An overview on medicinal plants used for combating coronavirus: Current potentials and challenges

Abstract

Worldwide, Severe acute respiratory syndrome Coronavirus (SARS-CoV-2) pandemic crisis, causing many morbidities, mortality, and devastating impact on economies, so the current outbreak of the CoV-2 is a major concern for global health. The infection spread quickly and caused chaos in many countries around the world. The slow discovery of CoV-2 and the limited treatment options are among the main challenges. Therefore, the development of a drug that is safe and effective against CoV-2 is urgently needed. The present overview briefly summarizes CoV-2 drug targets ex: RNA-dependent RNA polymerase (RdRp), papain-like protease (PLpro), 3-chymotrypsin-like protease (3CLpro), transmembrane serine protease enzymes (TMPRSS2), angiotensin-converting enzyme 2 (ACE2), structural protein (N, S, E, and M), and virulence factors (NSP1, ORF7a, and NSP3c) for which drug design perspective can be considered. In addition, summarize all anti-COVID-19 medicinal plants and phytocompounds and their mechanisms of action to be used as a guide for further studies.

Graphical abstract

1. Introduction

Due to the lack of effective anti-CoVs agents, its infection has spread rapidly and caused havoc worldwide [1]. Causes acute respiratory distress syndrome which can lead to death [2]. Corona vitus has high transmission efficiency and long life [[1], [3], [4]].The CoV-2 (Fig. 1 ) is similar to Severe Acute Respiratory Syndrome (SARS-CoV), and Middle East Respiratory Syndrome (MERS-CoV), belongs to the same genus BetaCoV [[1], [3], [4], [2], [5]], which includes the largest single-stranded RNA virus with positive significance [6]. Genome sequence analysis of these three CoVs showed that CoV-2 had a higher similarity with SARS-CoV compared to MERS-CoV [7]. CoVs contain at least four structural proteins: envelope protein (E), spike protein (S), nucleocapsid protein (N), and membrane protein (M) [8]. Among these, S protein promotes host binding and membrane fusion between the virus and cells during viral infection. Therefore, S protein is considered an important target.

Fig. 1.

CoVs anatomy [9].

For the sake of the development of a treat against COVID-19, the best and fastest path could be to discover powerful drugs from those available in the market. Once effective proved, it can be rapidly used for rapid clinical care of patients. Drug discovery against CoV is a major challenge because of frequent recombination events. Vaccine development is another important aspect. There is a great need for further details on the biological structure and life cycle of CoV that can accelerate the CoV drug/vaccine development. Again, as a precaution, close monitoring of virus changes on different hosts is important to predict an event [10].

Powerful anti-COVID-19 treatments could be divided into two classes upon their targets, the first class is targeting the human immune system and the other class of treatment is targeting the CoV. In relation to immunity, the immune system response plays a crucial role in inhibiting CoV replication and blocking human cell signaling pathways [11]. Therapies that inhibit the CoV include blocking CoVs from binding to host receptors angiotensin-converting enzyme 2 (ACE2) and preventing RNA synthesis and replication by inhibiting critical enzymes. In the fight against the CoV, researchers have suggested three strategies for developing new therapies [12]. The first strategy is to test existing broadband anti-virus agents [13]. This category includes interferon, ribavirin, and cyclophilin inhibitors, which are used to treat COVID. Their benefits include the nature of their metabolic properties, the high efficacy, the minimal side effects, and being available in acceptance dosage used, as it is clear that it is approved for the treatment of COVID. However, there are some disadvantages, for example, such kind of therapy is too "diversified" and cannot deliberately kill the CoV and in some cases show side effects. The second strategy is to use molecular screening for compounds that may have a powerful effect against CoV [14,15]. Through this strategy, new activities of many compounds can be discovered. The third strategy is based directly on the pathological and genomic information of CoVs to develop new targeted agents. Drugs discovered through this kind of therapy may show better anti-CoVs activities, but the process of testing for new drugs may take many years [11].

So far, numerous Chinese herbs and natural ingredients have been reported to have antiviral effects. Among the pharmacotherapy agents evaluated in China, some drugs evaluated included favipiravir, piperacin, artemisinin, adalimumab, leflunomide, dipyridamole, chloroquine, lopinavir/ritonavir, arbidol, and high-dose vitamin C. Other potent herbal mixtures being evaluated for example: Shen-Fu injection, Xiyanping injection, etc., the use of stem cells is also frequently assessed [10].

Herbal medicines are considered as protective agents in the fight against COVID-19 and provide a fast track approach in the treatment. Medicinal plants provide rich resources for the development of new antiviral drugs. Several natural medicines have been shown to have natural antiviral activity against many types of viruses, including herpes virus [[16], [17], [18], [19], [20], [21]], influenza virus [22,23], HIV [[24], [25], [26]], hepatitis B and C [27], SARS and MERS [28,29]. Tremendous efforts have also been made to uncover the antiviral action mechanisms of medicinal plants and their natural substances on virus lifecycle, such as virus entry (S protein, ACE2), replication (3CLpro, PLpro, helicase, N protein, and RdRp), assembly (E, and M protein), viral release, and host-specific interactions.

The present review briefly describes the latest developments in the structure features determination of CoVs. In addition, provides comprehensive and up-to-date information on medicinal plants and natural products with promising antiviral potential against the CoVs and discusses their molecular pathway.

2. CoV life cycle

Understanding the life cycle of the CoV is important for the development of anti-COVID-19 agents. CoV infection is triggered by the binding of the virus to cellular receptors. CoV enters humans via the respiratory tract, primarily through droplet transmission. In present review briefly summarize the CoV life cycle in ten steps, 1) Activation of S protein by TMPRSS2, 2) Binding of S protein to host receptor ACE2, 3) Membrane fusion, 4) Release of viral uncoated RNA into the host cell, 5) Translation into polyprotein, 6) Replication and translation, 7) Assembly into the virion, 8) Transport of the virions within vesicles, 9) Exocytosis (the vesicles containing the virus combine with the plasma membrane to release the virus), 10) Viral infection (Fig. 2 ) [30].

Fig. 2.

The CoV life cycle [30].

3. Screening for powerful drugs target CoV-2

The CoVs therapies can be divided into some categories (Fig. 3 ) based on their pathways for example: blocking CoV from binding to host cell receptors, preventing the virus from entering into host's cells, preventing viral RNA synthesis and replication, enhancing host's immunity, …etc.

Fig. 3.

CoVs therapies categories.

3.2. CoV targets

As a significant functional protein of the CoVs, RdRp, PLpro, 3CLpro, N protein, S protein, and helicase are considered the most important targets for the development of inhibitors. In addition, several non-structural proteins also play crucial roles in the synthesis and replication of viral RNA. Using these proteins could be very useful targets to detect anti-COVID-19 drugs. Table 1 summarizes CoVs targets and their natural inhibitors.

Table 1.

List of CoV target and their function.

