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The Natural Products Journal, XXXX, XX, 1-11 1

RESEARCH ARTICLE

Herbal Therapeutics as Potential Prophylaxis for SARS-CoV-2 Infection

Shipra Singhal1, Abhishek Kumar2, Deepti Katiyar3 and Vaishali M. Patil3,*

1
Department of Computer Aided Drug Design Lab, Department of Pharmaceutical Chemistry, KIET School of Pharma-
cy, KIET Group of Institutions, Delhi-NCR, Ghaziabad, India; 2Department of Pharmacology, KIET School of Pharma-
cy, KIET Group of Institutions, Delhi-NCR, Ghaziabad, India; 3Department of Pharmacognosy, KIET School of Phar-
macy, KIET Group of Institutions, Delhi-NCR, Ghaziabad, India
Abstract: Introduction: The global pandemic COVID-19 and its uncontrolled spread and lack of ef-
fective therapeutics demand to investigate the herbal resources in search of novel, safe and potent
therapeutics. Herbal medicines have proven the advantage of multi-target potential and thus can be
investigated for virus-host interaction protein and viral protein targets.
Objectives: The manuscript aims to provide an outcome-based analysis of studies performed to evalu-
ate herbal compounds as anti-COVID agents. The studies focus on the proposed mechanism of viral

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inhibition by herbal compounds.

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ARTICLEHISTORY
Methods: The details on modern drug discovery approach for investigating potential antiviral agents

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Received: January 12, 2022 include in silico screening, ADMET and molecular docking studies. It helps to establish the probable

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Revised: March 15, 2022 mechanism of viral inhibition as well as to establish pharmacophore. The reports explaining the role of
Accepted: April 01, 2022
herbal therapeutics/phytochemicals in antiviral drug development have been thoroughly searched.
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DOI:
10.2174/2210315512666220613101120
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Results: The study summarizes herbal therapeutics and phytochemicals based on their antiviral prop-
on P

erties against various pathogenic viruses. Herbal compounds that have an interesting role in the devel-
opment of therapeutics and herd immunity against SARS-CoV-2 are included and discussed.
rs or

Conclusion: The manuscript summarizes herbal resources and phytochemicals investigated as a po-
tential therapeutic option for SARS-COV-2 inhibition. It will be a useful resource for researchers in-
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terested in developing herbal therapeutics for the prevention and/or treatment of COVID-19.
A

Keywords: SARS-CoV-2, Herbal antiviral compounds, host endogenous antiviral response, herd immunity, COVID-19.

1. INTRODUCTION immunity are still a threat [1-4]. To prevent the transmission

or

and spread of the infection, some of the measures adopted

The global pandemic coronavirus disease 2019 (COVID-
worldwide include the isolation of infected confirmed and
19) witnessed by this century has alarmed the health emer-
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suspected individuals. The scientific community from vari-

gency. COVID-19 is caused by severe acute respiratory syn-
ous domains is working to provide a solution for the chal-
drome coronavirus-2 (SARS-CoV-2), which causes pneu-
lenges created by COVID-19. In developing effective thera-
monia, fever, muscle soreness, abnormal respiratory distress peutics, traditional and novel approaches are being adopted
syndrome, diarrhea, hemoptysis, headache, and sore throat
[5-6]. One of the prominent approaches is drug repurpos-
and shock (https://www.who.int). In the meantime, all the
ing/repositioning, which is used to investigate the antiviral
leading labs and pharmaceutical companies have initiated
properties of previously reported drugs/compounds against
efforts to develop the COVID-19 vaccine. Various platforms
SARS-CoV-2 [7]. The main objective is to save time and
have been investigated for vaccine development, such as
money and identify a drug with a known pharmacokinetic
virus vectored vaccines, protein subunits, genetic vaccines, and toxicity profile. For drug repurposing, drugs/compounds
and monoclonal antibodies for passive immunization. A few
from herbal sources are reliable for developing new thera-
vaccines have been developed and made available worldwide
peutics based on their structurally diverse properties and
as a preventive measure. At the same time, emerging mutants
safety profile. The success stories reported from clinical and
that escape the vaccine’s activity spectrum and waning
preclinical studies for various therapeutic targets associated
with infectious and non-infectious diseases necessitate the
*Address correspondence to this author at the Department of Pharmacogno- search for herbal compounds as the possible source for po-
sy, KIET School of Pharmacy, KIET Group of Institutions, Delhi-NCR,
Ghaziabad, India; E-mail: vaishuwise@gmail.com
tential inhibitors of SARS-CoV-2 [8-10]. Some studies have

