# Ethnopharmacological Potential of Phytochemicals and Phytogenic Products against Human RNA Viral Diseases as Preventive Therapeutics

Authors: Anamika Paul; Nilanjan Chakraborty; Anik Sarkar; Krishnendu Acharya; Anuj Ranjan; Abhishek Chauhan; Shilpi Srivastava; Akhilesh Kumar Singh; Ashutosh Kumar Rai; Iqra Mubeen; Ram Prasad
Journal: BioMed Research International
 (2023)

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## Abstract

RNA viruses have been the most destructive due to their transmissibility and lack of control measures. Developments of vaccines for RNA viruses are very tough or almost impossible as viruses are highly mutable. For the last few decades, most of the epidemic and pandemic viral diseases have wreaked huge devastation with innumerable fatalities. To combat this threat to mankind, plant-derived novel antiviral products may contribute as reliable alternatives. They are assumed to be nontoxic, less hazardous, and safe compounds that have been in uses in the beginning of human civilization. In this growing COVID-19 pandemic, the present review amalgamates and depicts the role of various plant products in curing viral diseases in humans.


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## Body

## 1. Introduction

The continuous increase in the human population has made globalization and contact between people, domestic animals, and wildlife inevitable. This increased connectivity between man and the wild has led to some devastating diseases from wildlife reservoirs with a heavy mortality toll. Some of them like the human immunodeficiency virus (HIV), H1N1 influenza, the highly pathogenic H5N1 avian influenza, Nipah virus, Hendra virus, severe acute respiratory syndrome coronavirus (SARS-CoV), Ebola virus (EBOV), and more recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have created havoc in the world [1, 2]. Studies of decades show that the RNA viruses are the most common class of virus, which are often highlighted as the preeminent member of pathogen class that is behind new human diseases, with a rate of 2 to 3 novel viruses being exposed each year [3, 4]. Meanwhile, vaccine development is introduced each time after the advent of new threats. Currently, a number of vaccines are considered to be a critical component in the prevention of viral infections [5], but most of them show side effects, and many of the viruses acquired resistance against them [6]. Therefore, the unavailability of potent vaccines increased mortality numbers. Vaccines are approximately only 50% effective; hence, there is a strong need for antiviral compounds with the ability to suppress viruses, devoid of any or any major side effects [6]. Fascinatingly, traditional medicine has been used in several parts of the worlds like in Asian, African, European, and South American countries. Because the traditional healthcare system is easily culturally acceptable and relatively cheaper compared to costly orthodox medicines [7]. Starting from past to present, wild plants are used traditionally due to having their medicinal properties in between rural communities and the societies to making a bridge in generation after generation, standing in this present scenario where the communication technology developed faster and spread data in wide distances that helps the people to enrich their traditional knowledge, which are essential in our daily life [8]. In addition, as compared to the orthodox system, plant-based natural pharmacotherapy can be used easily as proper alternatives for treating viral diseases [9]. In this review article, our main motive is to highlight the protective measures of RNA viral diseases in humans by using easily available medicinal plants, crude extracts, or active compounds.


## 2. Potential Pharmacological Targets of RNA Viruses in Host

RNA viruses contain RNA molecule to carry their genetic information. However, it also contains the information required for the synthesis of its own protein. These proteins may help in replication and spread to other susceptible host. Due to their reduced coding capacity, they are dependent on host cell to complete multiplication cycle [10]. This generalized strategy is followed by many other RNA viruses like human immunodeficiency virus (HIV) [11]. Corona virus disease 2019 (COVID-19) caused by the RNA virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a serious threat to mankind as well as the world economy [2]. Most interestingly, host RNA-binding protein is attached with the specific architecture of RNA. In case of SARS-CoV-2, infection cycle is started by the interaction of receptor-binding domain (RBD) with angiotensin-converting enzyme 2 (ACE2) receptors present on the cell surface of human. After binding, transmembrane protease and serine 2 cleaved S protein facilitate the entry of virus. The SARS-CoV-2 particles enter the host through either direct membrane fusion or endocytosis. After its translation to polypeptides, the main protease (Mpro) and papain-like protease (PLpro) cleaved the translated polypeptides to release nonstructural proteins (nsps), whereas RNA-dependent-RNA polymerase (RdRp) facilitates RNA transcription and replication. On the other hand, its mRNA is translated to produce structural and accessory proteins in endoplasmic reticulum (ER). Then, structural proteins are assembled with nucleocapsid into the secretory vesicles (lumen). Finally, the assembled SARS-CoV-2 particles were released by following the exocytosis method [12].


## 3. Efficiency of RNA Viruses for Pathogenesis

Till now, 13 families of single-stranded RNA (ssRNA) and 1 family of double-stranded RNA (dsRNA) virus have been included in virus classification [13]. ssRNA viruses are further classified with having either positive or negative sense strands [14]. Those viruses are capable to modify cellular metabolism upon successful infection [15]. They invariably use host cell ribosomes for the production of protein and related enzymes [16]. Interestingly, RNA viruses have tremendous adaptability to a new environment. They can also be able to handle harsh situations related to different selection pressures encountered, though the selective pressures not only include the host’s immune system and defense mechanisms but are also encountered by challenges created through the application of drugs such as protease inhibitors of hepatitis B and C virus and inhibitors of HIV-1 reverse-transcriptase [1]. Due to exceptionally shorter generation times and faster evolutionary rates, in a very short-time span, only the RNA viruses are able to transmit a disease to new host species [1]. The fast evolutionary rate of RNA viruses incurred due to the rapid rate of replication errors [17]. It is justified by many studies that the rate of mutation of RNA viruses is about six times greater than that of their cellular hosts. This is remarkably due to high mutation rate, which helps to maintain a distinctive rate of adaptive evolution that is shown in Figure 1 [1]. Basic mode of infection related to other factors are depicted in Figure 2.Figure 1
Natural outline of RNA viruses in causing disease.Figure 2
Basic mode of action and related inhibitory factors of virus.


## 4. Plant-Based Therapies against RNA Viral Disease

Medicinal plant (MP) contains a substantial amount of pharmacologically important secondary metabolites that can be used for therapeutic purposes. Since the very past, different plant parts or extracts had been utilized by local people to prevent many diseases up till now [18]. Interestingly, viral infections with sharp mortality and morbidity rates are one of the most key concerns of human deaths worldwide [6]. In this irresistible situation of global pandemic, world research has been shifted to find out potential vaccines [4]. Due to the lack of vaccines and other standard therapies, viral diseases grow rapidly throughout the world. In this situation, discovery of the novel antiviral drugs is of utmost importance. Moreover, cost-effectiveness and high efficacy are always a matter of concern for drug discovery [19]. In many cases, the synergistic effect of plant extract in combinations with other compounds has shown better results against these diseases [20]. Since the very early times, active compounds were isolated and identified by following the bioassay-guided fractionation techniques that take longer time and most of the times do not show positive results. The recent methods of drug discovery are more efficient due to quick isolation and faster progression of novel drug formulation that also includes rapid clinical trials [21]. A concise strategy for natural drug discovery is shown in Figure 3.Figure 3
Comprehensive scheme of natural drug discovery from the medicinal plants.On the other hand, commonly used natural plant products in Ayurveda are clearly mentioned in Susruta Samhita and Charaka Samhita or it can be obtained through traditional knowledges [22]. Conventionally used extracts of specific plant parts like roots, bark, stem, seeds, fruits and flowers, dietary supplements, plant derivatives (phyto-constituents), and nutraceuticals found wide applications in the treatment of wide range of diseases. Besides that, the survey report indicates that among commonly used medicines, one quarter of the compounds are isolated from plant sources [22]. Hence, the scientists working on drug discovery are trying to focus on the medicinal plants used in ethnobotany and trying to document them to establish their natural, inherent, and positive effects against specific diseases [7, 23]. But in comparison with the investigation of antimicrobial properties, the investigation of plant-derived antiviral substances is insufficient [24, 25].


