key: cord-0920109-7ondoxne
authors: Khan, Tariq; Khan, Mubarak Ali; Mashwani, Zia-ur-Rehman; Ullah, Nazif; Nadhman, Akhtar
title: Therapeutic potential of medicinal plants against COVID-19: The role of antiviral medicinal metabolites
date: 2020-12-11
journal: Biocatal Agric Biotechnol
DOI: 10.1016/j.bcab.2020.101890
sha: 47442df0155617d0412922782acad1104588dbc2
doc_id: 920109
cord_uid: 7ondoxne

There are numerous trials underway to find treatment for the COVID-19 through testing vaccines as well as existing drugs. Apart from the many synthetic chemical compounds, plant-based compounds could provide an array of suitable candidates for testing against the virus. Studies have confirmed the role of many plants against respiratory viruses when employed either as crude extracts or their active ingredients in pure form. The purpose of this review article is to highlight the importance of phytomedicine against COVID-19. The main aim is to review the mechanistic aspects of most important phytochemical compounds that have showed potential against coronaviruses. Glycyrrhizin from the roots of Glycyrrhiza glabra has shown promising potential against the previously epidemic coronavirus, SARS-CoV. Other important plants such as Artemisia annua, Isatis indigotica, Lindera aggregate, Pelargonium sidoides, and Glychirrhiza spp. have been employed against SARS-CoV. Active ingredients (e.g. emodin, reserpine, aescin, myricetin, scutellarin, apigenin, luteolin, and betulonic acid) have shown promising results against the coronaviruses. Phytochemicals have demonstrated activity against the coronaviruses through mechanisms such as viral entry inhibition, inhibition of replication enzymes and virus release blockage. However, compared to synthetic drugs, phytomedicine are mechanistically less understood and should be properly evaluated before application. Nonetheless, phytochemicals reduce the tedious job of drug discovery and provide a less time-consuming alternative for drug testing. Therefore, along with other drugs currently tested against COVID-19, plant-based drugs should be included for speedy development of COVID-19 treatment.

The current pandemic that struck the world in December 2019 and is ongoing till this day, has turned into the deadliest pandemic after influenza pandemic that took place in 1918. This is the third time that a coronavirus has caused an outbreak during the 21st century. The recent one is caused by the novel coronavirus termed as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the World Health Organization (WHO) and is responsible for a respiratory disease named as the coronavirus disease 2019 . However, COVID-19 has turned out to be more deadly than the previously spread SARS and MERS (Middle east respiratory syndrome) coronaviruses. Owing to this, 1.30 million people have died because of COVID-19 and 53.76 million have tested positive for the virus as of November 13, 2020 (Worldometer 2020) . The reason that it took only over two months to be declared as "pandemic" is the interconnectedness and ever increased worldwide travel.

The pandemic has led scientists from a diverse area of subjects to work on understanding the origin of the virus, its structure, the disease caused, diagnostic tools and treatment options. Along with the other equally important aspects of the disease, treatment has been the most sought-after aspect. As the virus and the disease it causes are very new, there is currently no vaccine available to get rid of the infection. The current options to treat COVID-19 patients are to focus on symptoms alleviation and provide medication to prevent co-infection with bacteria.

Researchers and scientists across the world are focusing on repurposing the existing drugs, passive immunity and looking for vaccines against the virus (Harrison 2020) . Among the available drugs, for instance, the antimalarials Chloroquine and hydroxychloroquine received attention after studies on its efficacy were conducted recently (Gautret et al., 2020; Keyaerts et al., 2004; Wang et al., 2020) . However, the medication soon became controversial regarding its efficacy and manifestations of side effects such as fulminant hepatic failure, serious cutaneous adverse reactions, and ventricular arrhythmias (Ferner and Aronson 2020) .

Owing to the experimentally proved efficacy of its analogues and their potential side effects, natural quinines could prove potent in alleviating the symptoms of coronaviruses without showing side effects based on its biocompatibility (Devaux et al., 2020) .