2210-3155/XX $65.00+.00 © XXXXBentham Science Publishers

 2 The Natural Products Journal, XXXX, Vol. XX, No. X Singhal et al.

applied herbal drug repurposing strategies to inhibit SARS- Scientific search engines such as PubMed [16-18], Scopus
CoV-2 [11]. Computational or in silico technologies have [19], Web of Science [20] and Google Scholar [21] were
altered natural product pharmacodynamic and pharmacoki- used to perform a detailed bibliographic search on the antivi-
netic properties and identified suitable alternatives [12-15]. ral herbal therapeutics with specific interest to SARS-CoV-2
Similarly, the techniques are adopted for designing and de- inhibition. During the literature search, the available books
veloping natural inhibitors of SARS CoV-2. on the role of herbal therapeutics as antiviral agents pub-
lished reports, and articles from peer-reviewed journals were
The manuscript aims to provide a constructive lead on
investigated. A total of 133 references were studied, and
various antiviral herbal sources, the active phytochemical,
most of the literature is from December 2019 onwards. The
and the mechanism of antiviral action with a major focus on
reported literature provides few experimental details on in
SARS-CoV-2 inhibitors. The objective is to identify and
elaborate on the developments related to in silico analysis of vitro/in vivostudies for SARS-CoV-2 inhibition [22, 23].
single- and/or multi-target herbal therapeutics such as SARS-
CoV-2 inhibitors. The concept of herd immunity and the role 3. ROLE OF HERBAL PHYTOCHEMICALS AS AN-
of indigenous herbal therapeutics in developing immunity TIVIRAL THERAPEUTICS
are discussed.
Herbal phytochemicals are a rich source for the discovery
of antiviral drugs. Understanding their inhibitory mechanism
2. METHODOLOGY during various stages of the viral life cycle is essential. The
viral targets required for antiviral properties are viral entry,
The details for ongoing research studies on herbal com-
viral replication, viral assembly, the release of virion parti-
pounds worldwide were required to provide broad coverage.
cles and virus-host-specific interactions [24, 25]. Detailed

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Table 1. Herbal compounds as SARS-CoV-2 inhibitors and observations from in silico studies.

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Investigational Herbal Phytochemicals In Silico Observations Refs.
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Active against SARS CoV2 pharmacological targets: Papain-like protease, spike
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Glabridin, Cinnamoyl echinadiol and neral [26]
glycoprotein and 3C-like proteinase
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Rhein, Withanolide D, Withaferin A, Enoxacin and PyRx virtual screening revealed their strong binding and stability with an amino
[27]
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Aloe-emodin acid residue of the active site of COVID-19 main protease

Belachinal, Macaflavanone E, and Vibsanol

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Inhibition of ‘SARS-CoV2 E’ protein activity [28]

Kaempferol, Quercetin, Luteolin-7-glucoside, De-

methoxycurcumin,
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Molecular docking through Autodock 4.2

Naringenin, Apigenin-7-glucoside, [29]
Displayed these compounds as potent COVID-19 Mpro inhibitors
Oleuropein, Curcumin, Catechin, Epicatechin-
gallate
or

Theaflavin, Betulinic acid, Kaempferol, Moupina- Displayed binding to RNA-dependent RNA Polymerase, papain-like protease
[30]
“F

mide, Quercetin and chymotrypsin-like protease

Myricitrin, Methyl rosmarinate, Calceolarioside B, These phytocompounds interacted with 3CLpro catalytic dyad residues through
[31]
Licoleafol, Amaranthin Hydrogen bonding

They were found to be active against chymotrypsin-like protease, papain-like

Quinadoline B, Scedapin C, Isochaetochromin D1 [32]
protease and cysteine proteases

Kamferol, Curcumin, Pterostilbene, Fisetin, Querce-

Exhibited good binding potential to the spike protein's S1 and S2 domain, which
tin, Isorhamnetin, Genistein, Luteolin, Resveratrol, [33]
attaches and internalizes the virus in the host cell.
Apigenin

Scopadulcic acid, Baicalin, Sylibinin, Solanidine,

Showed action against SARS-CoV-2 S-glycoprotein and protease (Mpro) [34]
Naringenin, Oleanane

