key: cord-0913944-szpk69v8
authors: Patel, Bhoomika; Sharma, Supriya; Nair, Nisha; Majeed, Jaseela; Goyal, Ramesh K.; Dhobi, Mahaveer
title: Therapeutic opportunities of edible antiviral plants for COVID-19
date: 2021-02-15
journal: Mol Cell Biochem
DOI: 10.1007/s11010-021-04084-7
sha: 17464e988c916def61a6082f16c279683df4975f
doc_id: 913944
cord_uid: szpk69v8

The pandemic of Serious Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2) that produces corona virus disease (COVID-19) has challenged the entire mankind by rapidly spreading globally in 210 countries affecting over 25 million people and about 1 million deaths worldwide. It continues to spread, afflicting the health system globally. So far there is no remedy for the ailment and the available antiviral regimens have been unsatisfactory for the clinical outcomes and the mode of treatment has been mainly supportive for the prevention of COVID-19-induced morbidity and mortality. From the time immortal the traditional plant-based ethno-medicines have provided the leads for the treatment of infectious diseases. Phytopharmaceuticals have provided potential and less toxic antiviral drugs as compared to conventional modern therapeutics which are associated with severe toxicities. The ethnopharmacological knowledge about plants has provided food supplements and nutraceuticals as a promise for prevention and treatment of the current pandemic. In this review article, we have attempted to comprehend the information about the edible medicinal plant materials with potential antiviral activity specifically against RNA virus which additionally possess property to improve immunity along with external and internal respiration and exhibit anti-inflammatory properties for the prevention and treatment of the disease. This will open an arena for the development of novel nutraceutical herbal formulations as an alternative therapy that can be used for the prevention and treatment of COVID-19.

In Wuhan, China in December 2019, a newly emergent novel coronavirus SARS-CoV-2 was reported to cause severe acute respiratory tract infections, coronavirus disease 2019 (COVID-19) [1] . After the first case of corona reported from Wuhan, there has been an unprecedented outbreak of COVID-19. As of the last week of August 2020, over 25 million cases of this disease have been reported from 210 countries with 3.32% deaths [2, 3] . The United Nations called the pandemics of COVID-19 as the worst global humanitarian crisis since World War II. Countries all over the world are taking aggressive steps and adopting all possible preventive measures to combat the spread of this disease. The disease is associated with high mortality risk (2-8% in different countries), a very high transmission rate combined with the lack of WHO or FDA approved specific prophylactic vaccines or therapeutic protocols for the effective prevention, treatment or management of the disease. A typical viral disease mechanism involves the entry of virus into the host via specific receptor, followed by uncoating, transcription and genome synthesis finally forming viral assembly and releasing of multiple copies in the host. The antiviral drugs are designed to act on such varied targets (Fig. 1) .

The current treatment appears to be mainly supportive in nature [4, 5] . From time immemorial, herbal medicine has provided remedies for majority of the diseases, for e.g., digitalis and reserpine for cardiac patients, artemisinin and quinine for malaria, vincristine and vinblastine for cancer. Some potential drug candidates including blockbuster antivirals like Remdesivir, Hydroxychloroquine, Lopinavir, Ritonavir, APN01 or Favipiravir are being tested for clinical trials across the globe. Still no therapy has been found to be effective or devoid of deleterious effects against COVID-19 as of now [6] [7] [8] . Keeping in view the shortcomings associated with available antiviral drugs therapies, i.e. viral resistance coupled with the problem of viral latency and conflicting efficacy in recurrent infection in immunocompromised patients, there is an increasing need for search of new compounds and therapy with antiviral activity that are highly efficacious and cost-effective for the management and control of viral infections. Moreover, the viral infections caused by Coronaviruses, Human immunodeficiency virus, Ebola virus, Nipah virus, Influenza virus, Enterovirus, Swine flu, Bird flu, Zika Virus, Hepatitis B and C, etc. have risen significantly and natural products play a vital role in the cure for some with no or less harmful effects [9, 10]. Novel bioactive phytomolecules bearing credible therapeutic potential against such viral diseases is the prime focus of the current medical research in order to gain an upper edge over such widespread infections and prevent the future ones [11, 12] . Identification of the antiviral mechanisms from these natural agents has shed light for further research targeting virus-host-specific interactions.

Indian subcontinent has been recognized as a treasure home for various plant species due to its varied agro-climatic zones and suitable topographical conditions and is placed among the list of top 12 mega diversity countries of the world. The Indian subcontinent is endowed with rich and diverse flora about which the ethnobotanical literature describes use as plant extracts, infusions and powders for diseases of infectious nature [13] . These medicinal herbs provide a wide approach in managing several diseases, including viral respiratory infections by modulating immune system and inflammatory responses. AYUSH system of medicine has provided a basic approach on prevention of infection through dietary modification, lifestyle management, Fig. 1 Typical viral disease mechanism and various targets for antiviral drugs remedies to boost immune system and preventive interventions based on the symptom [14] . Around 65-80% of the world population residing in developing countries utilizes traditional herbs in their primary health treatment. Additionally, the interest in the study of herbs have aroused due to their phytoactive/phytotherapeutic agents which can be utilized in the form of nutraceuticals, which possess druglike actions, and in some cases can be traced directly through the existing links between a local and biomedical use [15] . The lack of preventive and curative treatment of COVID-19 till date compels the researchers to look onto therapeutic alternatives that can be added in our daily diets in order to both prevent and cure such life-threatening infections and provide long-term protection. For centuries, numerous plants have been used in daily diets which serve as folk remedies by supporting the body system in one way or the other [16] .

This review aims to bring focus on the detailed information about herbal flora with antiviral activities that can be explored for development of novel nutraceutical herbal formulations. Advancement in separation technologies, adoption of modern drug discovery and the development of vector-based strategies for antiviral screening purposes offers a promise for edible medicinal plants usage in daily diet, and may serve as an alternative therapy for treatment of this pandemic and prevention of another one. The article also aimed to merge the ethnopharmacological knowledge with the modern technologies to devise drug targets for the SARS-COV-2 virus and identification of potential candidates from natural sources which may offer some preventive or even therapeutic value.