Taget	Function	References
Replication enzymes
3CLpro(Nsp5)	Control the activities of CoV replication	[31]
PLpro (Nsp3)	Essential in the replication and infection for CoV	[32]
	Cleaves the N terminal of replicase polyprotein
	Causing the release Nsp1,2,3 which are in turn involved in viral replication
Helicase (Nsp13)	Enhances the efficiency of viral replication and proliferation through its NTPase	[33]
RdRp (Nsp12)	Essential protease enzyme that catalyze the replication of RNA template	[34]
Host receptors
ACE2	Functional cellular receptor	[35]
TMPRSS2	Cleaves C terminal segment of ACE2	[36]
	Enhancing S protein viral infection
Virulence factors
Nsp1	Induces host mRNA degradation by interacting with the host 40S ribosomal subunit	[37]
	Inhibit type 1 interferon production
ORF7a	Blocking the activity of BST2 by disturbing glycosylation of BST	[38]
Nsp3c	Bind to the human ADP ribose to help the CoVs resist host immunity	[39]
Structural protein
E protein	Morphogensis, phathogenesis and assembly of virus	[40]
	Interact with M protein to form the envelop
	Play a vital role in the infectivity
M protein	Transmembrane envelop protein, determine shape of the envelop	[41,42]
	Virus assembly, binding and fusion
S protein	Targeted by host neutrilizing antibodies	[43,44]
	S1:binding to host cell receptors (ACE2)
	S2: fusion of the virus, assembly of cell membrane
N protein	Replication and transcription by binding with RNA to make helical ribonucleoprotein	[45,46]

3.2.1. Papain-like protease (PLpro)

Papain-like protease (PLpro-Nsp3), is responsible for cleaving the N-terminus from the replicating polyprotein to release Nsps which are essential for correcting replication [32]. PLpro has also been confirmed to be important in fighting human immunity [[47], [48], [49]]. As an indispensable enzyme in the infection and replication of the CoVs in the host, PLpro is a valuable target for CoVs inhibitors.

The screening reported by Wu et al. [7], showed many anti-COVID-19 agents from natural sources such as baicalin, platycodin D, phaitanthrin D, sugetriol-3,9-diacetate, and catechin compounds possess high inhibition activity to PLpro, suggesting the effectiveness of these natural ingredients against CoVs.

3.1.2. Main proteases 3-chymotrypsin-like protease (3CLpro)

Proteases 3-chymotrypsin-like protease (3CLpro-Nsp5), is a virus-specific enzyme and the main protease (Mpro) in CoV-2. 3CLpro is released from the polyprotein to produce a mature enzyme [50]. 3CLpro mediates the maturation of Nsps. Inhibiting 3CLpro, has attracted more attention by researchers because it prevents the virus from inoculating a host [51,52]. The 3CLpro has been validated as a potential target for drug development for COVID-19 treatment [[53], [54], [55], [56]]. Various natural inhibitors have been developed to target various sites and regions of 3CLpro such as isoquercitrin, kaempferol, epicatechin, apigenin, myricitrin, lactucopicrin [[57], [58], [59]]. These studies could provide potential agents for the development of new anti- COVID-19 drugs [60]. A detailed study of the structure and catalytic mechanisms of 3CLpro makes 3CLpro an attractive target for the development of anti-COVID-19 drugs. Inhibitors targeting 3CLpro mainly include small molecule and peptide inhibitors [61,62]. Antihypertensive drugs (telmisartan and nicardipine), and drugs treating hyponatremia are showing the highest binding affinity for 3CLpro. In addition, ketoamide [63], serine derivatives [62], flavonoids [[63], [64], [65], [66], [67], [68], [69], [70], [71]], chalcon [72], pyrazolones [54], pyrithiobac derivatives, dipeptidyl aldehyde bisulfite, and peptide aldehyde, can strongly inhibit 3CLpro. In addition, peptidomimetic can competitively inhibit 3CLpro. Gurung et al. [51] showed that bonducellpin, cesalmin, and 5,7-dimethoxyflavonone-4′-O-β-d-glucopyranoside have high inhibiting activity to 3CLpro compared to the newly drug. In addition, the flavonoids of Caesalpinia minaxare and Viscum album exhibit promising inhibition to CoVs. Flavonoid is considered as one of the most common phytocompounds in plants, being biologically active, flavonoids have diverse effects on health [[73], [74], [75], [76], [77], [78], [79], [80], [81], [82], [83]]. Khaerunnisa et al. [84] examined natural metabolites that can inhibit 3CLpro, highlighting the important results of quercetin, kaempferol, luteolin-7-glucoside, demethoxycurcumin, naringenin, apigenin-7-glucosin, catechins, curcumin, and epigallocatechin. Apart from promising results for flavonoids, mono and sesquiterpenoids are also specialized metabolites which provide very interesting results suggesting a possible use of these ingredients. Mono and sesquiterpenes geraniol, linalool, (E) -β-farnese and (E) -nerolidol were inhibit 3CLpro, these compounds are found in various types of plants such as Cymbopogon citratus, Melissa officinalis, Lavandula angustifolia, Ocimum basilicum, Pelargonium graveolens, Citrus reshn, Cinnamomum zeylanicum, Matricaria recutita, and Zingiber officinale [85]. Marine algae are also considered as a potential source of 3CLpro inhibitors [47], and suggest algal polyphenols, known as florotanines and quercetin derivatives isolated from the genus Sargassum, for the development of therapy for COVID-19. Overall, the inhibitors of 3CLpro could have great potential for the development of anti-COVID-19 drugs.

3.1.3. RNA-dependent RNA polymerase (RdRp)

A new pathway for the development of chemotherapy against COVID-19 is a very specific mechanism for inhibiting RdRp (Nsp12) and thus CoV-2 replication. It is expected that metabolites with this property will be less cytotoxic than TMPRSS2 or ACE2 inhibitors.

Although RdRp inhibitors are less toxic, their use in treating CoVs is rare. Bibliographic studies show that the only substance that inhibits RdRp of the CoVs is remdezivir (Hermann, 2017) [86]. Molecular docking also offers some commercial drugs yet their effectiveness has not been proven [87]. Although the natural CoV-2 RdRp inhibitors previously filtered in essential oil are potentially useful for treating viruses, they have a lower docking value than those available commercially [85]. The natural molecules with anti-tumor, anti-inflammation, and anti-virus effects possess high inhibiting activity to RdRp, for example; Gniditrin and gnidicin from Gnidia lamprantha, betulonal from Campanula xylocarpa, theaflavin from Camellia sinensis, and andrographolide derivative [7].

3.2.4. Helicase

Helicase (Nsp13) has been reported to be necessary for CoV replication. Therefore, it has been identified as a target for the detection of antiviral agents, but there are few reports of helicase inhibitors [88,89]. Based on structure modeling of helicase protein, anti-fungal drug itraconazole, anti-bacterial drugs; rolitetracycline, cefsulodine and lymecycline, anti-coagulant drug dabigatran, diuretic drug canrenoic acid, and anti-HIV-1 drug saquinavir, were predicted to be helicase inhibitors. The natural products, such as flavonoids (hesperetin, hesperidin, rutin, and homovitexin), xanthones, and triptexanthoside D, phyllaemblinol and phyllaemblicin showed high activity against helicase [7].

3.3. Structural proteins

The CoVs contain four structural proteins which are responsible for virus assembly (E, M, N, and S) [90]. The following paragraphs focus on the S protein and N protein (Table 2 ).

Table 2.

Summary of CoVs targets and their natural inhibitors.