Hypericin, Cyanidin 3-Glucoside, Baicalin, Glabrid-

ADMET analysis displayed these compounds as the potent protease inhibitors [35]
in, a-Ketoamide-11r
Herbal Therapeutics as Potential Prophylaxis for SARS-CoV-2 Infection The Natural Products Journal, XXXX, Vol. XX, No. X 3

comprehensive information about the role of herbal phyto- COVID-19 after subsequent evaluation [38]. Some of the
chemicals, their source, and mechanism of viral inhibition coronavirus-host target proteins, viral protein targets and
with reference to specific pathogenic viruses (32 viruses) is phytochemicals are elaborated on in Table 2.
provided as a supplementary file (Table 1).
4.2. Mechanism of Antiviral Action Emphasizing SARS-
CoV-2
4. HERBAL THERAPEUTICS AND SARS-COV-2 IN-
FECTION Ancient literature and traditional medicinal systems have
reported the utilization of herbs, extracts, and different herb-
4.1. SARS-CoV-2 Inhibitory Herbal Phytoconstituents
al-based formulations against various infections. Phytocon-
Herbal compounds which can prevent SARS-CoV-2 in- stituents have been studied for decades to evidence their effi-
fection may be used as potential prophylaxis and can be cat- cacy against different ailments. The reported pharmacologi-
egorized as - cal and in silico studies have supported global acceptance
and use of natural products. The current pandemic condition
1. compounds to block entry of virus;
has been supported by the developing of a few vaccines and
2. viral fusion inhibitors; drugs by various pharmaceutical and research labs all over
the world [44]. It has allowed researchers to evaluate various
3. viral replication inhibitors; and
available and new molecules acting through various mecha-
4. compounds to improve the endogenous host response. nisms against CoV-2. The available broad-spectrum antivi-
The search for potential inhibitors is facilitated with the ral, anti-malarial and antibiotic drugs have shown limited
help of computational drug discovery resources using in sili- pharmacological efficacy and increased side effects in many
co models. The world faces work restrictions due to lock- cases. On the other hand, ethnopharmacological approaches

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down, social distancing, and the absence of in vitro and in have revealed various bioactive phytoconstituents against

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vivomodels. During such situations, in silico studies have microorganisms, including viruses [26]. Several plant-

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derived secondary metabolites like alkaloids, terpenoids,

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helped screen potential compounds for in vitro/in vivoanaly-
sis rapidly and reasonably. Many herbal compounds have phenolics etc., have been explored for their antiviral poten-

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been analyzed for viral inhibitory potency by investigating tial against DNA or RNA viruses [45]. The newer approach-
es for drug discovery, targeting variable mechanisms in-
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their protein-ligand interactions. In addition, absorption, dis-
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tribution, metabolism, excretion, and toxicity (ADMET) volved in virus binding with the host cell, virulence mecha-
nisms, viral replication, viral protein formation and virion
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studies have been reported to predict pharmacokinetic prop-

erties. Various investigational herbal compounds have been assembly have been reported [45, 46]. Phytochemicals that
can inhibit the growth-promoting enzymes (RNA polymer-
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evaluated using in silico models against SARS-CoV-2 viral

targets, namely, spike protein, glycoprotein, protease, and ase, protease, reverse transcriptase), replication (protein
phosphorylation), and nucleic acid (RNA/DNA) synthesis in
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polymerase enzymes summarized in Table 1.

influenza, HIV, Herpes simples and various other viral infec-
The immune system protects the host from viral infec- tions have been studied before [47, 48]. The steps involved
tions by coordinating with the biological mechanism. In the in viral infection that different phytochemicals can target are
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immune system, the effector cells (monocytes/macrophages, graphically represented in Fig. (1). In any viral infection,
dendritic cells, natural killer cells, and NK-T cells) use viral entry of the virus is the primary step which is mediated by
pattern recognition receptors to initiate inflammation and the interaction of the structural protein with host cell recep-
antiviral immune response [36]. The pattern recognition re- tors. The reported structure of CoV-2 has shown the pres-
or