Apart from a primary food source, plants serve as a very important source of medicine. A thorough understanding of the pathways of plant's secondary metabolism along with their conservation status, ecology and ethnobotany is important for drug development (Nature 2020). To focus on this aspect, medicinal plants produce many important chemical compounds through their secondary metabolism, operating as a self-defense against stress induced by environmental triggers and pathogens. From using the raw plant to extraction of important compounds, medicinal plants are centuries old source in the various traditional herbal medicine systems. For instance, their importance lies in the fact that the WHO concludes that 80% of the world population relies on them for treatment (Bannerman et al., 1983) . It has been seen that there is a plethora of medicinal plants already employed against respiratory viruses. For instance, the trials on Traditional Chinese Medicine including that of extracts from the dried fruit of Forsythiae fructus are ongoing as a part of the world's race to develop effective treatment for COVID-19 (Maxmen 2020) . Therefore, it is no wonder that medicinal plants could be employed as a potent weapon against COVID-19. Traditional herbal medicine coming from these medicinal plants could serve at different fronts including alleviation of symptoms of COVID-19 patients as well as providing raw material for potent antiviral drugs. The current research for treatment of COVID-19 should, therefore, include on a largescale, medicinal plants as an important area of search. This review paper highlights the usefulness of medicinal plants in the fight against COVID-19 in many ways. The paper reviews the important plant derived compounds for immediate application in alleviation of symptoms, and important secondary metabolites as candidates for anti-COVID-19 drug discovery.

Many different plants have been utilized since centuries for improving symptoms such as coughing, weakness and digestive system disorders as well as alleviating anxiety. Plant products such as crude extracts, extract of a specific part i.e. roots, stem, flowers, fruits and seeds, plant-derived chemicals, and nutraceuticals are widely applied in dealing with general ailments including minor cough, flu to complex chest infections. In fact, the one-fourth of the most commonly employed medicinal compounds contain plant-based component.

Some of the most notable plants employed against respiratory problems include Artemisia vulgaris (Khan and Gilani 2009) , Boerhavia procumbens (Bokhari and Khan 2015) , Capparis spinosa L. (Trombetta et al., 2005) , Carum copticum (Gilani et al., 2005) , Cistanche tubulosa (Yamada et al., 2010) , Euphorbia hirta (Youssouf et al., 2007) , Hyoscyamus niger (Gilani et al., 2008) , and Zingiber officinalis (Naik et al., 2013) . Apart from these, there are hundreds of plants used for their activity in treating or reducing the symptoms of respiratory problems such as cough, asthma, cold, bronchitis, flu, respiratory tract infections, whopping cough and breathing problems (Table 1) . Among the medicinal plants, herbs are mostly used in respiratory problems in the form of decoction, powder, juice, tea or oil (Alamgeer et al., 2018) .

Furthermore, leaves of Alstonia scholaris were used by Channa et al. (2005) for their effect on asthma in rats and guinea pigs. The study recorded prostaglandin mediated broncho-vasodilatory activity of leaf extracts of A. scholaris. It was observed from the findings that the root extract of A. scholaris relaxes the calcium chloride induced contraction in guinea-pigs ileum and thus it was inferred that the extract interferes the influx of calcium ions into cells. Similarly, Shah et al. (2011) reported that aerial parts of the Artemisia maritima showed potent anti-asthmatic activities through bronchodilation. They suggested that the bronchodilation might have been mediated through blockade of calcium channels and phosphodiesterase. Furthermore, different medicinal plants are traditionally employed for treating breathing problems. For instance, Kapoor et al. (2011) used leaves extracts of Ficus religiosa to demonstrate the reduction of histamine & acetylcholine induced pre-convulsive dyspnea (shortness of breath) in guinea pigs. This implies that careful evaluation of important herbs backed by scientific experiments could prove helpful in finding naturally existing, biocompatible solution for alleviation of respiratory problems in COVID-19 patients.

The use of medicinal plants against human viruses has been in practice since long. Many herbal plants as leaf powder, decoctions, infusions, pastes and pills have been documented against viral infections (Akram et al., 2018) . There are hundreds of plants having medicinal properties against human viruses (Mukhtar et al., 2008) .

