resveratrol derivatives .
Baicalin has been reported as an antioxidant possessing anti-apoptotic properties, and it has been used for pulmonary arterial hypertension treatment . At the same time, this compound has a low toxicity in human cell lines . Baicalin showed considerable anti-viral properties on lipopolysaccharide-activated cells, while the oral application of baicalin expressively increased the survival rate of influenza A virus-infected mice . The in silico analysis of the inhibitory effect of baicalin showed that this flavone inhibits ACE2 in the case of COVID-19 disease.
Glycyrrhizin (a triterpene saponin) is one of the most important phytochemical components of theGlycyrrhiza glabra(licorice) root . Glycyrrhizin has anti-inflammatory and antioxidant properties used for treatments of different diseases such as jaundice, bronchitis, and gastritis . Glycyrrhizin could block the SARS-Cov virus attachment to the host cells, especially during the initial stage of the viral life cycle . An in silico analysis of glycyrrhizin behavior showed the inhibitory effect of this compound on SARS-Cov2 .
Narcissoside (synonym: narcissin) is a phytochemical belonging to the group of mono-methoxyflavones. This isorhamnetin-3-O-rutinoside flavonoid is extracted from leaves of various folk plants such asAtriplex halimusL.,Gynura divaricate,Caragana spinose, andManihot escylenta. An in silico analysis demonstrated that narcissoside has inhibitory potential for the viral COVID 19 protein 6W63 .
Moreover, antiviral properties of this compound have been reported against chikungunya virus (CHIKV), human papillomavirus (HPV), HIV-1 and HIV-2 proteases, emerging arboviruses like the Zika virus (ZIKV), influenza viruses, HIV, HSV-2, and hepatitis viruses . However, due to its rapid elimination, rapid metabolism, and poor absorption, curcumin has poor bioavailability, which reduces its therapeutic effect . It has been reported that the combination of this diarylheptanoid with other chemical compounds like piperine can increase bioavailability (by up to 2000%) and provide multiple benefits to human health . It has been reported that this plant-derived compound can inhibit the NF-κB activation caused by numerous inflammatory stimuli such as markers of soluble vascular cell adhesion molecule 1 (sVCAM-1), IL-1 beta, IL-6, and inflammation (soluble CD40 ligand (sCD40L)).
The antiviral activity of this compound has been reported against a broad spectrum of viruses such as hepatitis B virus (HBV; Hepadnaviridae), human papillomavirus (HPV; Papovaviridae), adenovirus (Adenoviridae), and herpes simplex virus (HSV; Herpesviridae). It has been observed that epigallocatechin gallate can inhibit (+)-RNA viruses such as chikungunya virus (CHIKV; Togaviridae), West Nile viruses (WNV; Flaviviridae), dengue virus (DENV; Flaviviridae), Zika virus (ZIKV; Flaviviridae), and hepatitis C virus (HCV; Flaviviridae). On the other hand, it can inhibit (−)-RNA viruses such as influenza virus (Orthomyxoviridae), Ebola virus (EBOV; Filoviridae), and HIV (Retroviridae)