ceptors are Toll-like, NK cell, and mannose-binding recep- ence of four structural glycoproteins (spike (S), envelop (E),
tors. Understanding the role of viral proteins in immune eva- membrane (M) and nucleocapsid (N)) with many accessory
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sion and degradation of host proteins will help develop ra- proteins on the outer surface [49]. The transmembrane S-
tional strategies. A recent study reports the complementary protein forms a homotrimer contributing to viral interaction
role of natural compounds that act through host targets and with human angiotensin-converting enzyme-2 (ACE-2) [50,
as a barrier for developing resistance. Homoharringtonine 51]. The host cell protease cleaves S-protein into S1 and S2
has blocked infections caused by vesicular stomatitis virus, subunits, which facilitate the identification of the host bind-
Newcastle disease virus, and porcine epidemic diarrhea vi- ing domain and mediate viral fusion with the host cell [52-
rus. It provides a new arena for the clinical development of 54]. Withanone (a Withania sominifera constituent) was re-
broad-spectrum antiviral agents [37]. For SARS-CoV-2 in- ported to significantly inhibit this interaction and proposed to
hibition, the data on using herbs and phytochemicals to im- have promising effects for inhibiting the binding [55]. The E
prove host endogenous immunity is limited. Some herbs structural protein contributes in envelop formation and other
and/or compounds obtained from them can be successfully vital steps of viral pathogenesis and assembly formation [56,
used to target viral proteins or proteins involved in virus and 57]. By utilizing in-silico approaches, several phytochemi-
host cell interactions. Some examples include triterpene gly- cals have been studied; namely, Belachinol, Macaflavone E
cosides (Heteromorpha, Bupleurum and Scrophularia scor- and Vibsanol B, and have been revealed to interact with the
donia), averting the attachment and invasion into the host. functioning of E-protein [28]. Viral nucleoprotein (N) is sig-
Persian herbs like Allium sativum, Cerasus avium, Berberis nificantly involved in the synthesis of nucleic acid (transcrip-
integerrima, Alcea digitata, Rubia tinctorum, Peganum har- tion), replication, host cell metabolic modulation and other
mala etc., have inhibitory action against ACE2 enzyme. essential steps of viral infection [58-60]. The role of N-
These natural inhibitors could be considered to prevent protein has been extensively studied for developing novel
4 The Natural Products Journal, XXXX, Vol. XX, No. X Singhal et al.

Table 2. Examples of coronavirus-host target proteins, viral protein targets and herbs/phytochemicals

Coronavirus-Host Target/ Viral Proteins Herbs/Phytochemicals Refs.

TGG (tetra-O-gallayl-β-D-glucose, from Galla Chinesis)Luteolin; Cimicifuga rhizome, Melia
cortex, Coptidis rhizome, Phellodendron cortex, and Sophora subprostrata radix; compounds
extracted from Stephania tetandra: bis-benzylisoquinoline alkaloids-tetrandine (TET),
fangchinoline (FAN), and cepharanthine (LEP); Dihydrotanshinone I; Licoflavonol (from
S PROTEIN
Glycyrrhiza uralensis), cosmosiin (from Scutellaria baicalensis), neohesperidin (from Citrus
aurantium), mangostin (from Garcinia mangostana), kouitchenside D (from Swertia kouitchen-
sis), excoecariatoxin (from Excoecaria agallocha), phyllaemblicin G7 (from Phyllanthus em-
blica) and piceatannol (from Vitis vinifera).
Phyllaemblicin G7 (from Phyllanthus emblica),
ACE-2 xanthones (from the plants of Swertiagenus),
neohesperidin and hesperidin (from Citrus aurantium).
Emodini Rhei Radix et Rhizoma, Polygoni multiflora radix, and Polygoni multiflora Caulis;
S/ACE2 Interaction
Hesperidin.
TMPRSS2 Phyllaemblicin G7, neoandrographolide, kouitchenside I, and others.
CATHEPSIN L MOL 736 (Aurantiamide acetate from Artemisia annua)
Isatis Indigotica, sinigrin, beta-sitosterol, indigo, aloe-emodin, and hesperidin; Tannic acid, 3-
isotheaflavin-3-gallate (TF2B), theaflavin-3,3’-digallate (TF3); Natural compounds from
MNPD and TCMD; Quercetin-3-β-galactoside; Betullinic acid and savinin; Houttuynia cor-
data; Torreya nucifera/ amentoflavone, apeginin, luteolin and quercetin; Tripterygium regelii/

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quinine–methide triterpenes – celastrol, pristimerin, tingenone, and iguesterin; and dihydro-

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celastrol; CBM (dried rhizome of Cibotum barometz); DBM (Dioscorea rhizome); Salvia
Miltiorrhiza and its tanshinone compounds; Ecklonia cava and its isolates, especially dieckol;

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Angelica keiskei and its compounds, especially xanthoangelol E (chalcone 6); Broussonetia