For a better insight on how nutraceuticals or phytomolecules can effectively work against novel coronaviruses, it is imperative to understand the structural characteristics and culpable targets and receptors associated with it. Moreover, understanding the mechanism of action of conventional antivirals and liable targets for drug designing may be useful for development of therapy regimen for COVID-19 from natural sources. SARS-CoV-2 like other HCoVs is positive-sense single-stranded RNA viruses with two groups of protein forming its characteristic markers: structural protein, such as Spike (S), Nucleocapsid (N), Matrix (M), Envelope (E); and non-structural proteins such as nsp12-RNA-dependent RNA polymerase (RdRp), Nsp3-Papain-like proteinases, Nsp5-3C-like main protease and nsP13 SARS-CoV helicase [17, 18] . Primarily, nsP13 helicase, 3CL protease, nsp12-RNAdependent RNA polymerase (RdRp) become primary target for drug development. Apart from these proteins, the viral spike glycoprotein (S) initial attachment and internalization within host cells ACE-2 receptor can also be targeted to prevent viral entry into newer host cells [19] . SARS-CoV-2 recognizes human angiotensin-converting-enzyme-2 (ACE-2), thereby proving its essentiality for host cell entry by invasion of alveolar epithelial cells, subsequent viral replication and primary host lung cells infection as ACE-2 is highly expressed in the heart, lungs, intestine, kidney and blood vessels [20] . The expression of ACE-2 is substantially increased in patients with diabetes and hypertension and the connecting link to this associated comorbidity has been the angiotensin-converting-enzyme-2 (ACE-2) receptor as it is the site of virus multiplication, and thus a strategy has been devised to develop antiviral newer drugs considering the ACE-2 as an attractive target [21] . Various plants produce phytomolecules that can be utilized in targeting these viral targets and so has been done previously in case of other viral diseases like SARS, HIV, HCV, etc. [22] [23] [24] .

At the molecular level, the virus SARS-CoV-2 binds to the angiotensin-converting-enzyme-2 (ACE-2) present in the lungs of the human host. Binding of the virus to the host cells through its trimeric spike glycoprotein makes this protein a key target for potential therapies and diagnostics. It was reported that in SARS-CoV-2, the S2 subunit in each spike monomer contains a fusion peptide, a transmembrane domain, and cytoplasmic domain which is highly conserved and could be a possible target for antiviral (anti-S2) compounds [25] . There occurs multiplication of the viruses that induces cellular responses. There occurs infiltration of huge number of inflammatory cells which comprise innate immune cells and adaptive immune cells [26, 27] . Neutrophils are majorly the innate immune cells which produce injury to lungs [28] . On the other hand, the adaptive immune cells are majorly the T cells viz. cytotoxic CD8+ T cells which not just kill virus but again contribute injury to lungs [29] . This accelerates the progression of systemic inflammatory response, leading to extensive increase in various cytokines like TNFα, IL1, IL6, IL10, etc. This is termed as the cytokine surge. Due to increase in various cytokines, there occurs inflammation and apoptosis of Type-1 and Type-2 cells in the alveoli. This interrupts the functions of oxygen transport resulting in cell death in alveoli of the lungs and causing Acute Respiratory Distress or syndrome (ARDS) [30] . Figure 2 depicts the pathogenesis of disease leading to cytokine storm and multiple organ dysfunction and ultimately death.

Among the proposed mechanisms of pulmonary injury caused by SARS-CoV-2, there is a "cytokine storm" triggered by an imbalanced response by type-1 and type-2 T helper (Th) cells leading to an uncontrolled and generalized inflammatory response [31] . Increased pro-inflammatory cytokines (Interferon γ, interleukin (IL-) 1β, IL-6, IL-12) and chemokines (CXCL10 and CCL2) circulating in the body are associated with pulmonary inflammation and ARDS pathogenesis due to inflammatory injury to the alveolar-capillary membrane, resulting in increased lung permeability and the exudation of protein-rich pulmonary edema fluid into the airspaces culminating into respiratory insufficiency and the main causes of complications leading to multi-organ failure [32] . Antiviral plants with added antiinflammatory properties protecting the lung against infections can be investigated, for that matter, to have a synergetic therapy.

Weak immune mechanisms coupled with cytokine surge is one of the major causes that finally leads to decreased cellular oxygenation at the level of alveoli, has been reported to be the main cause of death in COVD-19. Apart from this respiratory damage there occurs thrombotic events involving open reading frames (ORFs) especially the ORF8 proteins which upon binding with SARS-COV2 leading to dissociation of iron from the1-beta chain of hemoglobin getting attached to the surface glycoprotein porphyrin and thereby resulting in failure of internal respiration [33] .

SARS-CoV2 has a longer incubation period of 2-14 days on an average inside the human body, probably due to their immune evasion properties, efficiently escaping host immune detection at the early stage of infection [34] . Herbal preparations that possess immunomodulatory activity may serve as prophylactic treatment, if added in daily diet, for prevention of infection acquisition during this spell of critical community level spread and help contain the disease in community as well as help faster healing post infection. Considering the above strategies for treatment, management and prevention of COVID-19, a search for potential plants with above properties can help to devise natural plant-derived antiviral agents against the pandemic disease.

