Introduction

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).

Fig. 1
figure 1

Typical viral disease mechanism and various targets for antiviral drugs

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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]. Kee** 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, remedies to boost immune system and preventive interventions based on the symptom [14]. Around 65–80% of the world population residing in develo** 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 drug-like 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.

Pathogenesis of COVID-19 and strategy for using edible plants

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-RNA-dependent 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, 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.

Edible plants exhibiting antiviral property against RNA viruses: initial signals for COVID-19

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.

Table 1 Edible plants present in Indian biodiversity being used as food or nutraceutical showing anti-retroviral activity
Full size table

Plants preventing entry of virus in the host

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 SARS-coronavirus 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-CoV-2. Various edible medicinal plants, including Cynara scolymus [39], Cassia occidentalis [40] and Punica granatum [41], have shown ACE inhibitory effects, and the same can be explored for inhibition of ACE2 also.

Plants inhibiting viral replication

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 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.

Plants inhibiting viral envelop formation

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].

Antiviral plants with unknown mechanism

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 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 [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 [

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  1. Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, 382481, India

    Bhoomika Patel

  2. Delhi Pharmaceutical Sciences and Research University, New Delhi, 110017, India

    Supriya Sharma, Nisha Nair, Jaseela Majeed, Ramesh K. Goyal & Mahaveer Dhobi

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Patel, B., Sharma, S., Nair, N. et al. Therapeutic opportunities of edible antiviral plants for COVID-19. Mol Cell Biochem 476, 2345–2364 (2021). https://doi.org/10.1007/s11010-021-04084-7

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  • DOI: https://doi.org/10.1007/s11010-021-04084-7

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