Important anti-viral plants such as Sambucus nigra, Withania somnifera, Sylibum marianum and Moringa oleifera have been employed against human viruses such as influenza virus (Ataee et al., 2016) , human immunodeficiency virus (HIV) (Salehi et al., 2018) , Hepatitis C virus (Ferenci et al., 2008) and Herpes simplex virus type 1 (HSV-1) (Lipipun et al., 2003) . Different studies have reported a variety of plants for their potent antiviral activities including that of Ogbole et al. (2018) who studied twenty-seven medicinal plants from Southern Nigeria for their activity against positive stranded RNA viruses such as enteroviruses. Their study concluded that extracts of Macaranga barteri showed very strong activity against echoviruses. Similarly, studies are available that reviewed hundreds of medicinal plants have strong antiviral potential (Akram et al., 2018) . Such studies indicate that these antiviral plants after careful testing could be employed for alleviating the COVID-19 symptoms.

Furthermore, many studies have been conducted on pure compounds isolated from many different plants for their potent activities against different viruses (Hussain et al., 2017) . Notable plants from which anti-viral metabolites have been isolated include Aloe barbadensis (Aloe gel), Artemisia annua (artemisinin) (Efferth et al., 2008) , Glycyrrhiza 

(continued on next page) T. Khan et al. glabra (Glycyrrhizinic acid) (Pompei et al., 2009) , Sylibum marianum (Sylimarin) (Polyak et al., 2013) , and Phyllanthus urinaria (Ellagic acid) (Kang et al., 2006) . Experiments have revealed that there are many important plant-based compounds i.e. secondary metabolites with marked antiviral activities These include alkaloids, flavonoids (such as quercetin), lignans (phyllanthine), polyphenolcs (tannins), and terpenoids (Glycyrrhizinic acid), which have shown strong anti-HSV, influenza, HIV, HCV, and anti-dengue activities (Hussain et al., 2017) .

Viral respiratory infections (VRI) continue to be among the most (1994) common human illnesses. Antiviral plants have much to offer for patients with the acute bronchitis, acute respiratory syndrome, common cold, influenza, viral pharyngitis. Among these antiviral plants, there are many plants studied for their activity against respiratory viruses. These herbal medicines have been used to treat viral flu caused by influenza virus (Choi et al., 2019) , human respiratory syncytial viruses (hRSV) (Shin et al., 2013) , and notably during the previous epidemics of this century such as two coronavirus outbreaks (SARS-CoV in 2002 and MERS-CoV in 2012). Convincingly, there are innumerable herbs that have been shown to have a strong anti-VRI activity. These plants show direct antiviral activity (Glycyrrhiza spp), acts as analgesic (Calendula officinalis), antiinflammatory (Hedera helix), immune stimulator (Andrographis paniculate). Notably important antiviral herbs from important families include Lomatium dissectum (desert parsley), and Osmorhiza occidentalis (western sweet Cicely) from family Apiaceae, Rosmarinus officinalis (rosemary), and Prunella vulgaris (heal-all) from family Lamiaceae (Yarnell 2017) .

For instance, Tian et al. (2011) showed considerable anti-influenza A effects of aqueous extracts of five traditionally employed herbal medicine (Duchesnea indica, Fragaria indica, Liquidambar formosana, Lithospermum erythrorhizon, Melia toosendan and P. vulgaris). The study conducted by the Tian et al. (2011) revealed that these the extracts from these plants including P. vulgaris can act strongly against influenza virus through anti-neuraminidase activity.

For instance, Sornpet et al. (2017) demonstrated the biological activity of crude extracts of five medicinal plants found in Asia (Andrographis paniculata, Curcuma longa, Gynostemma pentaphyllum, Kaempferia parviflora, and Psidium guajava) against highly pathogenic avian influenza virus (H5N1). The study concluded that aqueous and methanolic extract of all the plants resulted in a significant antiviral activity. Among the plants C. longa and K. parviflora boosted the immune response against H5N1 by increasing the messenger RNA expression of tumor necrosis factor alpha (TNF-α), and interferon beta (IFN-β). Similarly, Rajasekaran et al. (2013) showed that fifty medicinal plants, originating from the tropical rainforests possess potent anti-influenza virus activity. The tested plants proved to be minimally cytotoxic and had significant potential for the inhibition of viral neuraminidase and hemagglutination. Similarly, Choi et al. (2019) , successfully employed Geranii Herba (Geranium thunbergii) for the inhibition of neuraminidase activity in influenza viruses. In fact, there are many studies available on the strong anti-influenza virus activity of different plants.