The secondary metabolites obtained from herbal drugs can also be utilized as nutraceuticals and can become a lead compound in the treatment therapy [35] . Studies have also shown promising results of nutraceuticals and phytomolecules in various pathological complications such as diabetes, atherosclerosis, cardiovascular diseases (CVDs), cancer and neurological disorders [14] . Since ages, herbs of Indian origin have been implemented in treatment and as preventive strategies for several diseases that include respiratory viral infections as the benefit of usage of these herbs against viral respiratory infections lies in immune stimulation and inflammation modulating effects. The AYUSH systems of medicine also promotes prevention of COVID-19 through lifestyle modification as well as dietary management and prophylactic interventions for improving the immunity [31]. All these have led to a revival of interest in herbal medicines, novel nutraceuticals and herbal formulations with antiviral potency based on any of the potential plants. Looking into the results of previously deciphered phytochemical-directed researches, a wide variety of phytomolecules present in Indian forest biodiversity can point towards their capability to be manipulated into devising antiviral drugs for SARS-CoV-2. Table 1 provides detailed information on edible plants used as food or nutraceutical showing antiviral activity against RNA viruses, their potential to be explored against COVID-19 on the basis of antiviral activity against various RNA viruses, their active phytoconstituents bearing potential anti-coronaviral activity and mechanism of action.

It has been reported that flavonoids can bind to the functional domains of the SARS-CoV-2S protein, a viral surface glycoprotein required for initial attachment and internalization within host cells. Emodin from plants of family polygonaceae can block the interaction with the SARScoronavirus spike protein by inhibiting the 3a ion channel of SARS-CoV and HCoV-OC43 [36]. Lectins, the natural proteins, also target the sugar moieties of a SARS-CoV spike protein. In time-of-addition assay conducted to understand mechanism of antiviral action, glucose-, galactose-, N-acetyl glucosamine-and N-acetyl galactosamine binding lectins and most importantly mannose binding lectin indicated their interference with virus attachment to spike protein making them early entry inhibitors. Lectins also carry prophylactic potentials as it agglutinates viral particles by binding to it, thereby not allowing it to bind to human cell receptors and complete its pathogenic cycle [37] . As SARS-CoV-2 also uses host receptor ACE-2 for the cellular entrance similar to SARS-CoV [38], medicinal herbs with the capacity to target ACE-2 therefore holds a promising effect in the prevention and infection of SARS- 

Studies on edible plants, such as Glycyrrhiza glabra [42], Allium sativum [43] , showed the inhibition of viral replication of SARS-CoV that can be further utilized as leads against SARS-CoV-2, due to similar homology between SARS-CoV and SARS-CoV-2 [44] . Edible antiviral plants like Aloe vera [45] , Gingko [46] , Olea europaea [47] , Cicer arietinum [48] , Nigella sativa [49] , Agrimonia Pilosa [50], Commelina communis [51] , Mangifera indica [52] , Syzygium cumini [53] that showed effects against influenza virus Spice [100] SARS-CoV [67] Whole plant ethanol extract [66] Mechanism not clear 9

A.

Juss./Meliaceae Neem, Indian-lilac Azadirachtin [101] Nutraceutical [101] Group B Coxsackieviruses [72] Methanolic leaf extract/ Flavonoids, triterpenes [72] Inhibits viral replication [72] 10 Spice [111] Respiratory syncytial virus [110] Curcumin [110] Inhibit viral replication [110] 15 Nutraceutical [113] Influenza A virus (H1N1) [59] Ethyl acetate fruit extract/Embelin [59] Inhibits viral replication [59] 17

Lam./Myrtaceae Jamun, Jambul Delphinidin, petunidin [114] Food [114] Influenza virus (H5N1) [115] Methanolic, hydromethanolic and aqueous leaf extract; aqueous bark extract [115] Interferes with viral envelop that are necessary for adsorption or entry into host cells [115] 18

L./Ginkgoaceae Maidenhair-tree,

Ginkgetin [46] Nutraceutical [116] Influenza virus [46] Ginkgetin [46] Inhibition of viral sialidase activity [46] 19 Food [120] H5N1 highly pathogenic avian influenza virus [121] Aqueous tea extract [121] Inhibited viral replication and viral antigens and genes expression [121] 22

Leucas aspera

Link/Lamiaceae Tumba, Chota halkusa Asperphenamate, sitosterol [122] Food [122] Anti-mouse coronaviral activity (a surrogate of SARS-CoV) [66] Aerial parts methanol extract [66] Mechanism not clear Food [125] Human immunodeficiency virus [126] MAP30 protein [126] Inhibit various stages of viral life cycle [126] 25 Spice [132] H9N2 avian influenza virus [49] Dried seeds/Thymoquinone [49] Inhibit viral replication [49] 28 Ocimum sanctum

Eugenol, linolenic acid [133] Herbal tea [133] Human immunodeficiency virus [57] Aerial parts methanolic extract/Flavonoids [57] Inhibit protease enzyme [57] 29 Food [137] Human immunodeficiency virus [138] Methanolic fruit extract [138] Inhibits HIV reverse transcriptase [138] 32 Food [142] Hepatitis C virus [65] Chloroform and methanol seed extract [65] Inhibits NS3 protease [65] 34 Syzygium cumini (L.) Skeels/Myrtaceae Jaman, Jambolan Ellagic acid, gallic acid [143] Food [143] Avian influenza virus (H5N1) [53] Aqueous leaf extract, aqueous bark extract [53] Interfere with viral envelop or mask viral structures which are necessary for adsorption or entry into host cells [53] can be studied rigorously to investigate any relatable target between SARS-CoV-2 and influenza virus.