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papyrifera polyphenols, especially papyriflavonol a; Betulinc acid, Coumaroyltyramine, Cryp-
3CLPRO*
totanshinone, Desmethoxyreserpine, Dihomo-γ-linoleic acid, Kaempferol, Lignan, N-cic-
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feruloyltyramine, Quercetin, Sugiol and Tanshinone lia; Flavone and coumarin derivatives;
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Andrographolidederivatives, chrysin-7-O-β-glucuronide and cosmosiin (from Scutellaria bai-
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calensis), betulonal (from Cassine xylocarpa), andrographiside and andrograpanin (from

Andrographis paniculata), 2β-hydroxy-3,4-seco-friedelolactone-27-oic acid, isodecortinol and
rs or

cerevisterol (from Viola diffusa), neohesperidin (from Citrus aurantium), 2,2-Di(3-indolyl)-3-

indolone (from isatis indigotica), theaflavin 3,3’-di-O-gallate (from Camellia sinesis), rosma- [38-43]
rinic acid (from Salvia verticillata), kouitchenside I and oleanolic acid (from Swertia genus),
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and others.
Salvia Miltiorrhiza and its tanshinone compounds; Paulownia tomentosa flavonoid derivative
compounds; Tribulus terrestris and its compounds; Angelica keiski and its compounds, espe-
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cially xanthoangelol E (chalcone 6); Broussonetia papyrifera polyphenols, especially pa-

pyriflavonol A (4); Tryptanthrin (from Strobilanthes cusia); Coumaroyltyramine, Crypto-
tanshinone, Kaempferol, Moupinamide, N-cis-feruloyltyramine, Quercetin, Tanshinone IIa;
PLPRO*
Platycodin D (from Platycodon gradiflorus), chrysin and baicalin (from Scutellaria bai-
calensis), neohesperidin (from Citrus aurantium), sugetriol-3,9-diacetate (from Cyperus rotun-
or

dus), phaitanthrin D and 2,2-di(3-indolyl)-3-indolone (from Isatis indigotica), Epigallocatechin

gallate (from Camellia sinesis), piceatannol (from Vitis vinifera), rosmarinic acid (from Salvia
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verticillate L), magnolol (from Magnolia officinalis), and others.

Houttuynia cordata; Cimicifuga rhizome, Melia cortex, Coptidis rhizome, Phellodendron cor-
tex, and Sophora subprostrata radix; Tryptanthrin (from Strobilanthes cusia); Betulonal (from
RdRp* Cassine xylocarpa), gnidicin and gniditrin (from Gnidia lamprantha), 14-deoxy-11,12-
didehydroandrogrpholide and andrographiside (from Andrographis paniculata), theaflavin
3,3’-di-O-gallate (from Camellia sinesis), baicalin (from Scutellaria baicalensis), and others.
Cimicifuga rhizome, Melia cortex, Coptidis rhizome, Phellodendron cortex, and Sophora sub-
prostrata radix; Sophorae radix, Acanthopanacis cortex, and Torilis fructus (mRNA7 and N
N protein* protein synthesis); Sanguinobae radix (only N protein synthesis); Compounds extracted from
Stephania tetandra: bis-benzylisoquinoline alkaloids-tetrandine (TET), fangchinoline (FAN),
cepharanthine (LEP).
Myrecetin/Scutellarin (from Scutellaria Baicalensis); Flavanoids from different sources (α-
glucosyl hesperidin, hesperidin, rutin, quercetagetin 6-O-β-D-glucopyranoside and homovitex-
Helicase*
in), xanthones (kouitchenside H, kouitchenside A, kouitchenside D), triptexanthoside D (from
Swertia genus), and others
Platycodin D (from Platycodon grandifloras), wogonoside (from Scutellaria baicalensis), Vi-
Nsp I, Nsp3c and ORF7a*
texin (from Vitex negundo), andrographolide derivatives, and xanthones (from Swertia genus).
Emodin; Kaempferol glycosides (juglanin, kaempferol, tiliroside, afzelin, kaempferol-3-O-α-
3a protein*
rhamnopyranosyl (1,2) [α-rhamnopyranosyl (1,6)]-β-glucopyranoside).
*
Note: Viral protein targets.
Herbal Therapeutics as Potential Prophylaxis for SARS-CoV-2 Infection The Natural Products Journal, XXXX, Vol. XX, No. X 5