Furthermore, Chathuranga et al. (2019) assessed the anti-RSV activity of herbs Plantago asiatica and Clerodendrum trichotomum. Through this study, it was reported that lower concentrations of P. asiatica and C. trichotomum extract significantly reduced replication and transcription in RSV genes and in turn reduced its protein synthesis thus reducing the RSV-induced cell death.

Among these antiviral herbs, those specifically important to mention are the anti-coronavirus medicinal plants. Plant extracts can be useful against COVID-19 because it belongs to the β genus of coronavirus and is thus closely related to the previous coronaviruses against which these plants have shown potent activity. There is a whole list of herbs assessed for their activity against SARS-CoV viruses (Table 2 ). Most notable among them are the Lycoris radiata (Li et al., 2005c) , Artemisia annua, Lindera aggregate, Isatis indigotica , Torreya nucifera (Ryu et al., 2010) , Houttuynia cordata (Lau et al., 2008) , Pelargonium sidoides (Whitehead et al., 2019) , and Glychirrhiza spp. (Fiore et al., 2008) .

For instance, I. indigotica root extract showed significant anti-SARS-CoV activity via inhibitory effects on 3C-like proteases (3CLpro) in the virus . Similarly, in another study, aqueous extract of H. chordata showed inhibition of RNA-dependent RNA polymerase (RdRp) and 3CLpro activity in SARS-CoV (Lau et al., 2008) . It was also revealed through flow cytometry-based analysis that extracts of H. chordata boosted immune response against SARS-CoV through increasing the proportion of cluster of differentiation (CD4 + and CD8 + ) T cells. Similarly, root extract of P. sidoides has been shown to interfere with replication of human coronaviruses (Whitehead et al., 2019) . Currently, there are numerous studies available on plant-based compounds from limited number of plants against coronaviruses. Plants used in the form of extracts or any other form against different respiratory viruses could be employed to work against COVID-19. One area that bears enormous potential exploring these and many other such plants which are used against viruses having similar structural features as that of COVID-19, exhibiting the same pattern of infection, similar pathophysiology, and similar symptoms. This can be demonstrated by a detailed analysis of replication cycle of the COVID-19 (Fig. 1) . For example, those plant products used against viruses belonging to the same origin as COVID-19 (Cyprus_Mail, 2020) , or those having genome of similar orientation (i.e. positive stranded RNA viruses (Ogbole et al., 2018) could be employed for fighting against COVID-19.

The diverse medicinal capabilities of plants lie in the complexities of their secondary metabolism. Although it is very easy to apply herbal medicine as a whole plant crude extract, decoction, tea, the efficacy of plant-based chemical compounds can be realized only if they are applied in their pure forms or in a mixture to form a compound drug. There are innumerable chemical compounds isolated from plants which are the potent antiviral drug (Denaro et al., 2020) . This study reviewed a diversity of polyphenolic compounds isolated from different plants for their antiviral activity. As indicated in Table 3 , studies have shown the efficacy of hundreds of different compounds against human viruses for their direct anti-viral activity or alleviation of symptoms (Amber et al., 2017a; Li and Peng 2013) . For instance, important compounds such as natural mixture of polyphenols from almond that include catechin, naringenin-7-O-glucoside, kaempferol-3-O-glucoside, epicatechin, isorhamnetin-3-O-rutinoside, and isorhamnetin-3-O-glucoside has been shown to reduce the HSV DNA accumulation and cytopathic effects by the virus (Musarra-Pizzo et al., 2019). Similarly, Pentagalloylglucose isolated from Phyllanthus emblica has been shown to inhibit HSV-induced rearrangements of actin cytoskeleton (Pei et al., 2011) . It has been observed that generally, phytochemicals acts by interference with viral entry via attachment to viral proteins (Kesharwani et al., 2017) , inhibits viral replication (Langland et al., 2018; Li et al., 2005a) , stops transcription (Yarmolinsky et al., 2012) , and expression of viral proteins (Kuo et al., 2006) .