Myricetin and scutellarein can act as novel chemical inhibitors of the SARS coronavirus helicase, nsP13 [54] . Flavonoids isolated from medicinal plants have been reported to show antiviral activity. Quercetin, epigallocatechin gallate and gallocatechin gallate showed inhibitory activity against 3CLpro of SARS-CoV [55] . Plants showing inhibitory effects on HIV proteases, such as Eugenia jambolana, Areca nut [56] , can be investigated for their effects on SARS-CoV-2. Similarly, plants like Ocimum sanctum [57] , Phaseolus vulgaris [58] , Phyllanthus emblica [59] having HIV reverse transcriptase activity can also be studied against SARS-CoV-2. Plants like Solanum nigrum [60] have been known to target the reverse transcriptase activity of HIV and can be studied for activity against SARS-CoV-2 as well; betulinic acid, savinin and some plant-based phenolic compounds are competitive inhibitors of SARS-CoV 3CL protease [61] . Azadirachta indica inhibits viral replication in Group B Coxsackieviruses virus and can be investigated for their possible effects against SARS-CoV-2 [62] . Another herb Aegle marmelos inhibited viral replication in human coxsackieviruses B1-B6 infection and can be used in the study against SARS-CoV-2 [62] . Another potential target that can be utilized for the inhibition of CoV replication is proteases [63] . Trachyspermum ammi [64] and Solanum nigrum [65] inhibited viral protease enzymes in hepatitis C virus (HCV) infection. Acalypha indica showed selective anti-VSV activity by protein interaction [64] , and Ocimum sanctum also inhibited HIV protease enzyme [57] ; therefore these plants can be studied against SARS-CoV-2 as they may target protease enzymes.

Sambucus ebulus has been known to inhibit the activity of enveloped viruses and can also be used to target this virus. Though the detailed mechanism remains unclear, Sambucus ebulus is indicated to inhibit the entry of enveloped viruses owing to the presence of lectins that block viral entry. Phenolic compounds like quertin 3-0-glucoside and isorhamnetin present in the plant have previously demonstrated the prophylactic potential against Ebola virus. The flavonoids, diosgenin and yomogenin of Sambucus species also showed viral entry inhibition against Hepatitis C viruses [61] .

A study on Abutilon indicum, Gymnema sylvestre, Leucas aspera showed anti-mouse coronaviral activity which is a surrogate of human SARS virus but its mechanism of action is still unexplored and requires more research in this area [66] . Leucas aspera has been shown to have anti-MCV and Nutraceutical [149] Influenza virus (H1N1) [148] Withaferin A [148] Inhibit neuraminidase, the key enzyme in the life cycle of influenza virus [148] 38

Roscoe./Zingiberaceae Ginger 6-Gingerol, 6-shogaol [150] Nutraceutical [151] , Spice [152] Human respiratory syncytial virus [150] Hot aqueous rhizome extract/Gingerols [150] Inhibits viral attachment and penetration [150] anti-HSV activities, Abutilon indicum extract was found active against influenza virus and Sindbis virus which is a surrogate to Hepatitis B virus. Gymnemic acid from Gymnema sylvestre has virucidal activity against Asian influenza virus, whereas Artemisia annua showed inhibitory effects against SARS-CoV and likely against SARS-CoV-2 but their mechanism of action is still unknown [67] .

As SARS-CoV-2 causes respiratory distress, plants used in human respiratory syncytial virus (HRSV) infection, such as Zingiber officinale [68] , Olea europaea [47] , Terminalia chebula [69] , might act as a preventive treatment in COVID-19. Aqueous rhizome extract of Zingiber officinale contains allicin which acts against HRSV by reducing the plaque formation in respiratory mucosa induced by stimulation of the respiratory mucosal cells to secrete IFN-β. Olea europaea act via multiple antiviral mechanisms: interfering with critical amino acid production essential for viruses, preventing virus assembly at the cell membrane, penetrating infected cells and stopping the viral replication or else primarily by neutralizing the production of reverse transcriptase and protease [47, 68] . On the other hand, Chebulagic acid and chebulinic acid from Terminalia chebula have shown efficacy to inhibit virus attachment and penetration comparable to Acyclovir as well as implement neuraminidase-mediated viral release similar to the antiviral drug oseltamivir [69] . Curcumin (diferuloylmethane), which is found in the spice Curcuma longa, exhibits anti-inflammatory as well as immunomodulatory activity by inhibiting PHA-induced T-cell proliferation, interleukin-2 production, NO generation, and lipopolysaccharide-induced nuclear factor-kappa B (NFkappa B), augments NK cell cytotoxicity as well as inhibits cell proliferation and cytokine production by inhibiting NF-kappa B target genes involved in the induction of these immune parameters [70] .

Medicinal plants such as Hibiscus sabdariffa [71] , Ocimum sanctum [57] , Azadirachta indica [72] . contain flavonoids which can be exploited for the development of the active compounds against COVID-19. Although numerous plants have been studied, a lot of scientific data are required to confirm their effects and hence further research needs to be maneuvered towards this direction. It should be noted that increased inflammatory responses occurs in the patients with COVID-19 which increases the death rate of the patients [73] ; therefore anti-inflammatory herbal drugs like Withania somnifera [74] , Zingiber officinale [68] , Camellia sinensis [75] , Nigella sativa [49] , Moringa oleifera [76] , Agrimonia Pilosa [50], Momordica charantia [77] can be investigated in supportive treatment against COVID-19 and can be incorporated in daily routine diet of patients, which could produce a reduction in the severity and mortality rate of the patients suffering from the disease. A study on herbal formulas also suggested that immunomodulators might show preventive effects against viral infections and likely COVID-19 [78, 79] . Edible herbs and nutraceuticals such as Allium sativum, Zingiber officinale, Glycyrrhiza glabra, Olea europaea, Cicer arietinum, Camellia sinensis can boost immune system, preventing the body from invading viruses [37] . As mentioned earlier, ACE2 is the entry point for the SARS-CoV-2. Considering this, search for the antiviral plants with added ACE2 inhibition property, anti-inflammatory and immunomodulatory activity should be the future line for research. Table 2 provides the details of the antiviral plants that show potential ACE inhibition, anti-inflammatory and/ or immunomodulatory activity.