Target/function	Natural compounds	Ref
3CLpro inhibitors (control the activity of CoV replication)	Taiwanhomoflavone A, isoquercitrin, kaempferol, epicatechin(4β,8)epicatechin-(4β,6)-catechin, apigenin, epicatechin(4′,8)epigallocatechin, afzelin, myricitrin, quercetin-3-glucosyl-(1,4)-rhamnoside, lactucopicrin, vitetrifolin D, lactucopicrin 15-oxalate, (−)-asperlicin C, cassameridin, oriciacridone F	[91]
	Amentoflavone, glabrolide, zeylanone, 5,7,3′,4′-tetrahydroxy-2'-(3,3-dimethylallyl) isoflavone, mirycitrin, methyl rosmarinate, amaranthin	[92]
	Betulinic acid, cryptotanshinone, N-cis-feruloyltyramine, sugiol	[58]
	Kaempferol, quercetin, apigenine-7-glucoside, zingerol, gingerol, Epicatechin-gallate	[84]
	E-β-Farnesene, α-Copaene	[85]
	Diadiazin, genestein, formotein, biochanin A, palmitic acid, chlorogenic acid, caffeic acid	[87]
	Silybin, tetrahydrocurcumin, corydine	[93]
	Aloin, baicalin, geniposide, dictyosphaeric acid A, durumolide K, microcarpin, isogemichalcone B	[94]
PLpro	Baicalin, platycodin D, phaitanthrin D, sugetriol-3,9-diacetate, and catechin	[7]
RdRp inhibitors	betulonal, gnidicin, gniditrin, theaflavin, andrographolide derivative	[7]
Helicase inhibitors	Myrecetin, scutellarin, hesperitin, hesperidin, rutin, homovitexin xanthones and triptexanthoside D, phyllaemblicin B and phyllaemblinol	[7]
Natural metabolite binding with ACE2	Taiwanhomoflavone A, isoquercitrin, kaempferol, epicatechin(4β,8)epicatechin-(4β,6)-catechin, apigenin, epicatechin(4′,8)epigallocatechin, afzelin, myricitrin, quercetin-3-glucosyl-(1,4)-rhamnoside, lactucopicrin, vitetrifolin D, lactucopicrin 15-oxalate, (−)-asperlicin C, cassameridin, oriciacridone F	[91]
	Silybin, tetrahydrocurcumin, corydine, aloin, isoaloresin, quercetin, withaferin A, hinokinin, philligenin, chloroquinea, isoaloresin, withaferin A, hinokinin, philligenin	[93]
	Narigin, naringenin, hesperidin, hesperetin, neohesperidin, nobiletin	[95]
	Hupehemonside, pseudojervine, imperialine-3-β-d-glucoside, verdine, zhebeininoside	[96]
	Esculin, lactose, gingerenone, shogaol	[97]
	Excavatolide M, schisphenin A, citocoline, 5-methoxyhydnocarpin, curtisian L, (−)-Epicatechin 3-O-(3′-O-methyl) gallate	[94]
TMPRSS2 inhibitors	Baicalein, baicalin, and silvonoids	[ [87,94]]
HSPA5 inhibitors	Diadiazin, biochanin A, chlorogenic acid, palmitic acid, formontein, genistein, caffeic acid, caffeic acid phenethyl ester, hydroxytyrosol, linolenic acid, cis-p-Coumaric acid, cinnamaldehyde, thymoquinone	[98]
S protein inhibitors	lycoflavonol, cosmosin, neohesperidin, mangosteen, Kautensida D, excaryatoxinl, emodin	[99,100]
N protein inhibitors	Resveratrol, cepharanthine, fangchinoline, bis-benzylisoquinoline	[29]
Virulance factors inhibitors	Platycodin, wogonoside, cefpyramide, piperacillin, streptomycin, limecycline, vogonoside, glycyrrhizic acid, galangan, gingerenone, shogaol, tetra platycodon grandifloras, vitexin, andrographolide and xanthones derivatives.	[[7,97]]

3.2.1. Protein S

Protein S is the main structural protein of the CoVs and is strung together to form a special coral structure on the surface of CoVs [38,39]. Protein S is a major protein that binds to human receptors (TMPRSS2 and ACE2) to mediate viral infection [101]. The S protein cleaves S1 and S2 from host proteases. The main function of S1 is to bind to receptors on the surface of the host cell, and the S2 subunit mediates the fusion between the virus and the host cell membrane. The structural integrity of the S protein and activation of cleavage plays a key role in viral invasion and virulence [102]. Therapeutic strategies to block the penetration of the CoVs in host cells with targeted control of S proteins are valuable for the development of anti-COVID-19 agents [99]. Based on the results of screening for low molecular weight molecules against S protein, several natural flavonoids, lycoflavonol, cosmosin, neohesperidin, mangosteen, Kautensida D, and excaryatoxinl exhibited high activity [100]. Various natural antiviral substances act on the antiviral S proteins. For example, emodin, has been shown to have an antiviral effect against CoVs by targeting S protein and blocking its binding with ACE2. Ginsenoside-Rb1, Lonicera Japonica and Eucalyptus globulus extracts have been reported to have anti-CoV effect due to their potential to interfere with the processing of the glycoprotein envelope [103]. Saicozaponin B2 has strong anti-CoVs activity by affecting the process of viral penetration, including viral adherence and penetration by interfering with viral glycoproteins [104]. The bisbenzylisoquinoline tetrandrine alkaloid from Stephaniae Tetrandrae Radixdrastically inhibits CoVs replication by targeting the S protein [105].

3.2.2. Target N protein

Protein N, is associated with replication/translation complex and is responsible for the incorporation of viral genetic material into the CoV. In addition, it is a major molecule of the ribonucleoprotein complex residing in the nucleus of the virus and therefore also plays a significant role in the structure of CoV through network interactions with M-protein, other N molecules, and RNA. In CoV, the N protein encloses the viral genome and plays a crucial role in the release of virus particles, and replication [40,41], so that it is considered as an important target for the development of anti-COVID-19 agents. Resveratrol has been shown to have anti- CoVs by targeting protein-N and prolonging cell survival [29].

3.4. Virulence factors

There are three virulence factors for the CoVs, (Nsp1, Nsp3c, and ORF7a), which are responsible for the inhibition of host immunity. Nsp1 interacts with the human 40 S ribosomal subunit to inhibit the production of type I interferon [ [32,106]]. Nsp3c has a high binding ability to the human ADP ribose to help the CoVs resist human immunity [34]. ORF7a inhibits bone marrow matrix antigen 2 which is responsible for the inhibition of CoVs release from human cells [33]. This evidence suggests that Nsp1, Nsp3c, and ORF7a are potential targets for the detection of antiviral drugs. Detailed screening results of virulence factors inhibitors show that many natural products with antibacterial and anti-inflammatory effects show high binding affinities for these factors such as cefpyramide, piperacillin, streptomycin, limecycline, vogonoside, glycyrrhizic acid, gingerenone, shogaol, tetra platycodon grandifloras, vitexin, andrographolide, and xanthones derivatives [ [7,97]].

3.5. Functional receptors or enzymes

There are many host receptors are recognized by CoVs ex: ACE2, TMPRSS2, O-Acetylated Sialic Acid, Heat Shock Protein A5 (HSPA5), and Aminopeptidase N [[107], [108], [109], [110]]. Here this review will focus on the most important host receptors HSP5A, ACE2, TMPRSS2.