### 4.1. Herbal Extracts against RNA Viral Diseases of the Human

Traditionally, medicinal plants are being used to cure various human diseases. Most of the Asian countries like China, Japan, and India have a great past history of usage of medicinal plant and mushroom extracts [26]. Amalgamation of conventional knowledge and advance research techniques in the field of natural drug discovery imports a huge number of novel products from plants. Due to less side effects and toxicity, it has been preferred by the common users. Not only that the cost-effectiveness of those natural products provides a value addition and also increased its accessibility [27]. Those products can be able to provide broad spectrum protective measures to numerous health hazards including viral infections. In case of the treatment of SARS-CoV-2, a formulation composed of 6.6% of each of the 15 plants, viz., Zingiber officinale (ginger), Adhatoda vasica (malabar nut), Piper longum (long pepper), Andrographis paniculata (bitterweed), Tragia involucrata (Indian stinging nettle), Syzygium aromaticum (clove), Terminalia chebula (chebulic myrobalan), Hygrophila auriculata (kokilaksha), Cyperus rotundus (java grass), Plectranthus amboinicus (Indian borage), Clerodendrum serratum (bharangi), Tinospora cordifolia (guduchi), Saussurea costus (costus), Sida acuta (teaweed), and Anacyclus pyrethrum (akarkara), has been recommended by the Ministry of AYUSH (Ayurveda, Unani, Yoga, and Naturopathy, Siddha, and Homoeopathy), Government of India [28]. The antiviral activity of many plant extracts and compounds of plant origin has been reported, which includes aqueous extracts of Cassine xylocarpa stem (Celastraceae), Maytenus cuzcoina root & bark (Celastraceae) [9], and crude methanolic extract of roots of four Lamiaceae members, viz., Thymus carmanicus (Thyme), Thymus vulgaris, Thymus kotschyanus, and Thymus daenensis [9, 29], which are used to cure HIV infection; aqueous extract of Nerium oleander (kaner, Apocynaceae) is used against Poliovirus type 1 [30]; methanolic extract of Bryophyllum pinnatum (life plant, Crassulaceae), Mondiawhitei (white’s ginger, Periplocaceae), Terminalia ivorensis (black afara, Combretaceae), Ageratum conyzoides (goat weed, Asteraceae) are used to cure echovirus [7]; aqueous and ethanol extracts of dried leaves of Andrographis paniculata (Acanthaceae) and Gynostemma pentaphyllum (poor man’s ginseng, Cucurbitaceae) are used to prevent avian influenza virus (H5N1) [31] etc. Table 1 summarizes the use of plant extracts against the human RNA-viral diseases.Table 1
Plant extract used as anti-RNA viral activity in human.
S. no.FamilyPlant nameAntiviral activity againstTraditional use of plantName of city and countries where these were usedExtraction method and parts usedMechanism of action/reduction of disease intensity1.AcanthaceaeAndrographis paniculata (Burm. f.) Nees [Bitterweed]Dengue virus (DENV)By tribal healers, ojha, baidya, medicine men of BiharBihar (state of India) [32]Crude extract of whole plantInhibits the activity of DENV-1 in infected Vero cells inin vitro assay [33]2.AcanthaceaeAndrographis paniculata (Burm. f.) Nees [Bitterweed]Avian influenza virus (H5N1)Aerial parts and roots used as traditional medicine in India, China, Thailand, and other Southeast Asian countries to treat many diseasesIndia, China, and Thailand (countries of Asia) [34]Water and ethanol extract of leaves [31]Induce upregulation ofIFN-β and TNF-α mRNA expression that inhibit viral replication in Madin-Darby canine kidney (MDCK) cells in an in vitro investigation [31]3.MoraceaeFicus fistulosa Reinw. ex BI. [Kelampung Bukit]Hepatitis C virusIn folk medicine against respiratory disorder, convulsion, and tuberculosis [35]80% population of some Asian and African countries and Bangladesh (country in South Asia) [36]Ethanolic extract of leaves [37]Inhibition of viral entry [37]4.AnacardiaceaeSchinus molle L. [American pepper]Human immunodeficiency virus (HIV)In folk medicine for treating ulcers, wounds, diarrhea, toothache, menstrual disorders, rheumatism, and respiratory problem that are found in many Brazilian medical literature, as stimulant, antitumor, antifungal, antiseptic, tonic, diuretic, anti-plasmodic, antioxidant, antibacterial agentBrazil (country of South America) [38]Crude methanolic extract of leaves [39]Protects MT-2 T-lymphoblastoid cell from cytopathic effect of HIV [39]5.CucurbitaceaeGynostemmapentaphyllum (Thunb.) Makino [Southern Ginseng or Miracle Plant]Avian influenza virus (H5N1)In Southeast Asian countries as herbal medicine to treat diabetes, as antioxidant, antitumor, cholesterol-lowering agent, treatment of chronic tracheitis, bronchitis, infectious hepatitis, pyelitis and gastroenteritis in Chinese medicineChina, (countries in East-Asia) and southeast Asian countries [31]Water and ethanol extract of dried leaves [31]Induce upregulation ofIFN-β and TNF-α mRNA expression that inhibit viral replication in Madin-Darby canine kidney (MDCK) cells in an in vitro investigation [31]6.EquisetaceaeEquisetum giganteum L. [Southern giant horsetail]Human immunodeficiency virus (HIV)In herbal medicine in Central and South America, diuretic agent in ethnomed [40] icineBrazil (country of South America) and some other countries of Central and South America [41]Crude methanolic extract of stem [39]Protects MT-2 T-lymphoblastoid cell from cytopathic effect of HIV [39, 41]7.ZingiberaceaeCurcuma longa L. [turmeric]Avian influenza virus (H5N1)Traditional medicine in India, Bangladesh, Pakistan, and China, as antiseptic for cuts, bruises, and burns in South AsiaIndia, Bangladesh, and Pakistan (countries in South-Asia) and China (country in East-Asia) [42]Water and ethanol extract of root [31]Induce upregulation ofIFN-β and TNF-α mRNA expression that inhibits viral replication in Madin-Darby canine kidney (MDCK) cells in an in vitro investigation [31]8.ApocynaceaeCalotropis procera (Aiton) W.T.Aiton [Calotrope]Dengue virus (DENV)By tribal healers, ojha, baidya, medicine men of BiharBihar (state of India) [33]Crude extract of leaf and bark [33]Kills larvae ofAedes aegypti [43]9.CaricaceaeCarica papaya L. [papaya]Dengue virus (DENV)By traditional healers and local people of Uttar Pradesh, Madhya Pradesh; local practitioners and traditional healers of Goa, local people of north eastern plain zone of IndiaUttar Pradesh, Madhya Pradesh, Goa (states of India) and north eastern plain zone of India (country in South Asia) [33, 44]Leaf extract [45]Increases platelets due to administration of extract [45]10.MeliaceaeAzadirachta indica A. Juss. [neem]Dengue virus type 2 (DENV-2)By traditional healers and tribals of various districts of BiharBihar (state of India) [33]Leaf extract [33]In vitro and in vivo study showed reduction of virus [33]11.ZingiberaceaeKaempferia parviflora Wall. ex Baker [Thai ginseng]Avian influenza virus (H5N1)In Thai medicine to treat leucorrhoea, oral disease, stomach discomfort, health promotion, as antifungal, antiflatulent, antiplasmodial agent, powder with ethanol used to cure peptic ulcers, diabetes, asthmaThailand (country in Asia)Water and ethanol extract of root [31]Induce upregulation ofIFN-β and TNF-α mRNA expression that inhibit viral replication in Madin-Darby canine kidney (MDCK) cells in an in vitro investigation [31]12.MagnoliaceaeMagnolia officinalis Rehder & Wilson [Houpo magnolia]Dengue virus type 2In eastern medicine, Chinese medicine Hou-Pu that have been used in analgesic, distension, or anxiety relief [46]China (country in East Asia)Methanolic extract of bark [47]Inhibits intracellular DENV-2 replicon [47]13.LamiaceaeThymus carmanicus Jalas [Avishan]Human immunodeficiency virus type 1 (HIV-1)Decoction and infusion used for cold in Iranian traditional medicine, as anti-inflammatory, digestive, carminative agentsIran (country in Western Asia)Methanolic extract of root [29]Effect on peripheral blood mononuclear cells (PBMCs) toxicity and HIV-1 replication [29]14.LamiaceaeThymus vulgaris L. [thyme]Human immunodeficiency virus type 1 (HIV-1)Decoction and infusion used for cold in Iranian traditional medicine, in folk medicine for asthma and bronchitis, as anti-inflammatory, digestive, carminative, antiseptic, antifungal, antiviral, antimicrobial agentsIran (countries in Western Asia)Methanolic extract of root [29]Effect on peripheral blood mononuclear cells (PBMCs) toxicity and HIV-1 replication [29]15.LamiaceaeThymus kotschyanus Boiss. & Hohen. [thyme]Human immunodeficiency virus type 1 (HIV-1)Decoction and infusion used for cold in Iranian traditional medicine, as anti-inflammatory, digestive, carminative agentsIran (country in Western Asia)Methanolic extract of root [29]Effect on peripheral blood mononuclear cells (PBMCs) toxicity and HIV-1 replication [29]16.LamiaceaeThymus daenensis Celak [thyme]Human immunodeficiency virus type 1 (HIV-1)Decoction and infusion used for cold in Iranian traditional medicine, as anti-inflammatory, digestive, carminative agentsIran (countries in Western Asia)Methanolic extract of root [29]Effect on peripheral blood mononuclear cells (PBMCs) toxicity and HIV-1 replication [29]17.MyrtaceaePsidium guajava L. [guava]Avian influenza virus (H5N1)In South-Eastern Nigeria to treat cough, malaria, stomach disorders, and loss of appetiteNigeria (country in West Africa) [48]Water and ethanolic extract of dried leaves [31]Induce upregulation ofIFN-β and TNF-α mRNA expression that inhibit viral replication in Madin-Darby canine kidney (MDCK) cells in an in vitro investigation [31]18.VerbenaceaeClerodendrum serratum (L.) Moon. [Bharangi]Yellow fever virusUsed in Yunani, Ayurveda, traditional Chinese medicine, Japanese Kampo medicineChina, Japan (countries in East Asia) [49]Ethanolic and methanolic extract of whole plant [50]Prevent viral infection through the bite of mosquito vector [50]19.CombretaceaeTerminalia chebula Retz. [Chebulic myrobalan]EnterovirusUsed in Yunani, Ayurveda, traditional Chinese medicine, Japanese Kampo medicineChina, Japan (countries in East Asia) [49]Ethanolic and methanolic extract of leaves [50]Inhibits viral replication [50]20.VitaceaeAmpelocissus tomentosa (Heyne ex Roth) Planch. [hairy wild grape]Chikungunya virusUsed in Yunani, Ayurveda, traditional Chinese medicine, Japanese Kampo medicineChina, Japan (countries in East Asia) [49]Ethanolic and methanolic extract of root [50]Inhibits viral replication [50]21.CrassulaceaeKalanchoe pinnata (Lam.) Pers. [flaming Katy]Chikungunya virusUsed in Yunani, Ayurveda, traditional Chinese medicine, Japanese Kampo medicineChina, Japan (countries in East Asia) [49]Ethanolic and methanolic extract of leaves [50]Inhibits viral replication [50]22.CupressaceaeThuja orientalis L. [Chinese thuja]Severe acute respiratory syndrome coronavirus (SARS-CoV)In traditional medicine and homeopath, to treat bronchitis, skin infection, excessive menstruation, arthritic pains, coughs, dysentery, named as Chinese Thuja, in other regions of the Asian continentChina (country in East Asia) and in other regions of the Asian continentOil extract of plant [51]Inhibits viral replication [51]23.CupressaceaeJuniperus oxycedrus L. [Cade juniper]Severe acute respiratory syndrome coronavirus (SARS-CoV)In infectious disease, colds, fungal infections, cough, gynecological disease, wounds in Turkish folk medicine, as anti-inflammatory and antinociceptiveTurki (lying partly in Asia and partly in Europe) [52]Oil extract of plant [51]Inhibits viral replication [51]24.ElaeagnaceaeHippophae rhamnoidesL. [Sea buckthorn]Dengue virus type-2 (DENV-2)In Tibetan traditional and Chinese medicineTibet is a part of China (country of East Asia) [53]Alcoholic extract of leaves [33]Decreases THF-α, increases INF-γ production, increases cell viability in in vitro assay against dengue virus type-2 [33]25MenispermaceaeTinospora cordifolia (Thunb.) Miers [Guduchi]Dengue virus (DENV)In traditional folk medicine of India for treating diabetesIndia (country in South Asia) [54]Decoction of stems [55]Reduce inflammation and fever, enhance the killing ability of macrophages [55]There is not a single medicine, which is globally accepted for the treatment of dengue fever. However, extracts obtained from different plants are expected to lower the severity of dengue viruses by increasing the platelet count, which includesCarica papaya leaf extract that is used by the local people of North Eastern plain zone of India, Madhya Pradesh [33, 56], whole plant of Andrographis paniculata (bitterweed), Alternanthera sessilis (sessile joyweed), Achyranthus aspera (prickly chaff flower), and Solanum xanthocarpum (yellow-fruit nightshade), and leaf and bark of Calotropis procera (calotrope) used in Bihar by traditional healers [32, 33]. In some clinical trials, it has been confirmed that the administration of leaf extract of Carica papaya (papaya) on patients with dengue fever increases their platelet count [33, 45]. More specifically, as we are facing SARS-CoV-2 in present days, so it is required to know the name of the phytochemicals and their classes to check the intensity of this virus [57]. Table 2 represents a list of phytochemicals acting against various targets of SARS-CoV-2, where most of the phytochemical binds with spike protein ACE2 (like anthraquinone, emodin, rhein, and cinnamaldehyde) or inhibits main protease (Mpro) (like somniferine, isorientin, and gallocatechin-3-gallate) [57].Table 2
List of phytochemicals acting against various targets of SARS-CoV-2.
Sl no.PhytochemicalClass of phytochemicalTargetsReference1.FisetinFlavonoidBind with spike protein like hACE2-S[58]2.QuercetinFlavonoidBind with spike protein[58]3.DithymoquinoneTerpeneInhibits spike glycoprotein-ACE2 interface[59]4.Glycyrrhizic acidSaponinBinds with spike protein RBD-ACE2[60, 61]5.HesperidinFlavonoidBind with spike protein ACE2[62]6.EmodinFlavonoidBind with spike protein ACE2[62]7.CarvacrolPhenolInteracts with spike protein ACE2[59]8.RheinFlavonoidBind with spike protein ACE2[62]9.KaempferolFlavonoidBind with spike protein hACE2-S[58]10.CinnamaldehydeFlavonoidInteracts with spike protein ACE2[59]11.Cinnamyl acetateStyreneInteracts with spike protein ACE2[59]12.ChrysinFlavonoidBind with spike protein ACE2[62]13.AnthraquinoneFlavonoidBind with spike protein ACE2[62]14.AnetholeFlavonoidInteracts with spike protein ACE2[59]15.GeraniolTerpeneInteracts with spike protein ACE2[59]16.L-4-terpineolTerpeneInteracts with spike protein ACE2[59]17.AndrographolideTerpenoidInhibits Mpro protease[63]18.Withanoside VInhibits Mpro protease[64]19.SomniferineInhibits Mpro protease[64]20.Epigallocatechin gallatePhenolInhibits Mpro protease[65]21.Gallocatechin-3-gallatePhenolInhibits Mpro protease[65]22.TinocordisideInhibits Mpro protease[64]23.ViceninInhibits Mpro protease[64]24.IsorientinInhibits Mpro protease[64]25.BerbamineTargets on spike protein ACE2[66]26.CastanospermineReduced viral RNA[67]27.Epicatechin gallatePhenolInhibits Mpro protease[65]Ethanolic and methanolic extracts ofAmpelocissus tomentosa (root), Clerodendrum serratum (whole plant), and Terminalia chebula (leaves) are effective against chikungunya virus, yellow fever virus, and entero virus, respectively [50]. Flavonoid extract of Litchi chinensis inhibits 3CLpro [51, 68], and plant extracts of Juniperus oxycedrus (cade juniper), Laurus nobilis (bay tree), Thuja orientalis (thuja) act as viral growth inhibitor [51] against SARS-CoV. Ethanolic extract of Broussnetia papyrifera (paper mulberry) containing Kazinol F and Broussochalcone A, and 3′-(3-methylbut-2-enyl)-3′,4,7-trihydroxyflavane showed noncompetitive inhibition on papain like protease (PLpro) of MERS-CoV and SARS-CoV, respectively [69, 70]. The flavonoids like cinnamaldehyde, chrysin, and anethole bind with spike protein ACE2 of SARS-CoV-2 virus [59, 62]; tinocordiside, somniferine, and withanoside V [64] inhibit Mpro protease, which cleaved translated polypeptides to liberate nonstructural proteins.