An epidemic of severe acute respiratory syndrome (SARS) that began in 2002 saw extensive usage and treatment with phytomolecules as auxiliary therapy to conventional medicine. Several anti-SARS formulae were recommended by the Ministry of Health of China to be used along conventional antiviral drugs. The very fact is that SARS-CoV-2 virus shares a striking similarity of 79.5% genetic homology to the SARS-CoV and MERS coronavirus as both are descendants of bat coronaviruses within the beta coronavirus genus [38]; this high genetic similarities between SARS-CoV-2 and SARS or MERS point towards the notion that similar-to-yester-years, administration of auxiliary therapy with plant-based product will prove effective and beneficial against novel coronaviral-generated pandemic too. As a matter of fact, phytomolecules and plant products as well as their analogues are already being employed as an early line of defense against SARS-CoV-2 also. In this section, we have described certain clinical studies for SARS-CoV and SARS-CoV-2 using herbal drugs. Chen et al. (2007) studied and reported that treatment with herbal drugs which consisted of more than different herbal medicines mainly including Anemarrhena asphodeloides Bunge, Atractylodes macrocephala Koidz., Aspidium, Artemisia annua L., Bupleurum chinense DC., Paeonia mascula (L.) Mill., Coptis chinensis Franch., Coptis deltoidea, Coptis teeta Wall., Curcuma, Salvia miltiorrhiza Bunge, Fritillaria was more effective in clearing up the lung infiltrate as well as shortening the time to abatement of a fever in SARS-infected patients than conventional treatment alone. The study also suggests that adjunctive use of medicinal plants and phytomolecules could significantly bring the average daily use of corticosteroids for reducing inflammatory responses as well as in tackling the issue of low counts of CD4 + and CD8 + . The patients who had received integrative medicine in the study showed to recover the lymphocyte cells with marked higher CD4 + counts at the end of study [80] .

In another study by Hsu et al., four of the severely confirmed SARS patients received routine supplementary treatment with combination of herbs: Bupleurum chinense, Gardenia jasminoides, Siler divaricatum, Scutellaria baicalensis, Notopterygium incisium, Schizonepeta tenuifolia, Poria cocos, Paeonia lactiflora Pallas, Paeonia veitchii Lynch, Pinellia ternata, Platycodon grandiflorum and Ophiopogon japonicus showed less morbidity than the patient on western medicine and placebo [81] . While in a controlled clinical study by , the adjuvant treatment with plant-derived pharmaceuticals resulted in marked improvement of symptoms and shortened the disease course [82] , in another study by Cinatl et al. (2003) Acalypha indica L Yes [88] Yes [155] No 3.

Aegle marmelos (L.) Correa Yes [156] Yes [157] No 4

Agrimonia pilosa Ledeb Yes [158] No No 5.

Allium sativum L Yes [159] Yes [160] Yes [161] 6.

Aloe vera (L.) Burm. f Yes [162] Yes [163] No 7.

Areca nut L Yes [97] No Yes [56] 8.

Artemisia annua L Yes [99] Yes [164] No 9.

Azadirachta indica A. Juss Yes [165] Yes [166] Yes [167] 10.

Camellia sinensis (L.) Kuntze Yes [168] Yes [169] Yes [170] 

Cassia occidentalis L Yes [171] Yes [105] Yes [41] 12.

Cicer arietinum L Yes [172] Yes [173] Yes [174] 13.

Commelina communis L Yes [175] No No 14.

Curcuma longa L Yes [176] Yes [177] Yes [178] 

Cynara Scolymus L Yes [179] No Yes [41] 16

Embelia ribes Burm. f Yes [180] Yes [181] Yes [41] 17.

Eugenia jambolana Lam Yes [182] Yes [183] Yes [184] 18.

Gingko biloba L Yes [185] Yes [186] Yes [187] 

Glycyrrhiza glabra L Yes [188] Yes [189] No 20.

Gymnema sylvestre (Retz.) Schult Yes [190] Yes [191] No 21.

Hibiscus sabdariffa L Yes [192] Yes [193] Yes [194] 

Leucas aspera (Wild.) Link Yes [195] Yes [196] No 23.

Mangifera indica L Yes [197] Yes [198] Yes [123] 

Momordica charantia L Yes [77] Yes [199] Yes [200] 

Moringa oleifera Lam Yes [76] Yes [201] Yes [202] 

Myrica esculenta Buch.-Ham. Ex D. Don Yes [203] No Yes [204] 

Nigella sativa L Yes [205] Yes [206] Yes [207] 28.

Ocimum sanctum L Yes [208] Yes [209] Yes [210] 

Olea europaea L Yes [211] Yes [212] Yes [213] 

Phaseolus vulgaris L Yes [214] Yes [78] Yes [215] 

Phyllanthus emblica L Yes [136] Yes [216] No 32.

Punica granatum L Yes [217] Yes [218] Yes [41] 33.

Solanum nigrum L Yes [219] Yes [220] No 34.

Syzygium cumini (L.) Skeels Yes [221] Yes [183] Yes [184] 

Terminalia chebula Retz Yes [144] Yes [222] Yes [223] 

Trachyspermum ammi (L.) Sprague ex Turrill Yes [146] Yes [224] No 37.

Withania somnifera (L.) Dunal Yes [225] Yes [226] Yes [227] 

Zingiber officinale Roscoe Yes [228] Yes [229] Yes [230] Glycyrrhizin, an active constituent in liquorice root, showed potential inhibition of replication of clinical isolates of SARS virus [42] . Chloroquine phosphate extracted from the bark of cinchona trees and hydroxychloroquine are being currently used for treating COVID-19 patients [83] . 

Despite the fact that a number of drug candidates are being tested for clinical trials for COVID-19 across the globe, no therapy has yet been found to be effective. Thus, there is need to look into any alternative solutions. Natural compounds have been used since decades in controlling infectious diseases. Based on previous experiences of coronavirus outbreaks (SARS-CoV in 2002 and MERS CoV in 2012), seasonal epidemics caused by various viruses showing effectiveness of natural products in the treatment of HIV, HCV and Influenza, herbal drugs and their phytoconstituents could be developed as a potential drug candidate against SARS-CoV-2. To be an effective therapy in treatment of COVID-19, the phytoconstituents need to have anti-inflammatory, antioxidants, antiviral activity and effects on cardiovascular targets in lieu of renin-angiotensin system being involved in COVID-19, with ACE-2 as the major target. Such herbal formulations can be used as complementary treatment for prevention of infection acquisition without causing any ill effects, provided the intake is on evidence-based protocols.