3.4.1. HSP5A

The unfolded protein HSP5A reported to be responsible for viral entry [111,112]. Different active phytocompounds that can block HSPA5 and compete for S protein-CoV recognition such as genistein, diadiazin, biochanin A, formontein, chlorogenic acid, thymoquinone, hydroxytyrosol, coumaric acid, caffeic acid, cinnamaldehyde, linolenic acid, caffeic acid phenethyl ester, and palmitic acid [87,98].

3.4.2. ACE2 inhibitors

Because ACE2 has been identified as the primary receptor for the CoVs in humans, attention is being taken to understand its regulation as a form of treatment for this virus. The ACE2 receptor has been shown to be a very specific receptor for the receptor-binding domain surge of CoV-2. Based on current research advances, ACE2 is seen as an acceptable target for treating COVID-19 by blocking CoV S protein and thus blocking the entry of CoV-2 into host cells. ACE-2 inhibitors play a crucial role in COVID-19 therapy [111]. Based on the results of virtual screening for ACE2 protein, troglitazone (antidiabetic drug), losartan (antihypertensive drug), ergotamine (analgesic drug), cefmenoxime (antibacterial drug), and silibin (hepatoprotective drug), possessed high binding affinity to ACE2. In addition, several natural products such as phylamblicin G7, xanthones, neohesperidin, and hesperidin showed a possible high binding affinity for the ACE2 protein. Although most of the promising natural ACE2-binding metabolites of CoV-2 are flavonoids [113]. Khandelwal, and Sharma [114] showed that the limonoid 6-α-acetoxygedunine and echitamine possess high binding interactions with ACE-2. So far, these two molecules have desired qualities to be potent ACE2 inhibitors.

There are numerous plants that have ACE-2 inhibiting activity, including several well-known types of medicinal plants and nutrients such as cinnamon, pepper, olive, hawthorn, black cotton, passion fruit and grapes ([91,115,116]). Natural ACE inhibitor products fall into several classes of phytochemicals, including flavonoids, xanthones, alkaloids, peptides, terpenes and tannins (111; 113; 116). Several compounds have shown ACE2 inhibitory activity, for example, phenolic compounds such as glycated myricetin and quercetin derivatives [ [84,117,118]]. Some of the natural metabolites suggested as possible bioactive substances against ACE2 are baicalein glucuronide, scotelarein glucuronide, glycyrrhizin, nicotianamine, neohesperidin, naringenin, hesperetin, naringin, hesperidin, and nobiletin [ [96,95]]. The class with the main representation and better affinity results is flavonoids [ [119,120]]. Results by Joshi et al. [111], Minatani et al. [121], and Meneguzzo et al. [95], suggest that naringin, naringenin, and glycated quercetin derivatives exhibit promising inhibitory activity against COVID-19 in particular.

3.4.3. Transmembrane serine protease enzymes TMPRSS2

Research has shown that inhibiting TMPRSS2 can prevent some CoVs from entering host cells [122]. As a possible target for the detection of antiviral drugs, the virtual screen results predict many antibacterial drugs (hetacillin, pivampicillin, cefoperazone, and clindamycin) and natural antiviral products (filaemblicin G7, quandraidol) to be a potential barrier to TMPRSS2. Demand for TMPRSS2 inhibitors was a suggested strategy in treating COVs [123,124]. It is known that TMPRSS2 is involved in the inoculation and replication of CoVs. The inhibition of TMPRSS2 requires structural properties such as the presence of aromatic ring and OH group for hydrogen bonding.

Transmembrane serine protease enzymes natural inhibitors include peptides, flavonoids, and terpenes. For example, the baicalein, baicalin, and silvonoids, have previously been reported to decrease the expression regulator TMPRSS-2 [ [96,125,126]]. Following promising molecular docking data [95], enriched fractions were tested with both molecules in vitro and showed antiviral activity similar to those of the newly established drug. Baicalin (found in Scutellaria and Oroxylum genera) had the most promising results [127]. These data confirm molecular docking experiments such as those obtained for baicalein [ [96,125,126]], can provide promising insights into possible natural anti-COVID-19 metabolites. Rahman et al. [94] have shown through silico studies that iridoids, tertpenes, and lignans have the promise of anti-COVID-19 through TMPRSS2 interactions. Natural metabolites with greater TMPRSS2 inhibitory potential are geniposides (iridoids). The natural sources proposed by Rahman et al. (2020) as anti-COVID-19 areCamellia sinensis, Shisandra sphenanthera and Asphodelus ramosus, marine soft corals, free-floating algae from the genus Sargassum, and fungi from the genus Paxillus [94].

4. Antiviral drugs (drug repurposing)

Wu et al. [7], docked these antiviral agents with CoV targets to predict their possible targets. There are special attentions to drugs that currently in clinical trials (Fig. 4 ). Remdezivir, a nucleoside analogue, is an RdRp inhibitor by forming three hydrogen bonds with RdRp active site. Remdezivir has shown some potential in treating first-time patients with COVID-19. Interestingly, remdezivir was thought to bind to the TMPRSS2 target. Chloroquine phosphate has been used to treat malaria and rheumatoid arthritis. Chloroquine inhibiting flaviviruses, retroviruses (anti-HIV), and CoVs. Chloroquine phosphate is converted to chloroquine in the body for therapeutic effects. Docking results indicate that chloroquine target is E-channel. Arbidol is a broad-spectrum antiviral drug mainly used against influenza A and B. Numerous reports have proven its potential as anti-CoVs activity by blocking replication and inhibiting viral fusion to human cells. The results of Arbidol docking to possible targets for new anti-COVID-19 drugs show that Arbidol interacts with Nsp7-Nsp8, Nsp14, Nsp15, E-channel or S protein complexes. Ritonavir and lopinavir (Anti-HIV-1) can inhibit CoVs replication. Molecular docking results indicated that the potential targets for ritonavir were Nsp3c or E-channel. Possible targets for lopinavir are Nsp3b, Nsp3c, helicase, NRBD or E-channel. Darunavir (anti-HIV-1/protease inhibitor) preventing the viral particles formation. Docking results indicate that the darunavir targets are PLpro, and Nsp3c [7].

Fig. 4.

The targets of anti-CoV drugs (contributed by Sagar Aryal; created with biorender.com).

5. Medicinal plants and their possible effect on COVID-19

The potent and ideal therapeutic choices for COVID-19 need to show anti-CoV-2 activity, have no side effects, no cytotoxicity, and high bioavailability. Numerous reports have been conducted to identify anti-CoVs drugs from medicinal plants [128]. This section summarize all updated studies about natural compounds and plant formulas of Traditional Chinese Medicine (TCM) with antiviral effects against CoVs and their mechanism of action.