Among the many compounds, there are many of them used against respiratory viruses. For instance, theaflavin has been shown to inhibit hemagglutinin and neuraminidase in H1N1 influenza virus, curcumin disrupts the envelop of H1N1 and H9N2 influenza viruses (Bahramsoltani et al., 2016) and glycyuralin F interferes with viral infection (Ji et al., 2016) . Similarly, apigenin, linalool and Ursolic acid isolated as pure constituents from Ocimum basilicum have showed anti-viral effects in bronchitis caused by human adenoviruses . Furthermore, other studies have also found activity of many different compounds against other respiratory viruses such as RSV and coronaviruses. Carnosic acid found in Rosmarinus officinalis has been found to be highly anti-hRSV-specific compound. The study showed that carnosic acid inhibited both A-and B-type hRSV, while it did not affect the replication of influenza A virus and thus could be used as a more specific treatment for hRSV (Shin et al., 2013) . Focusing on the scope of the current review and to have a deep insight into herbal medicine against coronaviruses, we will now highlight the phytochemicals that are previously employed against coronaviruses and thus bears potential against COVID-19. 

The pandemic caused by COVID-19 warrants search for safe antiviral compounds to treat the disease. At present, no specific treatment has been identified for COVID-19. The novelty of COVID-19 means that its behavior is very uncertain and, therefore, it is difficult to determine the efficacy of herbal products against the virus or as prophylactic agents. However, as the current COVID-19 viruses bears resemblance to the previous outbreak causing SARS-CoV and MERS-CoV, so the herbal compounds employed against the previous coronaviruses may prove as valuable drug candidates if researched properly. There are hundreds of different herbal products tested against the coronaviruses. Most of these products have their selectivity indexes up to 100 which hints towards their safety (De Clercq 2006) . Selectivity index (SI) (CC 50 /EC 50 ) is the measure of effectiveness of drugs. Higher SI values mean that the drug tested is theoretically more effective and safer during in vivo experiments.

For instance, after the first outbreak of SARS-CoV, reported that Glycyrrhizin, a saponin from Liquorice roots, can inhibit the replication of SARS-associated coronavirus with EC 50 value ranging from 300 to 600 mg/L (during and after virus adsorption, respectively). The CC 50 was recorded to be higher than 20,000 mg/L. This means that at a dose of 20,000 mg/L, there was only 20-30% reduction of cell viability recorded thus indicating the low cytotoxicity of the compound. It was demonstrated that glycyrrhizin given to infected cells at 4000 mg/L, completely blocked replication of the virus (Fig. 2) . The study also indicated that Glycyrrhizin is a safer alternative to other antiviral compounds such as Ribavirin which is usually responsible for hemolysis and a drastic reduction of haemoglobin in SARS patients (Cinatl et al., 2003b) . Although there are certain side effects to using untested herbal products and every product should be properly tested, phytochemicals are usually intrinsically safe based on their biocompatibility, lesser toxicity than xenobiotics and environment-friendliness. At the time of SARS outbreak in 2002, the mechanism of action of phytochemicals like Glycyrrhizin wasn't exactly clear. Further studies on Glycyrrhizin attempted to decipher the mechanism of action and produce a more potent form of the phytochemical against coronaviruses. Hoever et al. (2005) showed that addition of 2-acetamido-β-D-glucopyranosylamine into the glycoside chain of glycyrrhizin results in a 10-fold increase in its activity against the virus. The spike proteins (S-proteins) of coronaviruses are heavily glycosylated. This study showed that the addition of glycyrrhizin (with the added 2-acetamido-β-D-glucopyranosylamine) blocks the entry of the virus into the cells. Glycyrrhizin has also been shown to disappear from the blood plasma of treated subjects after oral administration of 100 mg glycyrrhizin. This might be because it is metabolized to glycyrrhetinic acid by intestinal bacteria which contain β-D-glucuronidase .

Coronaviruses acts against the host immune system through its proteases; papain like protease (PLpro) and 3CLpro. The PLpro of SARS-CoV antagonize the innate immune response. The host's immune response first recognizes viral RNA and then recruits adaptor mitochondrial antiviral-signaling proteins to transduce signals to the downstream kinase complex for activation of transcription factor, NF-κB and IRF-3. Next, these transcription factors induce the expression of type I interferons (IFN-α and -β). Type I IFN induces the activation of STAT transcription factors resulting in the expression of IFN-stimulated genes (ISGs), which establishes an antiviral state in surrounding cells. SARS-CoV PLpro acts either via deISGylating or deubiquitinating proteins or both within these pathways. This results in antagonism of the host antiviral response and thus successful evasion of immune response by the SARS-CoV (Báez-Santos et al., 2015) . This means that candidate drugs could be helpful if they either inhibit viral entry, replication or provoke immune response to produce Type I IFN against SARS-CoV. It became clear through many studies after the first outbreak of SARS-CoV, that plant extracts and plant-derived compounds act against viruses in different mechanisms. These range from direct antiviral activity, immune stimulator, analgesic, inflammation modulator, and symptom management. The direct antiviral activity encompasses inhibition of early replication via viral entry inhibition (Cheng et al., 2006a) , and late replication inhibition (Kim et al., 2011) (Fig. 3) (Fig. 4) .