agents against CoV-2 [61]. Further, M-protein is a key or- efficacy of Scopodulic acid and Dammarenolic acid against
ganizer in forming the viral envelope by interacting with all S-protein and Mpro. It also suggested silibinin as a multi-
structural proteins of CoV-2. Its contribution in the com- targeting agent against CoV-2 infection [34]. Another group
plexation of S-protein with Golgi complex (ERGIC: E-R was found to possess structural similarity and non-covalent
golgi intermediate compartment) during the formation and interactions between catalytic residues of Mpro with some
stabilization of new virion assembly is well studied [57, 62]. phytoconstituents (baicalin, cyanidin 3-glucoside, and a-
Various available molecules (repurposing) and novel agents ketoamide-11r) [35]. Various research groups use virtual
(new drug discovery) have been targeted at the structural screening tools to identify and propose potential antiviral
proteins to interfere with the vital steps of viral infections phytoconstituents for further screening against COVID-19
through in-silico, virtual screening, and homology modeling- acting through multiple mechanisms. Two fumiquinazoline
based studies. Another host-cell transmembrane protease alkaloids quinadoline B, scedapin C, and the polyketide
enzyme, TMPRSS2 (Cellular transmembrane protease seri- isochaetochromin, Aurnatiamide, Tanshinone II A/B, Ba-
ene 2), contributes to the viral penetration by causing con- vachinin, Neobavaisoflavone, Isobavachalcone 4′-O-
formational changes to S-protein and facilitating viral entry methylbavachalcone, Psoralidin, Corylifol A, Tryptanthrin,
to lungs and other tissues [63, 64]. Homology modeling and Indigodole B are reported to interact with PLpro in different
molecular docking approach investigated specific drugs such species of coronavirus as reported by virtual screening and
as rubitecan and loprazolam [65]. Chloroquine was reported are proposed for further analysis in more assenting evalua-
to interfere with the synthesis and functioning of structural tions [30, 32, 69-72].
S-protein by different mechanisms and thus inhibits the gly-
Coronaviruses are large, enveloped viruses with RNA as
cosylation of viral surface and its binding to host ACE-2
genetic material. In addition to all the probable targets dis-
protein [66]. Novel drug targeting may also interfere with the

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cussed above, drug targeting RNA replication is a potential
viral entry inhibition (endocytosis) and release (uncoating)

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drug development approach. RNA-dependent RNA poly-
of viral nucleic acids and proteins [67].

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merase (RNAp) is an essential enzyme for viral replication

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Once released in the host cell’s cytoplasm, viral RNA is [73]. Targeting RNAp can bring vital changes that hinder

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modified, undergoes encapsulation and polyadenylation code RNA replication from RNA template (transcription) in CoV-
for different structural and non-structural genes, and produc- 2 virulence [74]. Various RNAp inhibitors were developed
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es polyproteins. Specific cysteine proteases are released by earlier as successful antiviral candidates against RNA viruses
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the virus, which can fraction the polyproteins, leading to [74-76]. Researchers have utilized virtual screening tools to
mature non-structural proteins essential for viral replication investigate various phytochemicals from Traditional Chinese
rs or

[68]. Main protease (Mpro) or chymotrypsin-like protease Medicines and have reported the potency of theaflavin, quer-
(3CLpro) is a typical protease enzyme essential for pro- cetin and kaempferol against RNAp. Studies have proposed
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cessing the viral polyproteins, which are translated from further antiviral evaluation of these compounds countering
RNA [34, 35]. Specific papain-like protease (PLpro) splits CoV-2 [30, 74, 77-79]. Targeting RNA replication may in-
the polyproteins to produce negative RNA strands, which is terfere with the virion assembly formation and further viral
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essential for replication [36]. These two proteases play a release. Like RNAp, viral helicase (a non-structural protein)
vital role in the viral lifecycle. Hence, these are crucial tar- is also an important component of RNA replication. It is a
gets for antiviral drugs and many plant-based compounds cleaved product of polyproteins with a sequence of 601 ami-
[27, 36, 69]. Mpro is a common and important target for no acids, but a specific 3D structure for screening is still un-
or

drug development against all types of coronaviruses. Re- available [80-83]. RNA helicase mediates the unwinding of
searchers have explored the similarity in binding sites of nucleic acids in CoV-2. Hence, RNA helicase is a prone tar-
“F