### 4.2. Plant-Derived Active Compounds for Prevention of RNA Viral Diseases in Human

Nowadays, huge proportions of global population choose easily available natural product from their nearby sources to get relief from the emerging health problems. This awareness of common people has induced the interest of the scientists to invent new formulations of plant extracts on the basis of traditional ethnopharmacological knowledge. Sequentially, many pharmaceutical companies are now engaged to produce natural antimicrobial formulations to meet the demand of the global market [71]. Ignatov (2020) explained that high levels of potassium reported from Moringa oleifera helps the patient of COVID-19 to decrease the rate of infection caused by the SARS-CoV-2 virus. Different plants induce the production of numerous secondary metabolites such as phenolics, essential oils, glycosides, coumarins, alkaloids, terpenoids, and peptides mainly in response to microbial infections or to avoid herbivores and other organisms (Figure 4).Figure 4
Important phytochemicals obtained from medicinal plants.These metabolites have been accepted to play an essential role in boosting of the immune system and manifesting of antiviral potential [27, 72]. There are several phytochemicals, which are found to be effective against different RNA viruses also; some of which are listed in Table 3.Table 3
Lists of phytochemicals against RNA viruses causing human diseases.
RNA typeName of virusesFamilyTherapeutic phytochemicalsReferencePositive-sense ssRNADengue virusFlaviviridaeFlavonoid, alkaloid, phenol, and coumarins[73, 74]Hepatitis C virusFlaviviridaeFlavonoid, alkaloid, lignan, terpenes, and terpenoids[75, 76]Japanese encephalitis virusFlaviviridaeFlavonoid[77]Zika virusFlaviviridaeFlavonoid[78]Severe acute respiratory syndrome coronavirus (SARS-CoV)CoronaviridaeFlavonoid (luteolin, curcumin, myricetin, quercetin), anthraquinone (emodin)[51]Chikungunya virusTogaviridaeFlavonoid, terpenes, coumarins, and terpenoids[73, 76, 79]CoxsackievirusPicornaviridaeFlavonoids[80]Hepatitis A virusPicornaviridaeFlavonoids and alkaloids[81]EnterovirusPicornaviridaeFlavonoids[74]Human immunodeficiency virusRetroviridaeTerpenes and terpenoid lignan, and coumarin[82, 83]Negative-sense ssRNARespiratory syncytial virusParamyxoviridaeLignan[84]Infectious hematopoietic necrosis virusRhabdoviridaeCoumarin[85]Influenza virus (H3N2, H5N2, H5N1, H1N1)OrthomyxoviridaeFlavonoid, alkaloid, lignan, coumarin, terpenes, and terpenoid[86, 87]Few recurrent and non-recurrent viral infections include human immunodeficiency virus type 1 (HIV-1) and 2 (HIV-2) [27], hepatitis C virus [6], dengue virus [33], and poliovirus. Furthermore, the control and prevention of different emerging viral diseases are imposing a great challenge to the society [88]. About 500,000 plant species are estimated to be present in the world. Interestingly, 10-15% among them are being used as drugs and 10% as a source of food [89]. However, the rapid extinction of some species leads to irretrievable loss of potential phytochemicals and also imposes another serious threat. The anti-RNA viral activity of active compounds from some medicinal plants have been reviewed and summarized in Table 4.Table 4
Medicinally important plant-derived active compounds used for curing human RNA viral diseases.
S. no.FamilyPlant nameActive compoundFamily of virusVirus nameType of viral RNAHuman diseasesReference5.TheaceaeCamellia sinensis (L.) Kuntze [tea]TheaflavinCoronaviridaeSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2)Positive-sense ssRNACoronavirus disease 2019 (COVID-19)[90]6.AcanthaceaeAndrographis paniculata (Burm. f.) Nees [Kalmegh]AndrographolideTogaviridaeChikungunya virus (CHIKV)Positive-sense ssRNAChikungunya fever[91]7.AncistrocladaceaeAncistrocladuskorupensis D.W. Thomas & GereauNaphthylisoquinoline alkaloids from root barkRetroviridaeHuman immunodeficiency virus (HIV)Positive-sense ssRNAAIDS[27]8.BerberidaceaeBerbaris amurensis Rupr. [Amur barberry]BerbamineCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[66]9.AncistrocladaceaeAncistrocladus congolensis J, LéonardMichellamine-type dimeric naphthylisoquinoline alkaloids from root barkRetroviridaeHuman immunodeficiency virus (HIV)Positive-sense ssRNAAIDS[92]10.FabaceaeCastanospermum australe A.Cunn & C.Fraser ex Hook. [Blackbean]CastanospermineCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[67]11.HalymeniaceaeCryptonemiacrenulata (J.Agardh) J.AgardhGalactanFlaviviridaeDengue virus type 2, 3 and 4 (DENV-2, DENV-3, DENV-4)Positive-sense ssRNADengue (Breakbone fever)[39]12.ApiaceaeBupleurum sp.Triterpene glycosides (named Saikosaponins B2)CoronaviridaeHuman coronavirus 229E (HCoV-22E9)Positive-sense ssRNANosocomial respiratory viral infection (NRVI)[93]13.FabaceaeTephrosia madrensis Seem. [Hoarypea]Glabranine and 7-O-methyl-glabranine from leaves and flowersFlaviviridaeDengue virus (DENV)Positive-sense ssRNADengue (Breakbone fever)[94]14.ApiaceaeHeteromorpha sp.Triterpene glycosides (named Saikosaponins B2)CoronaviridaeHuman coronavirus 229E (HCoV-22E9)Positive-sense ssRNANosocomial respiratory viral infection (NRVI)[93]15.MoraceaeBroussnetiapapyrifera (L.) Vent. [paper mulberry]Kazinol F, Broussochalcone A from rootsCoronaviridaeMiddle Eastern respiratory syndrome coronavirus (MERS-CoV)Positive-sense ssRNAMiddle Eastern respiratory syndrome[69, 70]16.NelumbonaceaeNelumbo nucifera Gaertn. [lotus]IsoliensinineCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[95]17.NelumbonaceaeNelumbo nucifera Gaertn. [lotus]LiensinineCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[95]18.MoraceaeBroussnetiapapyrifera (L.) Vent. [paper mulberry]3′-(3-Methylbut-2-enyl)-3′,4,7-trihydroxyflavane from rootsCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[70]19.PolygonaceaeReynoutria multiflora (Thunb.) MoldenkeEmodinCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51]20.RanunculaceaThalictrum podocarpum Kunth ex DC. [Meadow-rue]HernandezineCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[96]21.PolygonaceaeRheum officinale L. [Chinese rhubarb]EmodinCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51]22.ZingiberaceaeCurcuma longa L. [turmeric]CurcuminCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51]23.NelumbonaceaeNelumbo nucifera Gaertn. [lotus]NeferineCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[95, 96]24.MyricaceaeMyrica faya Ait. [fire tree]MyricetinCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51]25.MeliaceaeToona sinensis (A.Juss.) M.Roem. [Chinese mahogany]QuercetinCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51]26.RubiaceaeCinchona officinalis L. [Lojabark]QuinacrineCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[97]27.LinaceaeLinum usitatissimum L. [Flax]HerbacetinCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51, 68]28.LamiaceaeScutellaria lateriflora L. [blue skullcap]ScutellareinCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51]29.FabaceaePterocarpus santalinus L. f. [red sanders]SavininCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51]30.CupressaceaeChamaecyparis obtusa var. formosana [Taiwan yellow cypress]Betulonic acid, Savinin, HinokininCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51]31.CelastraceaeTriterygium regelii Sprag. & Takeda [Regel’s threewingnut]Iguesterin, Tingenone, Pristimerin, CelastrolCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51]32.BrassicaceaeIsatisindigotica fortune [Chinese woad]Sinigrin, HesperetinCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51]33.AmaryllidaceaeAllium sativum L. [garlic]Allyl trisulfide, allyl disulfideCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51, 98]34.AcanthaceaeAndrographis paniculata (Burm. f.) Nees [Kalmegh]AndrographolideCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[88]35.MeliaceaeAglaia sp.SilvestrolCoronaviridaeHuman coronavirus 229E (HCoV-229E)Positive-sense ssRNANosocomial respiratory viral infection (NRVI)[70, 99]36.MeliaceaeAglaia sp.SilvestrolCoronaviridaeMiddle Eastern respiratory syndrome coronavirus (MERS-CoV)Positive-sense ssRNAMiddle Eastern respiratory syndrome[99]37.RanunculaceaeNigella sativa L. [black cumin]DithymoquinoneCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[59]38.SolanaceaeWithania somnifera (L.) Dunal [Ashwagandha]Withanoside VCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[64]39.SolanaceaeWithania