Viral entry inhibition by plant derived compounds is another promising area of finding the suitable drug candidate. Coronaviruses enter the cell after binding to the host cell receptor angiotensinconverting enzyme 2 (ACE2). This entry is made possible through the attachment of SARS-CoV spike (S) protein to ACE2. Many different phytochemicals have shown a strong inhibition of the interaction of SARS-CoV S protein and ACE2. For example, anthraquinone compounds; emodin, and rhein, and a flavonoid; chrysin, derived from genus Rheum and Polygonum were tested for their activity against SARS-CoV. The study found that emodin showed the strongest effect and significantly blocked the S protein and ACE2 interaction with IC 50 value of 200 μM (Ho et al., 2007) .

Flavonoids and polyphenolic compounds like luteolin, quercetin and etra-O-galloylβ-D-glucose have been shown to significantly block the entry of SARS-CoV into the cells. Yi et al. (2004) studied the effects of these small molecules on the entry of SARS-CoV. All three molecules (luteolin, quercetin and etra-O-galloylβ-D-glucose) showed promising results with EC 50 of 83.4 μM, 10.6 μM and 4.5 μM, respectively. Assays based on a human immunodeficiency virus (HIV)-luc/SARS pseudo-typed virus were used for experiments on viral entry inhibition. The results confirmed that along with luteolin, and etra-O-galloylβ-D-glucose, quercetin also had activity against HIV-luc/SARS with a lower cytotoxicity of quercetin. Therefore, as an FDA-approved drug ingredient, quercetin can be applied as a potential drug in the clinical treatment of COVID-19.

Furthermore, fractionation and purification of L. radiata extract resulted in isolation of an alkaloid, lycorine which was assessed as an anti-SARS-CoV component. The compound with an EC 50 value of 15.7 ± 1.2 nM and CC 50 value of 14980.0 ± 912.0 nM in cytotoxicity assay. Lycorine was found to inhibit viral replication at a concentration that is lower than that of glycyrrhizin. The results suggested that the phytochemical compound lycorine is a promising candidate for the development of new anti-SARS-CoV drugs in the treatment of SARS (Li et al., 2005c) .

The replication of SARS-CoV is usually inhibited by interfering with the functions of the main viral proteinase (Mpro, or 3CLpro). The 3CLpro regulates the activities of the coronavirus replication complex and has thus been one of the main targets in finding a drug against the coronaviruses (Anand et al., 2003) . Apart from these, replication of SARS-CoV has also been inhibited by Reserpine, an alkaloid isolated from the dried root of Rauvolfia serpentina (Indian snakeroot) and Aescin, a saponin from Aesculus hippocastanum (European chestnut tree).

The EC 50 values for Reserpine and were found to be 3.4 μM and 6.0 μM while the and CC 50 values were 25 μM and 15 μM, respectively. Different assays such as enzyme linked immunosorbent assay (ELISA), Western blot analysis, immunofluorescence and flow cytometry assays confirmed Table 3 Medicinal plant metabolites with known mechanism of action against SARS-CoV infection.

No.

Mode of action References the anti-SARS-CoV activity of these compounds. Reserpine and Aescin have been shown to interfere with the viral entry to the cell and also inhibit the activity of 3CLpro enzyme of the virus inside the cell (Wu et al., 2004) . Plant lectins have also been showed to potently block the entry of SARS-CoV into the cells. Keyaerts et al. (2007) showed that lectins isolated from many different plants showed a promising anti-SARS-CoV activity with EC 50 ranging from 0.45 to >100 μg/mL and CC 50 value ranging from 50 to 100 μg/mL. Among all of them, the highest anti-coronavirus activity through cytopathic effects was reported among mannose-binding lectins isolated from Allium porrum with a selectivity index of >222. The study revealed that apart from interference with viral replication during the viral life cycle, the lectins seemed to inhibit viral entry to the cell.