Medicinal plants are always used as a strategy to treat and prevent various diseases, including viral infections of the respiratory tract. The benefit of using these herbs for viral respiratory tract infections is that they establish inflammation-modulating and immune-stimulating effects on the management of the immune system. The World Health Organization focuses on prevention through diet management, lifestyle changes, and prophylactic medicinal herbs to increase immunity. Medicinal plants recommended anti-CoVs agents are summarized in Table 3 .Allium sativum [129], and Glycyrrhiza glabra [130] are known to target the CoV replication. Another plant, Clerodendrum inerme, deactivates viral ribosomes. This can be used as a drug that targets the translation of the CoV-2 protein [131]. Similarly, Cusia Strobilanthes blocked the synthesis of viral RNA genomes and induced PLpro activity that targets CoVs [132]. Most importantly, various medicinal plants exhibit inhibitory effects against ACE-2, including Boerhaavia diffusa, Coriandrum sativum, Coscinium fenestratum, Cynara scolymus, Punica granatum, and Cassia occidentalis. Among them, Punica granatum shows a competitive mode of action, while others are non-specific inhibitors [[133], [134], [135]]. Andrographis paniculata was found to inhibit the increase in NOD-like receptor protein 3, interleukin-1 and β caspase-1, which are heavily involved in the pathogenesis of SARS-CoV and possibly CoV-2 [[136], [137], [138], [139]]. Many plants also exhibit inhibitory activity against HIV proteases. These medicinal plants can be promising as anti-CoVs agents. These include Eugenia jambolana [140], Euphorbia granulate, and Acacia nilotica [141]. Several plants such as Ocimum sanctum [142], Ocimum kilim [143], and Solanum nigrum [144], have been tested against CoV-2. In addition, Sambucus ebulus [145] can inhibit enveloped viruses and can also be used to combat CoV. This plant can be used to attenuate COVID-19 symptoms. Table 3, includes a variety of medicinal plants that are used in vitro to combat COVID-19.

Table 3.

List of the anti-CoVs effects of medicinal plants and their bioactive compounds and their action mechanisms.

Plant	Active compounds	Mechanism	References
Allium sativum	Organosulfur and lectin	Inhibit viral replication	[146,147]
Andrographis paniculata	Andrographolide lactone	Suppress NLRP3, IL-1β, and capase-1,	[139]
	14-deoxy-11, 12-didehydroandrographolide diterpene
Camellia sinensis	Epigallocatechin gallate gallocatechin-3-gallateand epicatechingallate	Interact with catalytic residues of 3CLpro	[148]
Camellia sinensis	Epigallocatechin gallate	Inhibit S protein	[149]
Theonella swinhoei (Marine fungus)	Pseudotheonamides C and D	Inhibit 3CLpro	[47]
Sergassum spinuligerum (Brown algae)	1,3,5-Trihydroxybenzene	Inhibit 3CLpro	[[47,150]]
Ecklonia cava (Brown algae)	8,8′-Bieckol, 6,6′-Bieckol	Inhibit 3CLpro	[47]
	Phlorofucofuroeckoln Dieckol	Inhibit viral replication.	[151]
	Eckol 7‐Phloroeckol	Block binding virus to cells.	[151]
	Phlorotannins (Dieckol the most potent)	Competitively inhibit 3CLpro	[152]
Paulownia tomentosa	Diplacone 6‐geranyl‐4′,5,7‐trihydroxy‐3′,5′‐dimethoxyflavanone	Inhibit PLpro	[153]
	Mimulone
	3′‐O‐methyldiplacol
	3′‐O‐methyldiplacone
	4′‐O‐methyldiplacol
	4′‐O‐methyldiplacone
	Geranylated flavonoids (Tomentin A-E)
Toona sinensis	Leaves water extract Flavonoids (quercetin)	Inhibit replication	[55]
Lycoris radiata	lycorine, emetine, monensin sodium, phenazopyridine, mycophenolic acid, mycophenolate mofetil, and pyrvinium pamoate	Inhibit cell division	[154]
		Lycorine was the most potent compound
Lycoris radiata, Pyrrosia lingua, Artemisia annua, Lindera aggregate	Lycorine	Lycoris radiatawas the most potent than the control (IFN-α).	[103]
Radix Sophoraerhrizome	N.D	Inhibit replication	[155]
Acanthopanacis
Radix Sanguisorbae
Torilis fructus
Rhrizome Cimicifuga, rhrizome Coptidis, kory Meliae, and Phellodendron	N.D	Inhibit CoV production through reducing RNA synthesis and protein expression	[156]
Sambucus Formosana	Caffeic acid > chlorogenic acid > coumaric acid	Inhibit replication, plaque formation, and viral attachment	[157]
Sambucus nigra	Anthocyanins, lectins	Inhibit replication	[42]
Isatis Indigotica	Sinigrin, Beta‐sitosterol, Aloe emodin, Hesperetin	Inhibit 3CLpro.	[158]
	Indigo, Quercetin-3-β-galactoside	Sinigrinwas the most potent
Rheum officinalis and Polygonum multiflorum	Emodin	Inhibit interaction S protein with ACE2	[159]
Artemisia annua	Ethanolic extract and aurantiamide acetate	Inhibit the activity of CTSL in the molecular docking analysis.	[160]
Houttuynia cordata	N.D	Inhibit 3CLproand RdRp	[161]
The ethylacetate fraction of Houttuynia cordata	Quercetin, cinanserin, quercitrin and rutin	Inhibit both MHV and DEN-2.Quercetin inhibit both MHV and DEN-2. Quercetrin inhibited DENV-2only, while rutindid not show activity against both viruses.	[162]
Melia cortex, Coptidis root, Cimicifuga root, Phellodendron cortex, Sophora subprostrata	Ginsenoside, reserpine, and aescin	Inhibit viral RNA synthesis, N and S protein expression.	[156]
Cinnamomi cortex and Caryphylli Flos	procyanidin B1 and procyanidin A2	Inhibit ACE-2.	[163]
Ethanol extract of Torreya nucifera	Ferruginol, amentoflavone apigenin, quercetin and luteolin	Strongly inhibit 3CLpro	[164]
Celastrus orbiculatus	Celastrol, pristimerin, tingenone, and iguesterin dihydrocelastrol	Strongly inhibit 3CLpro	[164]
Sophorae radix, Acanthopanacis cortex, Sanguinobae radix, and Torilis fructus	N.D	Reduce N protein and mRNA7 synthesis	[156]
Herbal mixture Gentiana radix , Dioscorea rhizome, Taxillus, cibotii Cibotium chinensis, Loranthi ramus , barometz, Cassiae semen	Valinomycin	Inhibit 3CLpro	[165]
Scutellaria Baicalensis	Myrecetin, taraxerol, amentoflavone, and Scutellarin	Strongly inhibit helicase protein by inhibiting ATPase activity Inhibit nsP13.	[166]
Euphorbia neriifolia L	Ethanolic extract, 3β-Friedelanol, epitaraxerol and friedelin	Potent antiviral activity than positive control, Actinomycin D	[167]
Salvia miltiorrhiza	Rosmariquinone tanshinone(1-7) Dihydrotanshinone tanshinone 5 exhibit the most potentcompound	Ethanol extract inhibit 3CLpro and PLpro. Inhibit CoV replication and infection	[168]
Tribulus terrestris	Terrestrimine	Strongly inhibit CoV PLpro.	[169]
	Terrestrimine 6 (potent), Ferulic acid (inactive)
Ethanol extract of Angelica keiskei	Chalcon and coumarin	Competitively inhibit 3CLpro and PLpro. Inhibit ubiquitin and ubiquitin-like proteins.	[67]
	Xanthoangelol E
Stephania tetrandra	bis-benzylisoquinoline alkaloids cepharanthine, tetrandrine, and fangchinoline	Significantly inhibit CoVs S and N protein expression, inhibit replication, also reduce cytokines expression.	[105]
Strobilanthescusia	Tryptanthrin	Strongly inhibit CoVs yield, infectivity and replication	[132]
	Indigodole B	Strongly inhibit RdRp and PLpro activity
Anthemis hyalina, Nigella sativa, and Citrus sinensis extracts	N.D	Increase IL‐8 Significantly change the expression of TRPA1, TRPC4, TRPM6, TRPM7, TRPM8, and TRPV4 genes.	[170]
Torreya nucifera	Amentoflavone, Apigenin	Inhibit 3CL pro	[164]
Psoralea corylifolia	Bavachinin, corylifol, Isobavachalcone	Inhibit PLpro	[171]
Black teas	Tannic acid,	Inhibit 3CLpro	[172]
	3-isotheaflavin-3-gallatetheaflavin-3,3′-digallate	The extract was more potent
Torreya nucifera	Luteolin	Inhibit 3CLpro	[164]
Psoralea corylifolia	4′‐O‐methylbavachalcone	Inhibit PLpro	[171]
Tylophora indica	7‐Methoxycryptopleurine	Inhibit viral replication	[173]
		Inhibit protease
Psoralea corylifolia	Neobavaisoflavone	Inhibit PLpro	[171]
Broussonetia papyrifera	Papyriflavonol A	Strongly inhibit PLpro	[174]
	3′‐(3‐methylbut‐2‐enyl)‐3′,4,7‐trihydroxyflavane
	Broussochalcone A,B Broussoflavan A
	4‐Hydroxyisolonchocarpin
	Kazinol A,B,F,J
Psoralea corylifolia	Psoralidin	Inhibit PLpro	[171]
Torreya nucifera	Quercetin	Inhibit 3CLpro	[164]
Tylophora indica	Tylophorine	Inhibit protease and replication	[173]
Tylophora indica	Tylophorine	Inhibit viral RNA replication	[175]
Polygonum cuspidatum	Resveratrol	N.D	[29]
Panax ginseng	Ginsenoside-Rb1	Inhibits glycoprotein activity and viral replication	[176]
Rauvolfia serpentina	Reserpine	N.D	[176]
Aesculus hippocastanum	Aescin	Inhibit viral replication	[176]
Boenninghausenia sessilicarpa	Leptodactylone	N.D	[177]
Bupleurum chinense	Saikosaponin B2	Interferes with events of early viral entry	[103,104]
Stephania tetrandra	Tetrandrine	Inhibits p38 MAPK pathway	[105]
Stephania japonica	Cepharanthine	ACE inhibitor	[178]
Rheum palmatum	Emodin	Block S protein/ACE2 binding	[159]
Triterygium regelii	Celastrol	Inhibit 3CLpro	[164]
	Pristimererin
	Tingenone
	Iguesterin
Ginkgo biloba	Quercetin-3-β-galactoside	Competitively inhibit 3CLpro	[179]
Alnus japonica	Etnanolic extract and Hirsutenone	Inhibits PLpro	[180,181]
Myrica rubra	Myricetin	Inhibits ATPase	[182]
Aglaia foveolata	Silvestrol	Inhibit mRNA translation.	[183]
Mucuna pruriens	Isolinoleic acid	ND	[117]
Scrophularia scorodonia, Bupleurum sp,and Heteromorpha sp	Saikosaponins B2	Inhibit viral attachment and penetration stages.	[104]
Asclepiadaceae and Moraceae plant families	Phenanthroquinolizidines and Phenanthroindolizidines	Inhibit viral replication	[173]
Phyllanthus emblica	Phylamblicin G7	Inhibit ACE2	[113]
	Phyllaemblicin B	Inhibit helicase	[7]
	Phyllaemblinol
Swertiagenus plant	Xanthones	Inhibit ACE2	[7]
Citrus aurantium	Neohesperidin and hesperidin	Inhibit ACE2	[[96,95]]
Silybum marianum seeds	Silibin	Inhibit ACE2	[119,120]
Psorothamnus arborescens	5,7,3 ′, 4′-tetrahydroxy-2' - (3,3-dimethylalyl) isoflavone	Inhibit 3CLpro	[92]
Stephaniae Tetrandrae	bisbenzylisoquinoline tetrandrine alkaloid	Inhibit CoVs replication by targeting S protein	[105]
Nigella sativa	Thymoquinone	Increase immunity by increasing Nrf2	[184]