somnifera (L.) Dunal [Ashwagandha]SomniferineCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[64]40.PhyllophoraceaeGymnogongrusgriffithsiae (Turner) C. MartiusSulphated polysaccharide (named kappa carrageenan) from whole plantsFlaviviridaeDengue virus type 2 (DENV-2)Positive-sense ssRNADengue (Breakbone fever)[94]41.SolanaceaeAtropa belladonna L. [belladonna]l-hyoscyamine, atropine, Belldonic, Scopoletin (l-methyl aesculetin), hyoscine, and pyridine and N-methyl pralineFiloviridaeEbola virusNegative-sense ssRNAEbola haemorrhagic fever (Ebola HF)[100, 101]42.ScrophulariaceaeScrophularia scorodonia L. [Balm-leaved Figwort]Triterpene glycosides (named Saikosaponins B2)CoronaviridaeHuman coronavirus 229E (HCoV-22E9)Positive-sense ssRNANosocomial respiratory viral infection (NRVI)[93]43.ChordariaceaeCladosiphonokamuranusTokida [Mozuku]Fucoidan from whole plantsFlaviviridaeDengue virus type 2 (DENV-2)Positive-sense ssRNADengue (Breakbone fever)[94]44.FabaceaeLeucaena leucocephala (Lam.) de Wit [white leadtree]Galactomanan from seedsFlaviviridaeDengue virus (DENV)Positive-sense ssRNADengue (Breakbone fever)[94]45.TheaceaeCamellia sinensis (L.) KuntzeEpicatechin gallateCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[65]46.MenispermaceaeTinospora cordifolia (Thunb.) Miers [Gurjo]TinocordisideCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[64]47.FabaceaeMimosa scabrella Benth. [Bracatinga]Galactomanan from seedsFlaviviridaeDengue virus (DENV)Positive-sense ssRNADengue (Breakbone fever)[94]48.CelastraceaeCassine xylocarpa Vent. [Marbletree]Pentacyclic lupane-type triterpenoidsRetroviridaeHuman immunodeficiency virus (HIV)Positive-sense ssRNAAIDS[9]49.CelastraceaeMaytenus cuzcoina Loes.Pentacyclic lupane-type triterpenoidsRetroviridaeHuman immunodeficiency virus (HIV)Positive-sense ssRNAAIDS[9]50.PhyllanthaceaePhyllanthus emblica L. [Indian gooseberry]Highly oxygenated norbisabolane sesquiterpenoids (Phyllaemblicins H1-H14) from rootOrthomyxoviridaeInfluenza A virus strain H3N2Negative-sense ssRNAInfluenza (flu)[9]51.LamiaceaeOcimum sanctum L. [Tulsi]ViceninCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[64]52.MagnoliaceaeMagnolia officinalis Rehder & Wilson [Houpo magnolia]HonokiolFlaviviridaeDengue virus type 2 (DENV-2)Positive-sense ssRNADengue (Breakbone fever)[9]53.LamiaceaeOcimum sanctum L. [Tulsi]4′-O-glucoside 2″-O-p-hydroxybenzoagteCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[64]54.FabaceaeTephrosia madrensis Seem.Methyl-hildgardtol A from leaves and flowersFlaviviridaeDengue virus (DENV)Positive-sense ssRNADengue (Breakbone fever)[94]55.LamiaceaeOcimum sanctum L. [Tulsi]IsorientinCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[64]56.TheaceaeCamellia sinensis (L.) KuntzeGallocatechin-3-gallateCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[65]57.FabaceaeLeucaena leucocephala (Lam.) de Wit [White leadtree]Epicatechin gallateFlaviviridaeYellow fever virusPositive sense ssRNAYellow fever[94]58.PapaveraceaeChelidonium majus L. [greater celandine]Low-sulfated poly-glycosaminoglycan moiety from freshly prepared crude extractRetroviridaeRetrovirus (HIV)ssRNAAIDS[27]59.GentianaceaeSwertia bimaculata (Siebold & Zucc.) Hook. f. & Thomson ex C.B. Clarke [double-spotted Swertia]SesterterpenoidRetroviridaeHuman immunodeficiency virus (HIV)Positive-sense ssRNAAIDS[27, 102]60.GentianaceaeSwertia punicea Hemsl.XanthoneRetroviridaeHuman immunodeficiency virus (HIV)Positive-sense ssRNAAIDS[27]61.EuphorbiaceaeEuphorbia neriifolia L. [Indian Spurge Tree]Diterpenoids (named eurifoloids E and F)RetroviridaeHuman immunodeficiency virus (HIV)Positive-sense ssRNAAIDS[27]62.MenispermaceaeStephania tetrandra S. Moore [Fen Fang Ji]Tetrandrine, Cepharanthine, FangchinolineCoronaviridaeHuman coronavirus OC43 (HCoV-OC43)Positive-sense ssRNA—[70, 103]63.AcanthaceaeRhinacanthus nasutus (L.) Kurz [Snake jasmine]Lawsone methyl ether from leavesRetroviridaeHuman immunodeficiency virus (HIV)Positive-sense ssRNAAIDS[27]64.LauraceaeLaurus nobilis L. [bay tree]Beta-ocimene, 1,8-cineole, alpha-pinene, beta-pinene in extracted oil from plantCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51]65.RanunculaceaeNigella sativa L. [black cumin]Thymoquinone, nigellimineCoronaviridaeSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2),Positive-sense ssRNACoronavirus disease 2019 (COVID-19)[104]Few preidentified compounds from different traditional medicinal plants of China showed protective actions against SARS-CoV-2 like betulinic acid, lignin, and sugiol on replication and chymotrypsin-like protease (3CLpro); coumaroyltyramine, cryptotanshinone, kaempferol, N-cis-feruloyltyramine, quercetin, and tanshinone IIa on papain like protease (PLpro) and 3CLpro; desmethoxyreserpine on replication, 3CLpro, and entry; dihydrotanshinone on entry and spike protein; and dihomo-c-linolenic and moupinamide on 3CLpro and PLpro, respectively, to prevent COVID-19 [70, 105]. Furthermore, theaflavin of Camellia sinensis (tea) shows biological action by binding on RNA-dependent RNA polymerase against SARS-CoV-2 [90]. Several drugs, which are previously approved by FDA for other diseases, are again used for the treatment of COVID-19 patients. These drugs include chloroquine and hydroxychloroquine, which are generally used as inhibitors of endosomal acidification fusion and auranoin for redox enzymes that helps to treat rheumatoid arthritis [106, 107]. Allyltrisulfide and allyldisulfide isolated from Allium sativum (garlic) act as ACE2 receptor inhibitors [51, 98]; herbacetin from Linum usitatissimum (flax) [51, 68], betulonic acid, savinin, and hinokinin from Chamaecyparis obtusa var. formosana (Taiwan yellow cypress) act as 3CLpro inhibitor against SARS-CoV; Scutellaria lateriflora (blue skullcap) helps to prevent SARS-CoV by scutellarein as helicase inhibitor [51]. Furthermore, thymoquinone and andnigellimine from Nigella sativa (fennel flower) show the blocking of virus entry into pneumocyes and increasing the Zn2+ uptake to boost host immune response against SARS-CoV-2 [104]. The recent evidences showed that vicenin, isorientin, and 4′-O-glucoside 2″-O-p-hydroxybenzoagte obtained from Ocimum sanctum L. inhibit Mpro protease activity during SARS-CoV-2 viral infection [64].In case of the treatment of Ebola virus, many alkaloids are isolated fromAtropa belladonna that gives a positive result and cure of Ebola haemorrhagic fever (Ebola HF) [100, 101], whereas a sulfated polysaccharide, fucoidan isolated from Cladosiphon okamuranus, and sulphated polysaccharide (named kappa carrageenan) from whole plants of Gymnogongrus griffithsiae [94] worked against dengue virus type 2 (DENV-2). Cytarabine and matrine are two important active constituents found in the extract of Gillan’s plants such as chuchaq and trshvash, respectively, whereas these compounds have the potentiality of better binding interaction with the receptors and show anti SARS-CoV-2 activity by inhibiting the initiation of viral infection [108].There are three species ofTephrosia (viz. T. crassifolia, T. madrensis, and T. viridiflora), which can able to produce huge number of flavonoids and show antiviral activity against dengue virus. Among them, glabranine and 7-O-methyl-glabranine isolated from T. madrensis showed strong inhibitory effects on dengue virus replication in LLC-MK2 cells. Interestingly, moderate to low inhibitory effect was observed by methyl-hildgardtol A isolated from T. crassifolia. However, hildgardtol A of T. crassifolia and elongatine of T. viridiflora do not show any inhibitory effect on viral growth [94]. Honokiol (a lignin biphenol) derived from Magnolia tree has antiviral activity against serotype 2 dengue virus (DENV-2). This novel molecule can be able to interfere on the endocytosis of virus to reduce its double-strand RNA, by abrogating the colocalization of DENV envelope proteins. Inhibitory activity of honokiol was proved by suppressing the replication of DENV-2 in baby hamster kidney (BHK) and human hepatocarcinoma Huh7 cells [9, 47].In the Chinese herbal medicine, extracts ofLonicerae japonicae (Japanese honeysuckle), Flos (ragged-robin), and Fructus forsythia (Lianqiao) are used together as an antimicrobial and anti-inflammatory agent. Interestingly, chito-oligosaccharide in combination with herbal mixture can also act as an anti-influenza agent [64].