In the present review, a total of 38 plant species of Indian flora and biodiversity have been identified that are edible plants. They have potential antiviral activities on the basis of inhibition against various RNA viruses. Many of them contain phytoconstituents that possess the potential anti-coronaviral activity. The clinical spectrum of COVID-19 starts from simple cough, fever, chills, sore throat and headache. The edible nutraceuticals are being used in most countries with the history of complementary ancient medicine system and still being practiced to the extent of over 50%.

To conclude, there are several edible plants available as a source of natural antiviral agents and have a potential to develop as a nutraceutical for the COVID-19. More rigorous scientific research is needed to understand mechanistically their therapeutic value. The nutraceuticals thus developed may serve as adjuvant and complementary treatment to help the population in coping with such maliciously infectious pandemics and thereby protect the global population from current and future pandemics.

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

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The extracts of Solanum nigrum L for inhibitory effects on HIV-1 and its essential enzymes

Scope of natural plant extract to deactivate COVID-19

Aegle marmelos Corr) upon human coxsackieviruses B1-B6

Assessing activity and inhibition of Middle East respiratory syndrome coronavirus papain-like and 3C-like proteases using luciferasebased biosensors

Inhibitory effects of sudanese medicinal plant extracts on hepatitis C virus (HCV) protease

In-vitro antiviral activity of Solanum nigrum against hepatitis C virus

Medicinal plants of Tamil Nadu(Southern India) are a rich source of antiviral activities

Identification of natural compounds with antiviral activities against SARSassociated coronavirus

Fresh ginger (Zingiber officinale) has anti-viral activity against human respiratory syncytial virus in human respiratory tract cell lines

Broad-spectrum antiviral effect of chebulagic acid and punicalagin on respiratory syncytial virus infection in a BALB/c model

Immunomodulatory effects of curcumin

In vivo evidence of the immunomodulatory activity of orally administered Aloe vera gel

In vitro'antiviral activity of neem (Azadirachta indica. A. Juss) leaf extract against group B Coxsackieviruses

Drug treatment options for the 2019-new coronavirus (2019-nCoV)

Sundar D Non-nucleosidic inhibition of Herpes simplex virus DNA polymerase: mechanistic insights into the anti-herpetic mode of action of herbal drug withaferin A

Inhibitory effects of epigallocatechin gallate on the propagation of bovine coronavirus in Madin-Darby bovine kidney cells

Determination of flavonoids by LC/MS and anti-inflammatory activity in Moringa oleifera

Suppressive effects of wild bitter gourd (Momordica charantia Linn. var. abbreviata ser) fruit extracts on inflammatory responses in RAW 2647 macrophages

A hemagglutinin from northeast red beans with immunomodulatory activity and anti-proliferative and apoptosis-inducing activities toward tumor cells

Purification, antitumour and immunomodulatory activity of water-extractable and alkaliextractable polysaccharides from Solanum nigrum L

Effect of integrated traditional Chinese medicine and western medicine on the treatment of severe acute respiratory syndrome: a meta-analysis

The lesson of supplementary treatment with Chinese medicine on severe laboratory-confirmed SARS patients

Can herbal medicine assist against avian flu? Learning from the experience of using supplementary treatment with Chinese medicine on SARS or SARS-like infectious disease in 2003

Chloroquine and hydroxychloroquine as available weapons to fight COVID-19

Office of the National Health and Health Commission Office of the State Administration of Traditional

Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series

Ethnomedicinal uses and phytochemistry of Abutilon indicum (Linn.) Sweet: an overview

Traditional knowledge on wild food plants in Andhra Pradesh

Anti-inflammatory studies on Acalypha indica L. leaves by membrane stabilization

Bioavailability of calcium and its absorption inhibitors in raw and cooked green leafy vegetables commonly consumed in India: an in vitro study

Antiviral and cytotoxic activities of some plants used in Malaysian indigenous medicine

Chapter 20 -Review on the Protective Effects of the Indigenous Indian Medicinal Plant, Bael (Aegle marmelos Correa), in Gastrointestinal Disorders

Plants for human consumption

Nutraceutical use of garlic sulfur-containing compounds

Garlic as food, spice and Medicine: as prospective

Processing, food applications and safety of aloe vera products: a review

Aloe Polysaccharides Inhibit Influenza A Virus Infection-A Promising Natural Anti-flu Drug

Studies on anti-inflammatory and analgesic activities of betel nut in rodents

The phytochemistry, traditional uses and pharmacology of Piper betel linn (Betel Leaf): a pan-asiatic medicinal plant

Anti-inflammatory effect and modulation of cytochrome P450 activities by Artemisia annua tea infusions in human intestinal Caco-2 cells

Ethnobotany of spice and condiment plants and the associated indigenous knowledge on management, utilization and conservation of them in and around home gardens in Loma and Gena Bosa Districts ( Weredas ) of Dawuro Zone, Southern Ethiopia

Nutritional supplements: an overview

Inhibitory effects of (-)-epigallocatechin gallate on the life cycle of human immunodeficiency virus type 1 (HIV-1)

Tea Chemistry

Anti-influenza virus activity of green tea by-products in vitro and efficacy against influenza virus infection in chickens

Immunomodulatory potential of Rhein, an anthraquinone moiety of Cassia occidentalis seeds

Studies on physicochemical and nutritional properties of aerial parts of Cassia occidentalis L

Chickpea leaves as a vegetable green for humans: evaluation of mineral composition

Protective effect of homonojirimycin from Commelina communis (dayflower) on influenza virus infection in mice

Food, feed or medicine: the multiple functions of edible wild plants in Vietnam

Curcumin prevents replication of respiratory syncytial virus and the epithelial responses to it in human nasal epithelial cells