N.D not detected.

6. Chinese herbal formula against CoV

Traditional Chinese Medicine (TCM) has been used to treat epidemics with a long history and extensive experience. Therefore, antiviral activity is not limited to natural compounds but also extends to TCM formulas. For example, the capsules Lian-Hua-Qing-Wen capsules (LHQWC), a widely used Chinese medicine, are widely used in clinical practice to treat the influenza virus and play a very important role in combating CoV [[185], [186], [187], [188]] by inhibiting CoV-2 replication [189]. LHQWC improved clinical symptoms such as shortness of breath, cough, fever, and fatigue, in COVID-19 patients [188,189]. An open-label randomized trial of the effectiveness of LHQWC has been conducted on 284 confirmed cases of COVID-19. The results showed that patients with COVID-19 who were treated with LHQWC showed a significantly higher recovery rate and a significantly shorter average time to recovery. The results of this study are sufficient to confirm the safety and effectiveness of LHQWC in the treatment of COVID-19 patients [190,191].

As demonstrated by the tissue pharmacology approach, Ren-Shen-Bai-Du-San can inhibit cytokine storm formation in COVID-19 patients by regulating chemokines and increasing blood saturation with oxygen inhibition of signal converters and transcription activators (STAT), the mitogen-activated protein kinase (MAPK) signaling pathway, core factor-kB (NF-kB), phosphoinositide-3-kinase (PIK3K) and interleukin-6 (IL-6). Another TCM formula, Qing-Fei-Jie-Du Decoction (Lung Cleansing and Detoxification Boil) has been used to prevent and treat SARS and is also recommended for the treatment of COVID-19 under Diagnostic Guide 7th Edition and Treatment of COVID-19, issued by the Chinese National Health Commission. Based on this latest edition of the Guidelines, various TCM formulas are recommended for the prevention and treatment of patients with COVID-19, including formulas found in Table 4 .

Table 4.

List of traditional Chinese formulae used COVID-19 treatment.