## 4.1. Herbal Extracts against RNA Viral Diseases of the Human

Traditionally, medicinal plants are being used to cure various human diseases. Most of the Asian countries like China, Japan, and India have a great past history of usage of medicinal plant and mushroom extracts [26]. Amalgamation of conventional knowledge and advance research techniques in the field of natural drug discovery imports a huge number of novel products from plants. Due to less side effects and toxicity, it has been preferred by the common users. Not only that the cost-effectiveness of those natural products provides a value addition and also increased its accessibility [27]. Those products can be able to provide broad spectrum protective measures to numerous health hazards including viral infections. In case of the treatment of SARS-CoV-2, a formulation composed of 6.6% of each of the 15 plants, viz., Zingiber officinale (ginger), Adhatoda vasica (malabar nut), Piper longum (long pepper), Andrographis paniculata (bitterweed), Tragia involucrata (Indian stinging nettle), Syzygium aromaticum (clove), Terminalia chebula (chebulic myrobalan), Hygrophila auriculata (kokilaksha), Cyperus rotundus (java grass), Plectranthus amboinicus (Indian borage), Clerodendrum serratum (bharangi), Tinospora cordifolia (guduchi), Saussurea costus (costus), Sida acuta (teaweed), and Anacyclus pyrethrum (akarkara), has been recommended by the Ministry of AYUSH (Ayurveda, Unani, Yoga, and Naturopathy, Siddha, and Homoeopathy), Government of India [28]. The antiviral activity of many plant extracts and compounds of plant origin has been reported, which includes aqueous extracts of Cassine xylocarpa stem (Celastraceae), Maytenus cuzcoina root & bark (Celastraceae) [9], and crude methanolic extract of roots of four Lamiaceae members, viz., Thymus carmanicus (Thyme), Thymus vulgaris, Thymus kotschyanus, and Thymus daenensis [9, 29], which are used to cure HIV infection; aqueous extract of Nerium oleander (kaner, Apocynaceae) is used against Poliovirus type 1 [30]; methanolic extract of Bryophyllum pinnatum (life plant, Crassulaceae), Mondiawhitei (white’s ginger, Periplocaceae), Terminalia ivorensis (black afara, Combretaceae), Ageratum conyzoides (goat weed, Asteraceae) are used to cure echovirus [7]; aqueous and ethanol extracts of dried leaves of Andrographis paniculata (Acanthaceae) and Gynostemma pentaphyllum (poor man’s ginseng, Cucurbitaceae) are used to prevent avian influenza virus (H5N1) [31] etc. Table 1 summarizes the use of plant extracts against the human RNA-viral diseases.Table 1
Plant extract used as anti-RNA viral activity in human.
S. no.FamilyPlant nameAntiviral activity againstTraditional use of plantName of city and countries where these were usedExtraction method and parts usedMechanism of action/reduction of disease intensity1.AcanthaceaeAndrographis paniculata (Burm. f.) Nees [Bitterweed]Dengue virus (DENV)By tribal healers, ojha, baidya, medicine men of BiharBihar (state of India) [32]Crude extract of whole plantInhibits the activity of DENV-1 in infected Vero cells inin vitro assay [33]2.AcanthaceaeAndrographis paniculata (Burm. f.) Nees [Bitterweed]Avian influenza virus (H5N1)Aerial parts and roots used as traditional medicine in India, China, Thailand, and other Southeast Asian countries to treat many diseasesIndia, China, and Thailand (countries of Asia) [34]Water and ethanol extract of leaves [31]Induce upregulation ofIFN-β and TNF-α mRNA expression that inhibit viral replication in Madin-Darby canine kidney (MDCK) cells in an in vitro investigation [31]3.MoraceaeFicus fistulosa Reinw. ex BI. [Kelampung Bukit]Hepatitis C virusIn folk medicine against respiratory disorder, convulsion, and tuberculosis [35]80% population of some Asian and African countries and Bangladesh (country in South Asia) [36]Ethanolic extract of leaves [37]Inhibition of viral entry [37]4.AnacardiaceaeSchinus molle L. [American pepper]Human immunodeficiency virus (HIV)In folk medicine for treating ulcers, wounds, diarrhea, toothache, menstrual disorders, rheumatism, and respiratory problem that are found in many Brazilian medical literature, as stimulant, antitumor, antifungal, antiseptic, tonic, diuretic, anti-plasmodic, antioxidant, antibacterial agentBrazil (country of South America) [38]Crude methanolic extract of leaves [39]Protects MT-2 T-lymphoblastoid cell from cytopathic effect of HIV [39]5.CucurbitaceaeGynostemmapentaphyllum (Thunb.) Makino [Southern Ginseng or Miracle Plant]Avian influenza virus (H5N1)In Southeast Asian countries as herbal medicine to treat diabetes, as antioxidant, antitumor, cholesterol-lowering agent, treatment of chronic tracheitis, bronchitis, infectious hepatitis, pyelitis and gastroenteritis in Chinese medicineChina, (countries in East-Asia) and southeast Asian countries [31]Water and ethanol extract of dried leaves [31]Induce upregulation ofIFN-β and TNF-α mRNA expression that inhibit viral replication in Madin-Darby canine kidney (MDCK) cells in an in vitro investigation [31]6.EquisetaceaeEquisetum giganteum L. [Southern giant horsetail]Human immunodeficiency virus (HIV)In herbal medicine in Central and South America, diuretic agent in ethnomed [40] icineBrazil (country of South America) and some other countries of Central and South America [41]Crude methanolic extract of stem [39]Protects MT-2 T-lymphoblastoid cell from cytopathic effect of HIV [39, 41]7.ZingiberaceaeCurcuma longa L. [turmeric]Avian influenza virus (H5N1)Traditional medicine in India, Bangladesh, Pakistan, and China, as antiseptic for cuts, bruises, and burns in South AsiaIndia, Bangladesh, and Pakistan (countries in South-Asia) and China (country in East-Asia) [42]Water and ethanol extract of root [31]Induce upregulation ofIFN-β and TNF-α mRNA expression that inhibits viral replication in Madin-Darby canine kidney (MDCK) cells in an in vitro investigation [31]8.ApocynaceaeCalotropis procera (Aiton) W.T.Aiton [Calotrope]Dengue virus (DENV)By tribal healers, ojha, baidya, medicine men of BiharBihar (state of India) [33]Crude extract of leaf and bark [33]Kills larvae ofAedes aegypti [43]9.CaricaceaeCarica papaya L. [papaya]Dengue virus (DENV)By traditional healers and local people of Uttar Pradesh, Madhya Pradesh; local practitioners and traditional healers of Goa, local people of north eastern plain zone of IndiaUttar Pradesh, Madhya Pradesh, Goa (states of India) and north eastern plain zone of India (country in South Asia) [33, 44]Leaf extract [45]Increases platelets due to administration of extract [45]10.MeliaceaeAzadirachta indica A. Juss. [neem]Dengue virus type 2 (DENV-2)By traditional healers and tribals of various districts of BiharBihar (state of India) [33]Leaf extract [33]In vitro and in vivo study showed reduction of virus [33]11.ZingiberaceaeKaempferia parviflora Wall. ex Baker [Thai ginseng]Avian influenza virus (H5N1)In Thai medicine to treat leucorrhoea, oral disease, stomach discomfort, health promotion, as antifungal, antiflatulent, antiplasmodial agent, powder with ethanol used to cure peptic ulcers, diabetes, asthmaThailand (country in Asia)Water and ethanol extract of root [31]Induce upregulation ofIFN-β and TNF-α mRNA expression that inhibit viral replication in Madin-Darby canine kidney (MDCK) cells in an in vitro investigation [31]12.MagnoliaceaeMagnolia officinalis Rehder & Wilson [Houpo magnolia]Dengue virus type 2In eastern medicine, Chinese medicine Hou-Pu that have been used in analgesic, distension, or anxiety relief [46]China (country in East Asia)Methanolic extract of bark [47]Inhibits intracellular DENV-2 replicon [47]13.LamiaceaeThymus carmanicus Jalas [Avishan]Human immunodeficiency virus type 1 (HIV-1)Decoction and infusion used for cold in Iranian traditional medicine, as anti-inflammatory, digestive, carminative agentsIran (country in Western Asia)Methanolic extract of root [29]Effect on peripheral blood mononuclear cells (PBMCs) toxicity and HIV-1 replication [29]14.LamiaceaeThymus vulgaris L. [thyme]Human immunodeficiency virus type 1 (HIV-1)Decoction and infusion used for cold in Iranian traditional medicine, in folk medicine for asthma and bronchitis, as anti-inflammatory, digestive, carminative, antiseptic, antifungal, antiviral, antimicrobial agentsIran (countries in Western Asia)Methanolic extract of root [29]Effect on peripheral blood mononuclear cells (PBMCs) toxicity and HIV-1 replication [29]15.LamiaceaeThymus kotschyanus Boiss. & Hohen. [thyme]Human immunodeficiency virus type 1 (HIV-1)Decoction and infusion used for cold in Iranian traditional medicine, as anti-inflammatory, digestive, carminative agentsIran (country in Western Asia)Methanolic extract of root [29]Effect on peripheral blood mononuclear cells (PBMCs) toxicity and HIV-1 replication [29]16.LamiaceaeThymus daenensis Celak [thyme]Human immunodeficiency virus type 1 (HIV-1)Decoction and infusion used for cold in Iranian traditional medicine, as anti-inflammatory, digestive, carminative agentsIran (countries in Western Asia)Methanolic extract of root [29]Effect on peripheral blood mononuclear cells (PBMCs) toxicity and HIV-1 replication [29]17.MyrtaceaePsidium guajava L. [guava]Avian influenza virus (H5N1)In South-Eastern Nigeria to treat cough, malaria, stomach disorders, and loss of appetiteNigeria (country in West Africa) [48]Water and ethanolic extract of dried leaves [31]Induce upregulation ofIFN-β and TNF-α mRNA expression that inhibit viral replication in Madin-Darby canine kidney (MDCK) cells in an in vitro investigation [31]18.VerbenaceaeClerodendrum serratum (L.) Moon. [Bharangi]Yellow fever virusUsed in Yunani, Ayurveda, traditional Chinese medicine, Japanese Kampo medicineChina, Japan (countries in East Asia) [49]Ethanolic and methanolic extract of whole plant [50]Prevent viral infection through the bite of mosquito vector [50]19.CombretaceaeTerminalia chebula Retz. [Chebulic myrobalan]EnterovirusUsed in Yunani, Ayurveda, traditional Chinese medicine, Japanese Kampo medicineChina, Japan (countries in East Asia) [49]Ethanolic and methanolic extract of leaves [50]Inhibits viral replication [50]20.VitaceaeAmpelocissus tomentosa (Heyne ex Roth) Planch. [hairy wild grape]Chikungunya virusUsed in Yunani, Ayurveda, traditional Chinese medicine, Japanese Kampo medicineChina, Japan (countries in East Asia) [49]Ethanolic and methanolic extract of root [50]Inhibits viral replication [50]21.CrassulaceaeKalanchoe pinnata (Lam.) Pers. [flaming Katy]Chikungunya virusUsed in Yunani, Ayurveda, traditional Chinese medicine, Japanese Kampo medicineChina, Japan (countries in East Asia) [49]Ethanolic and methanolic extract of leaves [50]Inhibits viral replication [50]22.CupressaceaeThuja orientalis L. [Chinese thuja]Severe acute respiratory syndrome coronavirus (SARS-CoV)In traditional medicine and homeopath, to treat bronchitis, skin infection, excessive menstruation, arthritic pains, coughs, dysentery, named as Chinese Thuja, in other regions of the Asian continentChina (country in East Asia) and in other regions of the Asian continentOil extract of plant [51]Inhibits viral replication [51]23.CupressaceaeJuniperus oxycedrus L. [Cade juniper]Severe acute respiratory syndrome coronavirus (SARS-CoV)In infectious disease, colds, fungal infections, cough, gynecological disease, wounds in Turkish folk medicine, as anti-inflammatory and antinociceptiveTurki (lying partly in Asia and partly in Europe) [52]Oil extract of plant [51]Inhibits viral replication [51]24.ElaeagnaceaeHippophae rhamnoidesL. [Sea buckthorn]Dengue virus type-2 (DENV-2)In Tibetan traditional and Chinese medicineTibet is a part of China (country of East Asia) [53]Alcoholic extract of leaves [33]Decreases THF-α, increases INF-γ production, increases cell viability in in vitro assay against dengue virus type-2 [33]25MenispermaceaeTinospora cordifolia (Thunb.) Miers [Guduchi]Dengue virus (DENV)In traditional folk medicine of India for treating diabetesIndia (country in South Asia) [54]Decoction of stems [55]Reduce inflammation and fever, enhance the killing ability of macrophages [55]There is not a single medicine, which is globally accepted for the treatment of dengue fever. However, extracts obtained from different plants are expected to lower the severity of dengue viruses by increasing the platelet count, which includesCarica papaya leaf extract that is used by the local people of North Eastern plain zone of India, Madhya Pradesh [33, 56], whole plant of Andrographis paniculata (bitterweed), Alternanthera sessilis (sessile joyweed), Achyranthus aspera (prickly chaff flower), and Solanum xanthocarpum (yellow-fruit nightshade), and leaf and bark of Calotropis procera (calotrope) used in Bihar by traditional healers [32, 33]. In some clinical trials, it has been confirmed that the administration of leaf extract of Carica papaya (papaya) on patients with dengue fever increases their platelet count [33, 45]. More specifically, as we are facing SARS-CoV-2 in present days, so it is required to know the name of the phytochemicals and their classes to check the intensity of this virus [57]. Table 2 represents a list of phytochemicals acting against various targets of SARS-CoV-2, where most of the phytochemical binds with spike protein ACE2 (like anthraquinone, emodin, rhein, and cinnamaldehyde) or inhibits main protease (Mpro) (like somniferine, isorientin, and gallocatechin-3-gallate) [57].Table 2
List of phytochemicals acting against various targets of SARS-CoV-2.
Sl no.PhytochemicalClass of phytochemicalTargetsReference1.FisetinFlavonoidBind with spike protein like hACE2-S[58]2.QuercetinFlavonoidBind with spike protein[58]3.DithymoquinoneTerpeneInhibits spike glycoprotein-ACE2 interface[59]4.Glycyrrhizic acidSaponinBinds with spike protein RBD-ACE2[60, 61]5.HesperidinFlavonoidBind with spike protein ACE2[62]6.EmodinFlavonoidBind with spike protein ACE2[62]7.CarvacrolPhenolInteracts with spike protein ACE2[59]8.RheinFlavonoidBind with spike protein ACE2[62]9.KaempferolFlavonoidBind with spike protein hACE2-S[58]10.CinnamaldehydeFlavonoidInteracts with spike protein ACE2[59]11.Cinnamyl acetateStyreneInteracts with spike protein ACE2[59]12.ChrysinFlavonoidBind with spike protein ACE2[62]13.AnthraquinoneFlavonoidBind with spike protein ACE2[62]14.AnetholeFlavonoidInteracts with spike protein ACE2[59]15.GeraniolTerpeneInteracts with spike protein ACE2[59]16.L-4-terpineolTerpeneInteracts with spike protein ACE2[59]17.AndrographolideTerpenoidInhibits Mpro protease[63]18.Withanoside VInhibits Mpro protease[64]19.SomniferineInhibits Mpro protease[64]20.Epigallocatechin gallatePhenolInhibits Mpro protease[65]21.Gallocatechin-3-gallatePhenolInhibits Mpro protease[65]22.TinocordisideInhibits Mpro protease[64]23.ViceninInhibits Mpro protease[64]24.IsorientinInhibits Mpro protease[64]25.BerbamineTargets on spike protein ACE2[66]26.CastanospermineReduced viral RNA[67]27.Epicatechin gallatePhenolInhibits Mpro protease[65]Ethanolic and methanolic extracts ofAmpelocissus tomentosa (root), Clerodendrum serratum (whole plant), and Terminalia chebula (leaves) are effective against chikungunya virus, yellow fever virus, and entero virus, respectively [50]. Flavonoid extract of Litchi chinensis inhibits 3CLpro [51, 68], and plant extracts of Juniperus oxycedrus (cade juniper), Laurus nobilis (bay tree), Thuja orientalis (thuja) act as viral growth inhibitor [51] against SARS-CoV. Ethanolic extract of Broussnetia papyrifera (paper mulberry) containing Kazinol F and Broussochalcone A, and 3′-(3-methylbut-2-enyl)-3′,4,7-trihydroxyflavane showed noncompetitive inhibition on papain like protease (PLpro) of MERS-CoV and SARS-CoV, respectively [69, 70]. The flavonoids like cinnamaldehyde, chrysin, and anethole bind with spike protein ACE2 of SARS-CoV-2 virus [59, 62]; tinocordiside, somniferine, and withanoside V [64] inhibit Mpro protease, which cleaved translated polypeptides to liberate nonstructural proteins.