Turmeric, the golden spice: from traditional medicine to modern medicine

Globe artichoke: a functional food and source of nutraceutical ingredients

Endangered Medicinal Plant Embelia ribes Burm. f.: a review

Phytochemistry, traditional uses and pharmacology of Eugenia jambolana Lam. (black plum): a review

Antiviral activity of crude extracts of Eugenia jambolana Lam. against highlypathogenic avian influenza (H5N1) virus

Chapter 319-Ginkgo biloba

Pharmacological perspective of Glycyrrhiza Glabra Linn.: a mini-review

Economic importance of licorice

Herbal formulation of Gymnema sylvestre as a dietary aid

Hibiscus sabdariffa L.: a phytochemical and pharmacological review

High antiviral effects of hibiscus tea extract on the H5 subtypes of low and highly pathogenic avian influenza viruses

Total carotenoid and beta-carotene contents of forest green leafy vegetables consumed by tribals of south India

Phytochemical and in vitro and in vivo biological investigation on the antihypertensive activity of mango leaves (Mangifera indica L.)

Volatile flavour components of mango fruit

The balsam pear-an edible, medicinal and toxic plant

Anti-HIV and anti-tumor activities of recombinant MAP30 from bitter melon

Extracts of Moringa oleifera Lam. showing inhibitory activity against early steps in the infectivity of HIV-1 lentiviral particles in a viral vector-based screening

Assessment of antioxidant properties in fruits of Myrica esculenta: a popular wild edible species in indian Himalayan region

Marketing of indigenous fruits: a source of income among Khasi Women of Meghalaya, North East India

Efficient extraction of black cumin (Nigella sativa L.) seed oil containing thymol, using liquefied dimethyl ether (DME)

Nigella (Nigella sativa): a high value seed spice with immense medicinal potential

Tulsi-Ocimum sanctum: A herb for all reasons

Valuable nutrients and functional bioactives in different parts of olive (Olea europaea L.): a review

Beans (Phaseolus spp.)-model food legumes

Anti-inflammatory activity of extracts from leaves of Phyllanthus emblica

The emblic (Phyllunthus emblica L.)

Human Immunodeficiency Virus (HIV-1) reverse transcriptase inhibitory activity of Phyllanthus emblica plant extract

Changes in physical and chemical properties during pomegranate (Punica granatum L.) fruit maturation

Interactions of the active components of Punica granatum (pomegranate) with the essential renal and hepatic human Solute Carrier transporters

Anti-Influenza virus activity and phenolic content of pomegranate (Punica granatum L.) peel extract and fractions

Chapter 22-physical, hematological, and histopathological signs of toxicity induced by African medicinal plants

Comprehensive study of the phenolic composition of the edible parts of jambolan fruit (Syzygium cumini (L.) Skeels)

Anti-inflammatory activity of constituents isolated from Terminalia chebula

Nutritive value of the chebulic myrobalan (Terminalia chebula Retz) and its potential as a food source

The effect of aqueous extract of Trachyspermum ammi seeds and ibuprofen on inflammatory gene expression in the cartilage tissue of rats with collagen-induced arthritis

Extract of a spice-Omum (Trachyspermum ammi)-shows antiaggregatory effects and alters arachidonic acid metabolism in human platelets

Promising anti-influenza properties of active constituent of Withania somnifera ayurvedic herb in targeting neuraminidase of H1N1 influenza: computational study

Withania somnifera: From prevention to treatment of cancer

Fresh ginger (Zingiber officinale) has anti-viral activity against human respiratory syncytial virus in human respiratory tract cell lines

Gingerols and shogaols: important nutraceutical principles from ginger

The Agronomy and Economy of Turmeric and Ginger

Anti-inflammatory activity of Abutilon indicum extract

Immunomodulatory Activity of Abutilon Indicum linn on Albino Mice

Immunomodulation by leaf extract of Acalypha indica Linn in Oreochromis mossambicus (Peters)

Evaluation of the anti-inflammatory activity of Aegle marmelos (Bilwa) root

Immunomodulatory potential of methanol extract of Aegle marmelos in animals

Anti-inflammatory and anti-allergic effects of Agrimonia pilosa Ledeb extract on murine cell lines and OVA-induced airway inflammation

Antiinflammatory activity of sulfur-containing compounds from garlic

Immunomodulatory activity of aged garlic extract against implanted fibrosarcoma tumor in mice

Potential of garlic (Allium sativum) in lowering high blood pressure: mechanisms of action and clinical relevance

Antiinflammatory activity of extracts from Aloe vera gel

Immunomodulatory effects of Aloe vera and its fractions on response of macrophages against Candida albicans

Immunomodulation of artemisinin and its derivatives

Possible biochemical mode of antiinflammatory action of Azadirachta indica A. Juss. in rats

Immunomodulatory effects of neem (Azadirachta indica) oil

Kinetics of angiotensin-1 converting enzyme inhibition and antioxidative properties of Azadirachta indica seed protein hydrolysates

Anti-inflammatory effects of a polyphenols-rich extract from tea (Camellia sinensis) flowers in acute and chronic mice models

The immunomodulatory effect of green tea (Camellia sinensis) leaves extract on immunocompromised Wistar rats infected by Candida albicans

Inhibition of angiotensin converting enzyme (ACE) activity by polyphenols from tea (Camellia sinensis) and links to processing method

Anti-allergic, anti-inflammatory and anti-lipidperoxidant effects of Cassia occidentalis Linn

Anti-inflammatory activity of Cicer arietinum seed extracts

Pectic polysaccharides have relatively potent immunomodulatory activity compared to their hydrolysates from chickpea (Cicer arietinum L.) husk

Chickpea (Cicer arietinum L.) lectin exhibit Inhibition of ACE-I, α-amylase and α-glucosidase activity

Anti-inflammatory and antioxidant activities of Commelina diffusa (Commelinaceae)

Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research

Immune-stimulatory and anti-inflammatory activities of Curcuma longa extract and its polysaccharide fraction