Mpro in humans and animals. A complete understanding of get for developing agents that target RNA replication in
amino acid sequence and the development of 3D architecture CoV-2 [84]. Yu and coworkers have evaluated myricetin and
has exposed the targets for designing and developing novel scutellarein as potent inhibitors of CoV-2 in an in-vitro study
wide-spectrum antiviral compounds [27]. Based on this evi- [85].
dence, various photochemical are screened as newer agents
As discussed earlier, SARS-CoV-2 polyproteins, by the
or repurposed against COVID-19. Various phytochemicals
activity of enzymes like Mpro, PLpro, RNAp etc., produce
include flavonoids, terpenoids, organosulfur compounds,
various proteins that contribute to the release of nucleic acid,
limonoids, lignans, sulphides, polyphenolics, coumarins,
transcription, translation, and viral replication. It also brings
saponins, chlorophyllins, furyl compounds, alkaloids, poly-
several hosts related implications [86]. Studies have demon-
enes, thiophenes, proteins and peptides have been found to
strated glycogen synthase kinase as a potential target due to
possess therapeutic applications against genetically and func-
its role in phosphorylic activation of N-protein [87, 88]. Fur-
tionally diverse viruses. Chandel et al. investigated 19 prob-
ther heterogeneous nuclear ribonucleoprotein A1 could also
able inhibitors against Mpro utilizing an in-silico approach
regulate protein translation in host cells by interacting with
and revealed Rhein (anthraquinone from Rhubarb), Withaf-
N-protein to facilitate viral replication [89]. These proteins
erin A, Withanolide D, and aloe-emodin as the most effec-
are essential for assembly formation and viral release. Hence
tive natural products proposed for further analysis [27].
these are probable targets for new drug development or re-
Studying various plant-based compounds through in-silico
purposing of the available phytochemicals. As depicted in
studies, Shehu and coworkers have revealed the potential
Fig. (1), phytoconstituents could be analyzed using various
6 The Natural Products Journal, XXXX, Vol. XX, No. X Singhal et al.

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Fig. (1). Viral-host cell interaction, viral proteins and targets which are inhibited by phytochemicals. (A higher resolution / colour version of
this figure is available in the electronic copy of the article).
on P
rs or

techniques like virtual screening and target-based drug dis- diabetes complications. The recent well-entrusted approach
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covery (for targets, namely, steps of viral attachment, endo- involves the repurposing of existing drugs. Some drugs used
cytosis, uncoating, transcription, translation, replication, as- in clinical trials are of synthetic origins, such as favipiravir,
sembly formation and finally to viral morphogenesis). lopinavir/ritonavir, ivermectin, dexamethasone, etc. The re-
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4.3. Herbal Therapeutics and Herd Immunity quirement of effective and safe agents to stop SARS-CoV-2
infection can be achieved through well-documented and clin-
Herd immunity refers to the attenuation of the virus by ically proven herbal therapeutics. The investigated herbal
herbal compounds followed by inoculation. It might be diffi- phytochemicals or therapeutics can be used alone or in com-
or

cult for host cells to develop herd immunity. During a bination as an adjuvant to synthetic/semisynthetic drugs.
worldwide pandemic, the indigenous proposal to develop
Most studies reported for SARS-CoV-2 inhibitory prop-
“F

herd immunity through herbs is also gaining attention. The

erties of herbal phytoconstituents are in preliminary stages.
herd immunity strategy has been implemented to protect
In silico studies, including protein-ligand interactions
human health from measles, chickenpox or smallpox. Ex-
through molecular docking and molecular dynamics simula-
tracts of Amma Talli leaves have been used to develop herd
tion, are documented in the literature, but the majority of
immunity against viral infections [90]. The indigenous
them lack experimental and/or in vitro details. Computation-
knowledge can be used to investigate insights into the scien-
al approaches can effectively identify single/multicomponent
tific application of the concept of herd immunity to control
herbal formulations as antiviral therapeutics for treating
the global pandemic.
SARS-CoV-2 infection. One such example is clustering
4.4. Advantages and Limitations of Herbal SARS-CoV-2 analysis and scaffold analysis of Traditional Chinese Medi-
Inhibitors cines (TCM), where eight core combinations and ten novel
formulae of herbal drugs were reported. These investigated
The rapid and uncontrolled spread of SARS-CoV-2 in- combinations can be screened for their inhibitory properties
fection requires effective, preventive and curative therapeu- against SARS-CoV-2 infection [91]. Similarly, the ethnome-
tics like drugs and/or vaccines. Anti-viral drug development dicinal data provided by Ayurveda, the Indian Traditional
must overcome various limitations, namely, lack of/limited Medicine system, offers diverse medicinal properties due to
specific markers, long genome sequence, and integrated cap- the unique topographical, geographical, and climatic condi-
sid cover having a remarkable mutation rate. The infection is tions [92]. These have been entrusted as preventive and in-
complicated in elderly patients or those with lung/heart or hibitory therapeutics for various viral infections.
Herbal Therapeutics as Potential Prophylaxis for SARS-CoV-2 Infection The Natural Products Journal, XXXX, Vol. XX, No. X 7