Flavonoids have also been shown to possess a considerable activity against the coronaviruses. Ryu et al. (2010) reported that flavonoids such as apigenin, luteolin, and quercetin purified from ethanolic leaf extracts of Torreya nucifera, an Asian traditional medicinal plant also showed significant SARS-CoV 3CLpro inhibiting activity. The IC 50 values of the 3CLpro inhibitors (apigenin, luteolin, and quercetin) were recorded to be 280.8, 20.2, and 23.8 μM, respectively. The results of these of these enzymatic studies were confirmed through binding energy T. Khan et al. studies via molecular docking. Furthermore, among these compounds, a carbon moiety of apigenin showed stronger activity compared to other flavonoids.

Similarly, terpenoids were also found to be effective in blocking viral replication. Ferruginol, pinusolidic acid, and α-cadinol were purified from ethyl acetate extracts of Chamaecyparis obtuse, along with cedrane-3β,12-diol, and betulonic acid, isolated from Juniperus formosana and cryptojaponol isolated from Cryptomeria japonica. The study indicated that most of the terpenoids inhibited the replication of SARS-CoV at EC 50 between 3.8 and 7.5 μM and an CC 50 value greater than 250 μM. It was confirmed through ELISA that the terpenoids block the S proteins of the virus to induce replication inhibition activity. The study also confirmed a strong anti-3CLpro activity through docking studies and concluded that, in their pure form, terpenoids could be beneficial as drug candidates against SARS-CoV (Wen et al., 2007) . Apart from the viral replication inhibition and anti-3CLpro activity, plant-based compounds have proved effective in blocking the activity of important enzymes such as SARS helicase. Yu et al. (2012) studied the inhibitory effects of 64 purified natural compounds against the activity of SARS helicases. Among these flavonoids, myricetin and scutellarein, isolated from Aglaia perviridis showed significant anti-SARS-CoV activity. Studies on fluorescence resonance energy transfer (FRET)-based double-strand DNA unwinding assay and colorimetry-based ATP hydrolysis assay confirmed that flavonoids such as scutellarein and myricetin potently inhibit the SARS-CoV helicase protein in vitro by affecting the ATPase activity. Based on their lower IC 50 values, 2.71 ± 0.19 μM and 0.86 ± 0.48 μM, respectively, and no cytotoxicity against breast cancer cell lines, myricetin and scutellarein could thus prove as SARS-CoV chemical inhibitors.

Phytochemicals can also play a role in other aspects of the SARS-CoV infection. For instance, Schwarz et al. (2011) showed that, emodin, the anthraquinone from family Polygonaceae can inhibit the 3a ion channel of coronavirus and thus inhibit the release of SARS-CoV form infected cells (Fig. 3) . Apart from this, phytochemicals can be effective in the immune modulation against coronaviruses (Lau et al., 2008) and can also act analgesics, and symptom management such as reduction of hypoxemia and dyspnea management. These studies suggest that phytochemicals can be employed against SARS-CoV-2, for their diverse roles and potency against other coronaviruses such as SARS-CoV.

The research related to bringing plant-based drugs from bench to boardroom is lagging behind synthetic drugs despite the fact that phytomedicine have an enormous potential in treatment an array of ailments. The lag is especially prominent when it comes to comparing the rapidity of its availability to synthetic drugs. This is one of the most important reasons that put medicinal plants biotechnology research on a priority list. This has created a plethora of information regarding medicinal plants and their utility against different disease-causing agents. The information available are scattered throughout different databases and web sources (Gu and Chen 2014) . For this purpose, a counter approach is sought through the use of computational tools. Bioinformatic tools play an important role in analyzing the available data and thus choosing the best drug candidates aided with the wet lab research. Furthermore, Computational approaches offer their value in terms of deciphering genetic pathways that are associated with the production of antiviral secondary metabolites from medicinal plants (Sharma and Sarkar, 2013 . Several databases have been developed to provide catalogue information related to scientific publications in general including the National Center for Biotechnology Information (NCBI), and Kyoto Encyclopedia of Genes and Genomes (KEGG).