## 4.2. Plant-Derived Active Compounds for Prevention of RNA Viral Diseases in Human

Nowadays, huge proportions of global population choose easily available natural product from their nearby sources to get relief from the emerging health problems. This awareness of common people has induced the interest of the scientists to invent new formulations of plant extracts on the basis of traditional ethnopharmacological knowledge. Sequentially, many pharmaceutical companies are now engaged to produce natural antimicrobial formulations to meet the demand of the global market [71]. Ignatov (2020) explained that high levels of potassium reported from Moringa oleifera helps the patient of COVID-19 to decrease the rate of infection caused by the SARS-CoV-2 virus. Different plants induce the production of numerous secondary metabolites such as phenolics, essential oils, glycosides, coumarins, alkaloids, terpenoids, and peptides mainly in response to microbial infections or to avoid herbivores and other organisms (Figure 4).Figure 4
Important phytochemicals obtained from medicinal plants.These metabolites have been accepted to play an essential role in boosting of the immune system and manifesting of antiviral potential [27, 72]. There are several phytochemicals, which are found to be effective against different RNA viruses also; some of which are listed in Table 3.Table 3
Lists of phytochemicals against RNA viruses causing human diseases.
RNA typeName of virusesFamilyTherapeutic phytochemicalsReferencePositive-sense ssRNADengue virusFlaviviridaeFlavonoid, alkaloid, phenol, and coumarins[73, 74]Hepatitis C virusFlaviviridaeFlavonoid, alkaloid, lignan, terpenes, and terpenoids[75, 76]Japanese encephalitis virusFlaviviridaeFlavonoid[77]Zika virusFlaviviridaeFlavonoid[78]Severe acute respiratory syndrome coronavirus (SARS-CoV)CoronaviridaeFlavonoid (luteolin, curcumin, myricetin, quercetin), anthraquinone (emodin)[51]Chikungunya virusTogaviridaeFlavonoid, terpenes, coumarins, and terpenoids[73, 76, 79]CoxsackievirusPicornaviridaeFlavonoids[80]Hepatitis A virusPicornaviridaeFlavonoids and alkaloids[81]EnterovirusPicornaviridaeFlavonoids[74]Human immunodeficiency virusRetroviridaeTerpenes and terpenoid lignan, and coumarin[82, 83]Negative-sense ssRNARespiratory syncytial virusParamyxoviridaeLignan[84]Infectious hematopoietic necrosis virusRhabdoviridaeCoumarin[85]Influenza virus (H3N2, H5N2, H5N1, H1N1)OrthomyxoviridaeFlavonoid, alkaloid, lignan, coumarin, terpenes, and terpenoid[86, 87]Few recurrent and non-recurrent viral infections include human immunodeficiency virus type 1 (HIV-1) and 2 (HIV-2) [27], hepatitis C virus [6], dengue virus [33], and poliovirus. Furthermore, the control and prevention of different emerging viral diseases are imposing a great challenge to the society [88]. About 500,000 plant species are estimated to be present in the world. Interestingly, 10-15% among them are being used as drugs and 10% as a source of food [89]. However, the rapid extinction of some species leads to irretrievable loss of potential phytochemicals and also imposes another serious threat. The anti-RNA viral activity of active compounds from some medicinal plants have been reviewed and summarized in Table 4.Table 4
Medicinally important plant-derived active compounds used for curing human RNA viral diseases.
S. no.FamilyPlant nameActive compoundFamily of virusVirus nameType of viral RNAHuman diseasesReference5.TheaceaeCamellia sinensis (L.) Kuntze [tea]TheaflavinCoronaviridaeSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2)Positive-sense ssRNACoronavirus disease 2019 (COVID-19)[90]6.AcanthaceaeAndrographis paniculata (Burm. f.) Nees [Kalmegh]AndrographolideTogaviridaeChikungunya virus (CHIKV)Positive-sense ssRNAChikungunya fever[91]7.AncistrocladaceaeAncistrocladuskorupensis D.W. Thomas & GereauNaphthylisoquinoline alkaloids from root barkRetroviridaeHuman immunodeficiency virus (HIV)Positive-sense ssRNAAIDS[27]8.BerberidaceaeBerbaris amurensis Rupr. [Amur barberry]BerbamineCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[66]9.AncistrocladaceaeAncistrocladus congolensis J, LéonardMichellamine-type dimeric naphthylisoquinoline alkaloids from root barkRetroviridaeHuman immunodeficiency virus (HIV)Positive-sense ssRNAAIDS[92]10.FabaceaeCastanospermum australe A.Cunn & C.Fraser ex Hook. [Blackbean]CastanospermineCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[67]11.HalymeniaceaeCryptonemiacrenulata (J.Agardh) J.AgardhGalactanFlaviviridaeDengue virus type 2, 3 and 4 (DENV-2, DENV-3, DENV-4)Positive-sense ssRNADengue (Breakbone fever)[39]12.ApiaceaeBupleurum sp.Triterpene glycosides (named Saikosaponins B2)CoronaviridaeHuman coronavirus 229E (HCoV-22E9)Positive-sense ssRNANosocomial respiratory viral infection (NRVI)[93]13.FabaceaeTephrosia madrensis Seem. [Hoarypea]Glabranine and 7-O-methyl-glabranine from leaves and flowersFlaviviridaeDengue virus (DENV)Positive-sense ssRNADengue (Breakbone fever)[94]14.ApiaceaeHeteromorpha sp.Triterpene glycosides (named Saikosaponins B2)CoronaviridaeHuman coronavirus 229E (HCoV-22E9)Positive-sense ssRNANosocomial respiratory viral infection (NRVI)[93]15.MoraceaeBroussnetiapapyrifera (L.) Vent. [paper mulberry]Kazinol F, Broussochalcone A from rootsCoronaviridaeMiddle Eastern respiratory syndrome coronavirus (MERS-CoV)Positive-sense ssRNAMiddle Eastern respiratory syndrome[69, 70]16.NelumbonaceaeNelumbo nucifera Gaertn. [lotus]IsoliensinineCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[95]17.NelumbonaceaeNelumbo nucifera Gaertn. [lotus]LiensinineCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[95]18.MoraceaeBroussnetiapapyrifera (L.) Vent. [paper mulberry]3′-(3-Methylbut-2-enyl)-3′,4,7-trihydroxyflavane from rootsCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[70]19.PolygonaceaeReynoutria multiflora (Thunb.) MoldenkeEmodinCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51]20.RanunculaceaThalictrum podocarpum Kunth ex DC. [Meadow-rue]HernandezineCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[96]21.PolygonaceaeRheum officinale L. [Chinese rhubarb]EmodinCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51]22.ZingiberaceaeCurcuma longa L. [turmeric]CurcuminCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51]23.NelumbonaceaeNelumbo nucifera Gaertn. [lotus]NeferineCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[95, 96]24.MyricaceaeMyrica faya Ait. [fire tree]MyricetinCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51]25.MeliaceaeToona sinensis (A.Juss.) M.Roem. [Chinese mahogany]QuercetinCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51]26.RubiaceaeCinchona officinalis L. [Lojabark]QuinacrineCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[97]27.LinaceaeLinum usitatissimum L. [Flax]HerbacetinCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51, 68]28.LamiaceaeScutellaria lateriflora L. [blue skullcap]ScutellareinCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51]29.FabaceaePterocarpus santalinus L. f. [red sanders]SavininCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51]30.CupressaceaeChamaecyparis obtusa var. formosana [Taiwan yellow cypress]Betulonic acid, Savinin, HinokininCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51]31.CelastraceaeTriterygium regelii Sprag. & Takeda [Regel’s threewingnut]Iguesterin, Tingenone, Pristimerin, CelastrolCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51]32.BrassicaceaeIsatisindigotica fortune [Chinese woad]Sinigrin, HesperetinCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51]33.AmaryllidaceaeAllium sativum L. [garlic]Allyl trisulfide, allyl disulfideCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51, 98]34.AcanthaceaeAndrographis paniculata (Burm. f.) Nees [Kalmegh]AndrographolideCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[88]35.MeliaceaeAglaia sp.SilvestrolCoronaviridaeHuman coronavirus 229E (HCoV-229E)Positive-sense ssRNANosocomial respiratory viral infection (NRVI)[70, 99]36.MeliaceaeAglaia sp.SilvestrolCoronaviridaeMiddle Eastern respiratory syndrome coronavirus (MERS-CoV)Positive-sense ssRNAMiddle Eastern respiratory syndrome[99]37.RanunculaceaeNigella sativa L. [black cumin]DithymoquinoneCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[59]38.SolanaceaeWithania somnifera (L.) Dunal [Ashwagandha]Withanoside VCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[64]39.SolanaceaeWithania somnifera (L.) Dunal [Ashwagandha]SomniferineCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[64]40.PhyllophoraceaeGymnogongrusgriffithsiae (Turner) C. MartiusSulphated polysaccharide (named kappa carrageenan) from whole plantsFlaviviridaeDengue virus type 2 (DENV-2)Positive-sense ssRNADengue (Breakbone fever)[94]41.SolanaceaeAtropa belladonna L. [belladonna]l-hyoscyamine, atropine, Belldonic, Scopoletin (l-methyl aesculetin), hyoscine, and pyridine and N-methyl pralineFiloviridaeEbola virusNegative-sense ssRNAEbola haemorrhagic fever (Ebola HF)[100, 101]42.ScrophulariaceaeScrophularia scorodonia L. [Balm-leaved Figwort]Triterpene glycosides (named Saikosaponins B2)CoronaviridaeHuman coronavirus 229E (HCoV-22E9)Positive-sense ssRNANosocomial respiratory viral infection (NRVI)[93]43.ChordariaceaeCladosiphonokamuranusTokida [Mozuku]Fucoidan from whole plantsFlaviviridaeDengue virus type 2 (DENV-2)Positive-sense ssRNADengue (Breakbone fever)[94]44.FabaceaeLeucaena leucocephala (Lam.) de Wit [white leadtree]Galactomanan from seedsFlaviviridaeDengue virus (DENV)Positive-sense ssRNADengue (Breakbone fever)[94]45.TheaceaeCamellia sinensis (L.) KuntzeEpicatechin gallateCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[65]46.MenispermaceaeTinospora cordifolia (Thunb.) Miers [Gurjo]TinocordisideCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[64]47.FabaceaeMimosa scabrella Benth. [Bracatinga]Galactomanan from seedsFlaviviridaeDengue virus (DENV)Positive-sense ssRNADengue (Breakbone fever)[94]48.CelastraceaeCassine xylocarpa Vent. [Marbletree]Pentacyclic lupane-type triterpenoidsRetroviridaeHuman immunodeficiency virus (HIV)Positive-sense ssRNAAIDS[9]49.CelastraceaeMaytenus cuzcoina Loes.Pentacyclic lupane-type triterpenoidsRetroviridaeHuman immunodeficiency virus (HIV)Positive-sense ssRNAAIDS[9]50.PhyllanthaceaePhyllanthus emblica L. [Indian gooseberry]Highly oxygenated norbisabolane sesquiterpenoids (Phyllaemblicins H1-H14) from rootOrthomyxoviridaeInfluenza A virus strain H3N2Negative-sense ssRNAInfluenza (flu)[9]51.LamiaceaeOcimum sanctum L. [Tulsi]ViceninCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[64]52.MagnoliaceaeMagnolia officinalis Rehder & Wilson [Houpo magnolia]HonokiolFlaviviridaeDengue virus type 2 (DENV-2)Positive-sense ssRNADengue (Breakbone fever)[9]53.LamiaceaeOcimum sanctum L. [Tulsi]4′-O-glucoside 2″-O-p-hydroxybenzoagteCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[64]54.FabaceaeTephrosia madrensis Seem.Methyl-hildgardtol A from leaves and flowersFlaviviridaeDengue virus (DENV)Positive-sense ssRNADengue (Breakbone fever)[94]55.LamiaceaeOcimum sanctum L. [Tulsi]IsorientinCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[64]56.TheaceaeCamellia sinensis (L.) KuntzeGallocatechin-3-gallateCoronaviridaeRespiratory syndrome coronavirus-2 (SARS-CoV-2)Positive-sense ssRNACOVID-19[65]57.FabaceaeLeucaena leucocephala (Lam.) de Wit [White leadtree]Epicatechin gallateFlaviviridaeYellow fever virusPositive sense ssRNAYellow fever[94]58.PapaveraceaeChelidonium majus L. [greater celandine]Low-sulfated poly-glycosaminoglycan moiety from freshly prepared crude extractRetroviridaeRetrovirus (HIV)ssRNAAIDS[27]59.GentianaceaeSwertia bimaculata (Siebold & Zucc.) Hook. f. & Thomson ex C.B. Clarke [double-spotted Swertia]SesterterpenoidRetroviridaeHuman immunodeficiency virus (HIV)Positive-sense ssRNAAIDS[27, 102]60.GentianaceaeSwertia punicea Hemsl.XanthoneRetroviridaeHuman immunodeficiency virus (HIV)Positive-sense ssRNAAIDS[27]61.EuphorbiaceaeEuphorbia neriifolia L. [Indian Spurge Tree]Diterpenoids (named eurifoloids E and F)RetroviridaeHuman immunodeficiency virus (HIV)Positive-sense ssRNAAIDS[27]62.MenispermaceaeStephania tetrandra S. Moore [Fen Fang Ji]Tetrandrine, Cepharanthine, FangchinolineCoronaviridaeHuman coronavirus OC43 (HCoV-OC43)Positive-sense ssRNA—[70, 103]63.AcanthaceaeRhinacanthus nasutus (L.) Kurz [Snake jasmine]Lawsone methyl ether from leavesRetroviridaeHuman immunodeficiency virus (HIV)Positive-sense ssRNAAIDS[27]64.LauraceaeLaurus nobilis L. [bay tree]Beta-ocimene, 1,8-cineole, alpha-pinene, beta-pinene in extracted oil from plantCoronaviridaeSevere acute respiratory syndrome coronavirus (SARS-CoV)Positive-sense ssRNASevere acute respiratory syndrome (SARS)[51]65.RanunculaceaeNigella sativa L. [black cumin]Thymoquinone, nigellimineCoronaviridaeSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2),Positive-sense ssRNACoronavirus disease 2019 (COVID-19)[104]Few preidentified compounds from different traditional medicinal plants of China showed protective actions against SARS-CoV-2 like betulinic acid, lignin, and sugiol on replication and chymotrypsin-like protease (3CLpro); coumaroyltyramine, cryptotanshinone, kaempferol, N-cis-feruloyltyramine, quercetin, and tanshinone IIa on papain like protease (PLpro) and 3CLpro; desmethoxyreserpine on replication, 3CLpro, and entry; dihydrotanshinone on entry and spike protein; and dihomo-c-linolenic and moupinamide on 3CLpro and PLpro, respectively, to prevent COVID-19 [70, 105]. Furthermore, theaflavin of Camellia sinensis (tea) shows biological action by binding on RNA-dependent RNA polymerase against SARS-CoV-2 [90]. Several drugs, which are previously approved by FDA for other diseases, are again used for the treatment of COVID-19 patients. These drugs include chloroquine and hydroxychloroquine, which are generally used as inhibitors of endosomal acidification fusion and auranoin for redox enzymes that helps to treat rheumatoid arthritis [106, 107]. Allyltrisulfide and allyldisulfide isolated from Allium sativum (garlic) act as ACE2 receptor inhibitors [51, 98]; herbacetin from Linum usitatissimum (flax) [51, 68], betulonic acid, savinin, and hinokinin from Chamaecyparis obtusa var. formosana (Taiwan yellow cypress) act as 3CLpro inhibitor against SARS-CoV; Scutellaria lateriflora (blue skullcap) helps to prevent SARS-CoV by scutellarein as helicase inhibitor [51]. Furthermore, thymoquinone and andnigellimine from Nigella sativa (fennel flower) show the blocking of virus entry into pneumocyes and increasing the Zn2+ uptake to boost host immune response against SARS-CoV-2 [104]. The recent evidences showed that vicenin, isorientin, and 4′-O-glucoside 2″-O-p-hydroxybenzoagte obtained from Ocimum sanctum L. inhibit Mpro protease activity during SARS-CoV-2 viral infection [64].In case of the treatment of Ebola virus, many alkaloids are isolated fromAtropa belladonna that gives a positive result and cure of Ebola haemorrhagic fever (Ebola HF) [100, 101], whereas a sulfated polysaccharide, fucoidan isolated from Cladosiphon okamuranus, and sulphated polysaccharide (named kappa carrageenan) from whole plants of Gymnogongrus griffithsiae [94] worked against dengue virus type 2 (DENV-2). Cytarabine and matrine are two important active constituents found in the extract of Gillan’s plants such as chuchaq and trshvash, respectively, whereas these compounds have the potentiality of better binding interaction with the receptors and show anti SARS-CoV-2 activity by inhibiting the initiation of viral infection [108].There are three species ofTephrosia (viz. T. crassifolia, T. madrensis, and T. viridiflora), which can able to produce huge number of flavonoids and show antiviral activity against dengue virus. Among them, glabranine and 7-O-methyl-glabranine isolated from T. madrensis showed strong inhibitory effects on dengue virus replication in LLC-MK2 cells. Interestingly, moderate to low inhibitory effect was observed by methyl-hildgardtol A isolated from T. crassifolia. However, hildgardtol A of T. crassifolia and elongatine of T. viridiflora do not show any inhibitory effect on viral growth [94]. Honokiol (a lignin biphenol) derived from Magnolia tree has antiviral activity against serotype 2 dengue virus (DENV-2). This novel molecule can be able to interfere on the endocytosis of virus to reduce its double-strand RNA, by abrogating the colocalization of DENV envelope proteins. Inhibitory activity of honokiol was proved by suppressing the replication of DENV-2 in baby hamster kidney (BHK) and human hepatocarcinoma Huh7 cells [9, 47].In the Chinese herbal medicine, extracts ofLonicerae japonicae (Japanese honeysuckle), Flos (ragged-robin), and Fructus forsythia (Lianqiao) are used together as an antimicrobial and anti-inflammatory agent. Interestingly, chito-oligosaccharide in combination with herbal mixture can also act as an anti-influenza agent [64].