Additionally, screening herbal phytochemicals can iden- secondary metabolites such as alkaloids, terpenoids, glyco-
tify potential therapeutic nuclei or lead molecules of diverse sides, steroidal compounds, lactones, and polysaccharides.
structural features. Structural optimization of these identified Due to this, it exhibits its medicinal potency as an immuno-
lead nuclei to improve pharmacokinetic and pharmacody- modulatory agent, anti-viral herb, and effective against sev-
namic properties is a reliable drug discovery approach. The eral other human ailments [105]. In silico studies have also
limitations observed with phytochemicals are low yield dur- revealed that the main phytochemicals of Tinospora cordifo-
ing the extraction process, a requirement of a retrosynthetic lia can control the protein function of 3CLpro owing to its
approach, and cost. Thus, irrespective of the number of stud- inhibition and thus can regulate viral replication [106]. The
ies underway for phytochemicals, very few could successful- results of another in silico investigation have shown that its
ly reach the clinical stage. components can hinder the fastening of SARS CoV-2 spike
protein with the human receptor ACE2 protein [107]. Thus,
4.5. SAGE Uses, Benefits and Dosage the population of developing countries can rely on Tinospora
cordifolia, which shall provide a preventive therapy against
Traditionally, SAGE is known for multiple pharmacolog-
COVID-19.
ical uses and is commonly known as the “Salvation Plant.” It
is evident to reduce perspiration and is effective against The major drug discovery and development challenge is
menstrual irregularity, including menopausal hot flashes, to targeting the viral enzymes and investigating drugs that can
improve appetite and digestion and act against many micro- inhibit viral replication or prevent disease progression. This
bial infections, including gastroenteritis and other infections manuscript discusses the role of herbal compounds with de-
[93, 94]. Also, many recent studies report on anti- tails of present investigation status against SARS-CoV-2
inflammatory and antinociceptive effects related to pain re- viral targets. To effectively control the current pandemic,

”
lief, effects on neuropharmacology like antioxidant, antide- herbal compounds may be effectively used to improve the

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mentia effects related to Alzheimer’s disease, antimicrobial host endogenous response. Similarly, using herbal com-

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effects related to various infections including worm infesta- pounds for developing herd immunity is a time requirement.

U ofs
tions and gastroenteritis, anticancer and antimutagenic ef- The herbal compounds can play an important complemen-

O
fects related to various cancers such as colon or breast can- tary role in the fight against the SARS-CoV-2 pandemic. In
cer, and very important hypoglycemic and hypolipidemic drug discovery, the role of herbal products needs to be de-
al ro
se
effects related to metabolic diseases such as non-alcoholic fined as rationalized therapeutics for the prophylaxis of
fatty liver or diabetes [94-96]. Various extracts of the sage SARS-CoV-2 infection.
on P

plant have been reported for the occurrence of rosmarinic,

rs or

ursolic, caffeic, oleanolic acids [97], borneol, carnosic acid,

AUTHORS’ CONTRIBUTIONS
and ursolic acid. These have proven specific pharmacologi-
Pe uth

cal activity like dose-dependent topical anti-inflammatory All authors contributed equally to this work and have
activity, anti-hyperlipidemic properties, improved pancreatic read and approved the final paper.
function, reduced body weight, etc. [98-100]. Sage admin-
A

istration-induced improvement of memory and cognitive CONFLICT OF INTEREST

functions, pain relief, especially for sore throat, and
significant improvement in blood glucose (including HbA1c The authors declare no potential conflict of interest.
and post-prandial glucose) and lipid profile (especially an
or

increase of high-density lipoprotein, HDL), obesity, non- FUNDING

alcoholic liver disease, metabolic syndrome, various types of
The work is not supported by any funding agen-
“F

cancer, and cardiovascular diseases has been reported in the

clinical studies [94, 101-104]. cy/institution.

ACKNOWLEDGEMENTS
CONCLUSION AND FUTURE PERSPECTIVE
The authors acknowledge the support provided by the
Nature has endowed mankind with an answer to every KIET Group of Institutions, Delhi-NCR, India and Dr. A. P.
trouble. Thus, for the current pandemic situation, when no J. Abdul Kalam Technical University, Lucknow, India, for
effective remedy is available, we look back towards tradi- the present work.
tional medicines that involve the use of herbs present abun-
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