TCM formula	Herbal mixtures	Reference
Qingfei paidu decoction	Glycyrrhizae root, Ephedrae Herba, apricot seeds, Gypsum Fibrosum, Pogostemonia Hebra, Cinnamomi Ramulus, Atractylodis Macrocephalae Rhizoma, mushroom, Bupleuri Radix, Scutellariae root, Pinellia ternate tuber, ginger root, Asteris Radix root, Tussilago farfara flower, Belamcandae Chinensis Rhizoma, Manchurian Wildginger root, Dioscoreae Rhizoma, Aurantii Fructus Immaturus, Citrus reticulata fruit peel, and Alisma orientale root	[192]
Yupingfeng San	Astragalus root, Ledebouriella root and Atractylodes lancea root	[193]
Lian-Hua-Qing-Wen Capsule	Forsythiae Fructus fruits, Lonicerae Japonicae flower, Ephedrae sinica herba, apricot seeds, Isatis indigotica root, Dryopteris crassirhizoma root, Houttuynia cordata herba, Pogostemon cablin herba, Rhubarb Root, Rhodiolae Crenulatae Radix root, Glycyrrhizae root, and Gypsum Fibrosum	[[185], [186], [187], [188]]
Shu-Feng-Jie-Du Capsule	Patrinia scabiosaefolia herba, Bupleuri Radix, Glycyrrhizae root, Isatidis Radix, Verbena officinalis herba, Polygonum cuspidatum root, Forsythiae Fructus, and Phragmitis Rhizoma	[[194], [195], [196]]
Ren-Shen-Bai-Du-San	Angelicae Pubescentis Radix, Bupleuri Radix, Peucedani Radix, Notopterygium incisum root, Ligustici Chuanxiong root, Platycodon grandiflorum root, Glycyrrhizae root, Ginseng root, Poria cocos mushroom, Aurantii Fructus	[189]
Jin-Hua-Qing-Gan Granule	Lonicerae Japonicae flower, Gypsum Fibrosum, Ephedrae herba, apricot seeds, Scutellariae Radix, Forsythiae Fructus, Fritillariae Thunbergii Bulbus, Anemarrhenae Rhizoma, Arctii Fructus, Artemisiae Annuae herba, Menthae Haplocalycis herba, Glycyrrhizae root	[[192,197,198]]
Xue-Bi-Jing Injection	Angelicae Sinensis root, Carthami flower, Chuanxiong root, Salvia officinalis, Paeonia lactiflora root, and Salvia Miltiorrhiza root	[199]

7. Virtual screening

Virtual screening for bioactive molecules is a useful tool to reduce the time required for screening of some extracts. This approach is known as silica analysis by molecular docking [ [58,98,91,200]]. Natural metabolites of various chemical classes show promising anti-COVID-19 activity (Table 4). Despite their different molecular structures, different chemical classes such as terpenes, alkaloids, quinones, flavonoids, fatty acids, and steroids have a similar activity of antiviral drugs with the same target involved in CoVs replication. Many phytocompounds with antiviral activities, among them, monoterpenes can disrupt the lipid envelope of the virus, while polyphenols attack viral proteins. Both monoterpenes and polyphenols are active against free viral particles, but not after a virus has entered the host cell. Another group of phytocompounds is directed against RNA or DNA. These are called alkaloids. DNA intercalators stabilize nucleic acids and inhibit the replication, and translation of genetic material. These alkaloids can inhibit viral replication and development in cells. Since chloroquine, a chemical derivative of the alkaloid quinine, an intercalator of appears to be of clinical benefit against CoV-2 infection, it is assumed that intercalating alkaloids may be interesting candidates for the development of new anti-COVID-19 agents [201].

A number of alkylated chalcones were examined for their inhibitory activity against 3CLpro [67]. Alkylated chalcones which had the dihydroxyl group showed the strongest inhibitory effect. These results suggest that the dihydroxyl group may be important for binding to 3CLpro. In addition, the docking studies for alkylated chalcones with 3CLpro shows that C O and OH groups form H bonds with His163 and Ser144, respectively. In particular, the dihydroxyl groups form strong H-bonds with Cys145 residue [202]. Various natural ingredients have demonstrated strong antiviral effects against CoVs [103,125,176]. The natural product 5,7,3′,4′-tetrahydroxy-2'-(3,3-dimethylalyl) isoflavone forms H-bonds with the catalytic site of 3CLpro [92]. Pseudotheonamides C and D form covalent bonds with Cys145 residue from 3CLpro. These two molecules occupy the same position at the catalytic center by forming H-bonds. These compounds act in a similar manner to the covalent michael acceptor (peptidyl) inhibitor [47]. Florotanines 6,6′-Bieckol and 8,8′-Bieckol form H bonds with His41 and Cys145 residues from 3CLpro [47].

It was shown that escin and reserpine had significant anti-SARS activity [176]. Ginsenoside-Rb1, was reported to have activity against CoVs [203]. It has been shown that leptodactylon and lycorin have strong anti-CoV activity. Lung et al. [204] studied practically 83 compounds found in TCM for activity against CoV-2 RdRp and identified theaflavins, as potential inhibitors. Similarly, according to Zhang et al. [205] 115 compounds found in TCM have been studied as anti-COVID-19 agents. Some of them are natural polyphenol compounds such as quercetin and kaempferol [206,207].

A recent study aimed at reorienting a clinically approved drug as anti-COVID-19 agents revealed that cefarantine demonstrated strong inhibition of CoV-2 [178]. Dihydrotanshinone is an important lipophilic compound isolated fromSalviae Miltiorrhizaeroot and is commonly used in TCM as it exhibits an inhibitory effect against MERS-CoV. Saikozaponin B2 showed strong antiviral activity against CoVs. The mechanism of the antiviral effect of saicozaponin B2 is mediated by blocking the entry of the virus into cells, preventing absorption and penetration, and inhibiting viral adhesion. Tetrandrine was found to inhibit CoV replication [105]. All of these anti-CoV natural ingredients and their mechanisms of action are summarized in Table 5 .

Table 5.

List of phytocompounds that inhibit CoVs.

Compound type	Compounds	Mechanism	References
Indol	Isatin	Inhibit 3CLpro	[[92], [93], [94], [125], [126], [127], [128], [129], [130], [131], [132], [133], [134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144], [145], [146], [147], [148], [149], [150], [151], [152], [153], [154], [155], [156], [157], [158], [159], [160], [161], [162], [163], [164], [165], [166], [167], [168], [169], [170], [171], [172], [173], [174], [175], [176], [177], [178], [179], [180], [181], [182], [183], [184], [185], [186], [187], [188], [189], [190], [191], [192], [193], [194], [195], [196], [197], [198], [199], [200], [201], [202], [203], [204], [205], [206], [207], [208], [209]]
Steroid	Ginsenoside-Rb1	Disrupt envelope protein processing	[103,176]
Phenolic	Alkylated chalcon	Competitively inhibit 3CLpro	[67]
Phenolic	coumarin	Inhibit 3CLpro.	[207]
Lignin	Savinin	Competitively Inhibit 3CLpro	[165]
Lignan	Hinokinin	Inhibit 3CLpro	[165]
Fatty acids	Linolenic acid	Inhibit HSPA5	[98]
	Linoleic acid
Cardiac glycoside	Ouabain	Diminish both the viral titers and viral yields. Reduction of the number of viral RNA copies.	[210]
Anthraquinone	Emodin	Strongly inhibit 3a ion channel and completely inhibit viral release.	[211]
	Rhein	Inhibit virus replication	[28]
		Inhibit interaction of S protein and ACE2.	[159]
Saponin	Saikosaoinin	Block S ptotein	[103,104]
	Glycyrrhizin	Upregulate nitrous oxide synthase and nitrous oxide production	[212]
	Aescin	ND	[125]

7.1. Terpenoids

Terpenoids are the major secondary plant constituents, with more than 36,000 species [213]. These phytocompounds have countless medicinal activities [[214], [215], [216]]. Terpenes, very effective in controlling CoV2 by interfering with amino acids in the enzymatic cavity to inhibit viral protease [217]. All anti-CoV terpenoids and their mechanisms of action are summarized in Table 6 and Fig. 5 .

Table 6.

List of anti-CoV terpenoids.