## 5. Major Challenges and Future Perspectives

Nowadays, the acceptance of herbal medicines is increasing for many reasons as it is less expensive, with less or null side effects and better patient tolerance. From the past to recent studies, it can be speculated that quality and safety study of plant-derived compounds with medicinal importance is required. Therefore, scientific, accurate, and informative studies are obligatory for any potent compound, which have isolated from plants [21]. About half million plants with medicinal properties are estimated to be present around the world. Surprisingly as well as grievously, most of them are yet not investigated [109]. It is required to give more attention to taxonomic characters and identification of wide range of medicinal plants throughout the world [21]. Various pharmacologically important peptides or proteins obtained from different medicinal plants can be introduced in the production of vaccines and therapeutics. The main challenge in this field of research is the extraction procedure. In this connection after establishment of a compound as a potent therapeutic agent, researchers have to increase its production in both in vitro and ex vitro conditions. This is also very challenging but can be resolved by using sophisticated techniques of recombinant DNA technology, elicitation, etc. [26]. Along with these, identification of biosynthetic pathway of that particular product and application of transgenic approach can be used as feasible way to enhance the production of that particular product. Different scientific approaches can also be taken to identify the newer plant-derived compounds with potential pharmacological activities. This can be considered as an emerging field of scientific research with global profit. Furthermore, it was already expected by [21] that within the year of 2020, the whole market in Asia-Pacific for herbal supplements reached more than US$115 billion and about more than that much turnover happened in 2021, i.e., US$140 billion [21]. It is also explained in the report of Asia Pacific Nutritional Supplements Market Size, Share & Trends Analysis Report with a report ID of GVR-4-68038-105-4 that it is expected that it will expand about 6.1% at a compound annual growth rate (CAGR) starting from 2022 to 2030. So, it is clear that the use of herbal supplements and ethnic medicines are increasing day by day. In the recent days, several RNA interference (RNAi)-based technologies and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas technology have appeared to control viruses. It helps by either directly targeting the viral RNA or DNA or by inactivating plant host susceptibility gene [110]. The CRISPR-Cas system is a technology, which uses in diagnosis of various infectious RNA viruses like SARS-CoV-2 and HIV. This is undertaken as a potential technology for its accuracy both in therapeutic and molecular diagnosis [111].


## 6. Conclusion

Standing in the current circumstance of global pandemic of COVID-19, that causes huge damage of human health and also destroys economic backbone of a country, researchers are constantly trying to find out the way by which mankind will be safe from the fourth or fifth wave of virus onslaught. At this time of high crisis period, we all want something to eradicate or bypass the disease. We reviewed the plant extracts and/or extracted and identified active compounds from the medicinal plants that are useful for prevention of many RNA viral diseases, focusing on plant extracts and phytochemicals that have already reached in clinical trials and having highlighting properties to prevent the viruses. Along with disruption of global health, RNA viruses have immense potential to stop the economic growth of a country. However, for prevention of those diseases and to secure human populations, antiviral drug discovery is needed. Till date, many traditional medicinal plants were reported to have strong antiviral activities. Medicinal plants contain active compounds like alkaloids, saponins, flavonoids, tannins, polysaccharides, proteins, and peptides. These compounds can help in the prevention of viral diseases by blocking the virus entry and/or via the inhibition of viral replication at the different stages by regulating the enzyme actions as well and specially without having any known side effects. Finally, the improvement of newly discovered medicinal plant products is vital and required for controlling the constant threats of deadly contagious RNA viruses. This review enlightens some way with lesser hazard to combat in this epidemic era of RNA virus like COVID-19. It is necessary to further examine by highlighting drug delivery system of antiviral phytochemical to reach successfully in their intended site of action.



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