In vitro antidiabetic and inhibitory potential of turmeric (Curcuma longa L) rhizome against cellular and LDL oxidation and angiotensin converting enzyme

Chemicals compositions, antioxidant and anti-inflammatory activity of Cynara scolymus leaves extracts, and analysis of major bioactive polyphenols by HPLC. Evid Based Complement Alternat Med

Antitumor, antiinflammatory and analgesic property of Embelin, a plant product

Role of medicinal plants as immunostimulants in health and disease

Antiinflammatory activity of Eugenia Jambolana in Albino rats

Immunomodulatory activity of methanolic extract of Syzygium cumini seeds

Quantification of phenolics in Syzygium cumini seed and their modulatory role on tertiary butyl-hydrogen peroxide-induced oxidative stress in H9c2 cell lines and key enzymes in cardioprotection

Anti-inflammatory effects of Ginkgo biloba extract against trimethyltin-induced hippocampal neuronal injury

Immunomodulatory effect of Ginkgo biloba exocarp polysaccharides on immunosuppressive mice induced by cyclophosphamide

Three novel ACE inhibitory peptides isolated from Ginkgo biloba seeds: purification purification, inhibitory kinetic and mechanism

Antioxidant and anti-inflammatory activities of flavanones from Glycyrrhiza glabra L. (licorice) leaf phytocomplexes: identification of licoflavanone as a modulator of NF-kB/MAPK pathway

Evaluation of immunomodulatory activity of Glycyrhiza glabra L. roots in combination with zing

Evaluation of anti-inflammatory activity of Gymnema sylvestre leaves extract in rats

Immunomodulatory effect of gymnema sylvestre (RBr). leaf extract: an in vitro study in rat model

Anti-inflammatory effects of Hibiscus Sabdariffa Linn. on the IL-1β/IL-1ra ratio in plasma and hippocampus of overtrained rats and correlation with spatial memory

Immunomodulatory effect of extracts of Hibiscus sabdariffa L. (Family Malvaceae) in a mouse model

Inhibition of angiotensin convertin enzyme (ACE) activity by the anthocyanins delphinidin-and cyanidin-3-O-sambubiosides from Hibiscus sabdariffa

Evaluation of anti-inflammatory activity of alcoholic extract of leaves of Leucas Aspera in albino rats

Evaluation of immunomodulatory activity of ethyl acetate extract of Leucas aspera in Swiss albino mice

Anti-inflammatory 5-(11'Z-heptadecenyl)-and 5-(8'Z,11'Z-heptadecadienyl)-resorcinols from mango (Mangifera indica L.) peels

Immunomodulatory activity of alcoholic extract of Mangifera indica L. in mice

In vitro and in vivo evaluation of immunomodulatory activity of methanol extract of Momordica charantia fruits

Screening, discovery, and characterization of angiotensin-I converting enzyme inhibitory peptides derived from proteolytic hydrolysate of bitter melon seed proteins

Characterization of soluble dietary fiber from Moringa oleifera seeds and its immunomodulatory effects

Partial purification and characterization of angiotensin converting enzyme inhibitory alkaloids and flavonoids from the leaves and seeds of Moringa oleifera

Anti-allergic activity of stem bark of Myrica esculenta Buch-Ham (Myricaceae)

A new monoterpenoid glycoside from Myrica esculenta and the inhibition of Angiotensin I-converting enzyme

Nigella sativa as an anti-inflammatory agent in asthma

Potential immunomodulation effect of the extract of Nigella sativa on ovalbumin sensitized guinea pigs

Identification of a potent Angiotensin-I converting enzyme inhibitory peptide from Black cumin seed hydrolysate using orthogonal bioassay-guided fractionations coupled with in silico screening

Anti inflammatory activity of fresh tulsi leaves (Ocimum Sanctum) in albino rats

Evaluation of immunomodulatory potential of Ocimum sanctum seed oil and its possible mechanism of action

Ocimum sanctum L. a potential angiotensin converting enzyme (ACE) inhibitor useful in hypertension

Suppression of Src and Syk in the NF-ÎoB signaling pathway by Olea europaea methanol extract is leading to its anti-inflammatory effects

Immunomodulatory properties of Olea europaea leaf extract in intestinal inflammation

Isolation of an angiotensin converting enzyme (ACE) inhibitor from Olea europaea and Olea lancea

Antioxidant and anti-inflammatory activities of bean (Phaseolus vulgaris L.) hulls

Identification of ACE-inhibitory peptides from Phaseolus vulgaris after in vitro gastrointestinal digestion

Augmentation of murine natural killer cell and antibody dependent cellular cytotoxicity activities by Phyllanthus emblica, a new immunomodulator

Anti-inflammatory effects of Punica granatum Linne in vitro and in vivo

Immunomodulatory activity of Punica granatum in rabbits: a preliminary study

Potential anti-inflammatory steroidal saponins from the berries of Solanum nigrum L. (European Black Nightshade)

Antitumor and immunomodulating effects of polysaccharides isolated from Solanum nigrum Linne

Antiinflammatory and related actions of Syzygium cuminii seed extract

Preliminary immunomodulatory activities of the aqueous extract of Terminalia chebula

Chebulin: Terminalia chebula Retz. fruit-derived peptide with angiotensin-I-converting enzyme inhibitory activity

In vitro immunomodulatory potential of macromolecular components derived from the aqueous extract of ajowan

Evaluation of anti-inflammatory effect of Withania somnifera root on collagen-induced arthritis in rats

Immunomodulatory activity of Withania somnifera

Interaction studies of Withania somnifera's key metabolite withaferin a with different receptors associated with cardiovascular disease

Anti-inflammatory effects of the essential oils of ginger (Zingiber officinale Roscoe) in experimental rheumatoid arthritis

In vitro anti-hydatic and immunomodulatory effects of ginger and [6]-gingerol

Inhibition of angiotensin-1-converting enzyme activity by two varieties of ginger ( Zingiber officinale ) in rats fed a high cholesterol diet

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