Terpenoids		Mechanism	References
Bisnorterpenes	Isoiguesterinol	Inhibit 3CLpro	[218]
	Isoiguesterin
	20-Epi-isoiguesterinol
	6-Oxoisoiguesterin
Monoterpene	Thymoquinone	Increase innate immunity	[184]
		Inhibit HSPA5
	Thymoquinone	Inhibit protease	[217]
	Salvinorin
	Bilobalide
	Citral
	Menthol
Sesquiterpene	Sugetriol-3,9-diacetate	Inhibit PLpro	[7]
	Artemisinin	Regulate immune system	[219,220]
		Stop cytokines storm
	Ginkgolide A	Strong protease inhibitors	[217]
Diterpenoids	Stevioside	Immunomodulatory	[221]
	8β‐hydroxyabieta‐9(11),13‐dien‐12‐one	Inhibit replication	[165]
	3β,12‐diacetoxyabieta‐6,8,11,13‐tetraene	Inhibit replication	[165]
	Ferruginol	Inhibit viral replication	[165]
	Tanshinone	Inhibit PLpro	[180,181]
	3- Benzoylhosloppone	Inhibit 3CLpro	[218]
Triterpenoids	Betulonic acid	Inhibit viral replication.	[165]
		Competitively inhibit3CL pro
	Limonoids (6-Acetylswietenolide)	Inhibit 3CLpro	[218]
	Platycodin D	Inhibit PLpro	[7]
	Celastrol	Inhibit 3CLpro	[164]
	Pristimererin
	Tingenone
	Iguesterin
Pentacyclic triterpenes	22-Hydroxyhopan-3-one	Inhibit 3CLpro	[218]
	20-Epibryonolic acid
	Oleanolic acid
	3-Oxolupenal
	3-O-betulinic acid p-coumarate
	3 -Hydroxylupenal
	3-Friedelanone

Fig. 5.

Anti-CoV-2 potential of artemisinin (A) and glycyrrhizin (B) [222].

7.2. Alkaloids

Weber and Opatz [223] demonstrated that alkaloids have many pharmacological activities include anti-inflammatory, anticancer, and anti-oxidative activities. Alkaloids significantly inhibited virus-induced cell death at the early stage of virus infection, as well as dramatically suppressed the replication of CoV and inhibited viral S and N protein expression. All anti-CoV alkaloids and their mechanisms of action are summarized in Table 7 and Fig. 6 .

Table 7.

List of anti-CoV alkaloids.

Alkaloids	Mechanism	References
Cepharanthine	Inhibit protease	[105]
	Suppress replication by targeting S ptotein inhibit ACE2
Lycorine	Inhibit viral cell division	[[103,154]]
Phaitanthrin D	Inhibit PLpro	[7]
Tetrandrine	Inhibit p38 MAPK	[105]
Homoharringtonine	Decreases viral RNA levels	[224,225]
	Block viral replication
Reserpine	N.D	[125]
Oxysophoridine	N.D	[[58,205]]
Emetin	Inhibit RNA, DNA and protein synthesis.Inhibit DNA polymerase,	[154]
	Reverse transcriptase, topoisomerase, protein
	Synthesis, DNA intercalation
Berbamine	N.D	[154]
Indigo	Inhibit 3CLpro cleavage activities	[158]
Tetrandrine, cepharanthine fangcholine	DNA intercalator	[105]
	inhibit S and N protein expression
	Inhibit viral replication
Sanguinarine, chelidonine chelerythrine	Very strong DNA intercalator	[ [226,227]]
Berberine, berberrubine, berbamine, dicentrine	Strong DNA intercalator
Quinine, cinchonine, quinidine, cinchonidine	Inhibit DNA polymerase
Dictamine, evolitrine, skimmianine, cryptolepine, ellipticine, fagarine	DNA intercalation
Harmine, β-Carboline harmaline	Inhibit DNA polymerase, reverse transcriptase, topoisomerase
Fagaronine, Alstonine	Strong 3CLpro inhibitors	[218]
10-Hydroxyusambarensine
Annonidine F
Chrysopentamine
Strychnopentamine
Isostrychnopentamine
Liriodenine

Fig. 6.

Anti-CoV-2 potential of alkaloids [228].

8. Limitations of the studies on herbal medication and critical considerations

Several limitations have been observed in many studies concerned with using natural products as remedies. No follow-up studies have been published as a result of previous discoveries of herbal and natural compounds. This review also missed studies on drug-herbal interactions when treating COVID-19. For example, concurrent use of ritonavir/lopinavir with some herbal medicinal products, such as Hypericum perforatum, is not recommended, and can significantly reduce plasma concentrations. Glycyrrhizin can compete with ritonavir/lopinavir. RdRp blocking agents, such as the phellodendron cortex, and ritonavir, may interact with each other. In addition, the interaction between phytocompounds that can block the ACE-2 receptor and the ACE-2 drugs should also be considered. Nevertheless, not all drug-herbal interactions are dangerous, and combining them can be beneficial.

Apart from COVID-19 infection, there are indications of reactivation of COVID-19 cases. Therefore, clinical therapeutic procedures should also anticipate possible consequences and reactivation of the virus and continuously identifying the source of new viruses and classifying them accordingly. More measures to promote detoxification and to elevate the immunomodulatory potential of COVID-19 patients should be investigated. Many plants may prove usefulness for this purpose.

9. Concluding report and future perspectives

The current COVID-19 outbreak, caused by CoV-2, is a major global health concern So far, no drug or vaccine has been shown to be effective to treat COVID-19. The slow detection of CoV-2 and the limited therapeutic options for COVID-19 are major challenges. There is a social and ethical responsibility for communities and scientists around the world to work together to effectively combat the disease. In light of these major global challenges, many studies are working on a cure for COVID-19 that can be quickly established and distributed easily. Natural products can solve this dilemma because they often have low toxicity and are used in the pharmaceutical industry for their bioactivity, including antiviral agents.

In this review, various medicinal plants and natural substances have been stated that show activities as antiviral agents against CoVs. In particular, many have demonstrated their ability to intervene CoVs life cycle, such as membrane fusion, entry of the virus into host cells, translation, transcription, replication, release and assembly of viruses. The data shows that these medicinal plants and natural compounds have enormous potential as therapeutic options for fighting COVID-19. Developing complementary and synergistic herbal medicines that block/inhibit some of the protein pathways from the viral host will certainly be strong allies in the fight against COVID-19. An important consideration is the fact that several studies have used ethanol and aqueous extracts with good results in the treatment of COVID-19. However, since the digestion of the active ingredients is dependent on patient's digestive system, the use of isolated phytocompounds may offer the benefits of a more targeted approach. Therefore, these phytocompounds will act not only in terms of concentration and dose, but also in terms of time. All of these ideas are worth investigating in the future.

The review provides up-to-date information on a number of medicinal plants and natural products that could be promising as anti-COVID-19 agents. However, since much of the research on the antiviral effects of TCM in this area is only preliminary, in vivo studies on animal models are needed to shed light on the cellular and molecular mechanisms. Promising pharmacokinetic studies of medicinal plants and natural products need to be carried out to obtain pharmacokinetic profiles, including parameters of distribution, absorption, excretion, and metabolism. In addition, clinical trials are needed to test the safety and effectiveness of anti-COVID-19 natural agents in humans. More importantly, research should be conducted to examine possible interactions between TCM and available antiviral drugs to determine their effect on COVID-19.

Funding

There is no fund for this manuscript.

Availability of data and materials

(a statement on how any datasets used can be accessed).

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

Data will be made available on request.