Similarly, databases like the Arabidopsis information resources (TAIR), Medicinal Plant Database for Drug Designing (MPD3), and the International Ethnobotany Database (ebDB) provide more specific and useful information about medicinal plants and their metabolic pathways. The later of these is a noncommercial repository for ethnobotanical research providing complete location information, strong searching and data export features (http://ebdb.org). Similarly, MPD3 is a free database that provides information about phytochemicals including their structure and potential activities through reference to original research papers. These databases have already helped researchers to evaluate the potential of phytochemicals/traditional Chinese medicinal compounds against protiens and enzymes of the novel SARS-CoV-2. For instance (ul Qamar et al., 2020) , assessed the activity of phytochemicals from a medicinal plant library containing 32,297 potential anti-viral phytochemicals/traditional Chinese medicinal compounds against the viral 3-chymotrypsin-like cysteine protease (3CLpro). Their analyses concluded at least nine hits for a potential class of drugs among the phytochemicals against the SARS-CoV-2. Similarly, molecular docking studies of stilbenoids against SARS-CoV-2 spike proteins have shown that stilbene based compounds (especially resveratrol) and flavonoids such as quercetin, fisetin, and kaemferol can be promising anti--SARS-CoV-2 drug candidates acting through disruption of the spike protein (Wahedi et al., 2020 ) (Pandey et al., 2020 . Apart from stilbenoids and flavanoids studied for their in silico molecular dynamics, amongst the phytochemicals studied, essential oils have also been shown to possess potent acitivity against SARS-CoV-2. For instance, Abdelli et al. (2020) concluded that natural compounds (Isothymol, Limonene, P-cymene, Thymol and γ-terpinene) can block the activity of angiotensin converting enzyme 2 (ACE2) as a receptor for SARS-CoV-2 that is hampering the attachment of the virus to the cell surface.

This paper highlights the importance of phytotherapeutic agents as candidates in search for drugs against COVID-19. Based on the novelty of the virus and the disease caused, safety concerns still loom over the use of phytomedicine. Therefore, safety aspects must be taken into consideration. Insufficient data exist for most of the plants to guarantee their quality, efficacy and safety. Untested use of pure compounds is not recommended, and these compounds should first go through the proper efficacy and safety testing. The Food and Drug Administration (FDA) for example provides guidelines for safe use of natural products as drugs (FDA 2006) . Similarly, the European Medicines Agency (EMA), asserts that herbal medicinal products should only be used traditionally if they have been used for at least 30 years, including at least 15 years within the European Union and are not administered by injection. Furthermore, marketing and well established use should only be authorized after scientific literature is available that confirms that the pure constituent/active ingredient of the herbal product has a recognized efficacy (Calapai 2008; EMA 2001) . However, there is a wrong perception, that herbal drugs are fully safe and free from any side effects. There are hundreds of toxic constituents in different plants. Compared to synthetic compounds, natural products and plant-based compounds have shown lesser toxicity and thus requires less stringent evaluation. However, to avoid the side effects of the unregulated use of these plant-based compounds, safety regulation on the use of the products is important (Calixto 2000) . It is, suggested that while bringing harmony with other agencies, regulatory authorities should work for regulating herbal products and using them as drug candidates for treating COVID-19.

Medicinal plants can provide a very plausible platform for the search for drug candidates to be tested against COVID-19. The secondary metabolism of many plants serves as a treasure of phytochemicals, which have shown promising results against human viruses. More specifically, phytochemicals serve as phytotherapeutic agents against the coronaviruses especially SARS coronaviruses. Phytochemicals are advantageous in their timeliness, the sense that they are biocompatible and less toxic to synthetic drugs. Based on studies of phytomedicine against the previous SARS-CoV, the most potent phytochemicals could be filtered and put to test against COVID-19. Similarly, while trials are underway for testing vaccines, traditional herbal medicine in the form of decoctions, tea or powder could be tested (based on enough evidence of efficacy) for the alleviation of symptoms.

Khan MA conceived the idea, Khan T and Khan MA wrote the whole manuscript, Mashwani Z curated the tabulated data, Nadhman A made the animated figures and Ullah N reviewed the article and fixed the language mistakes.

The authors declare that there is no conflict of interest regarding the publication of this paper.

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