THE UNIVERSITY OF BURDWAN

M.Sc. 4th Semester Examination 2021

Term Paper
Natural Product as the Vital Source of Discovery for Prevention
and Therapy of COVID-19

Major elective – Molecular Biology and Genetics

Paper: MZJT- 405
Submitted by:
SADANANDA KUMBHAKAR
Roll no: BUR ZOO 2019/054
Reg. No: 201601032289 of 2016-2017
Session: 2019-21
 ACKNOWLEDGEMENT
This Term Paper is truly the result of the collaborative efforts of so
many individuals and organizations, each contributing in a significant
way. I am immensely grateful to each and every individual who
believed in and supported this endeavor.
First, I would like to thank The Department of Zoology of The
University of Burdwan for giving me the opportunity to work on this
topic as a part of the curriculum in M.Sc. 4th Semester. In addition to
that, I would like to acknowledge all the faculty members of The
Department of Zoology and specially the faculty of my Major
Elective Paper: Molecular Biology and Genetics, for their immense
support in this work.
My Acknowledgement will never be complete without special
mention of Dr. Paramita Mandal, Asst. Professor (Department of
Zoology, The University of Burdwan) for her valuable guidance for
my term paper. Without her enthusiasm and continuous support, this
term paper would not be possible.
Finally, I would like to thank my friends for their moral support and
motivation which always drives me to give my best.

Thanking You

Date: 18.08.2021 Sadananda Kumbhakar

Roll No.: BUR ZOO2019/054

 Natural Product as the Vital Source of Discovery for Prevention
and Therapy of COVID-19

Abstract: Coronaviruses are the large family of viruses that cause common cold to severe
diseases. The novel coronaviruses (COVID-19) was reported in 2019 in Wuhan, China. The
COVID-19 pandemic has daramaticaly changed the human life and it gives out unparalled
challenge to public health. Standing on current situation there is no specific drug to response
against COVID-19 diseases and also vaccine has no long term effectiveness. In this review,
we have highlighted on alternative method of treatment, prevention and therapeutic approach
using nutraceuticals (such as omega‑3 fats, β‑glucans, amino acids, probiotics, vitamins and
minerals) and phytochemicals from herbal extracts and their mode of action. Natural
products can be both effective and safe. It also shows tolerable toxicity. Many compounds
directly target the viral genomic content and translational mechinary. Thus, it is suggested
that these products can prevent the ongoing increase no of COVID cases. Some natural
products such as bioactive substances and phytochemical classes such as flavonoids,
alkaloids, and peptides are successfully tested against COVID-19. This review intends the
natural products, their mechanism of action, sources and previous usages. We focused to
provide a new outlook regarding therapeutic treatment of COVID-19 and its prevention based
on natural products.

Keywords: COVID-19 treatment, Natural products, Nutraceuticals, Phytochemicals,

Herbal medicine

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 CONTENTS
1. Introduction......................................................................................................3-4
2. Historical aspects of using Natural products in disease prevebntion.............4
3. Important natrural product and their function for respiratory disease
prevention.........................................................................................................4-5
4. Natural products against SARS CoV-2.........................................................5-8
5. Differential mode of actions of natural product against SARS CoV-2....8-14
5.1. ACE2 Inhibitor...................................................................................8-10
5.2. TMPRSS2 Inhibitor.........................................................................11-12
5.3. RNA polymerase Inhibitor..................................................................12
5.4. 3CLpro Inhibitor..................................................................................13
6. Nutraceuticals against SARS CoV-2.........................................................15-17
6.1. Vitamins...............................................................................................15
6.2. Minerals...............................................................................................15
6.3. Amino acids....................................................................................15-16
6.4. Fatty acids............................................................................................16
6.5. Probiotics.............................................................................................16
7. Available herbal medicine against SARS CoV-2......................................17-18
8. Therapeutic benefits of natural products for respiratory diseases.........18-19
9. Conclusion...................................................................................................,......19
10. References.....................................................................................................20-24

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1. Introduction
The current pandemic of coronavirus disease 2019 ( COVID-19) is a threat to public health
worldwide that is spreading across countries originated in Wuhan, China [1]. The cause of
this highly transmissible disease is a novel coronavirus, called severe acute respiratory
syndrome (SARS-CoV-2), which is the 7th known virus of the Coronaviridae family able to
infecting humans [2]. As of 17th August, 2021 20.8Cr individuals infected and approximately
43.7L individuals have succumbed by this virus. The United States of American has the
highest number of COVID19 cases (3.7Cr cases), followed by India (almost 3.23Cr cases)
and Brazil (over 2.04Cr cases) [3]. Mainly, seven types of corona viruses infects us that are
severe acute respiratory syndrome coronavirus (SARS‑CoV), Middle East respiratory
syndrome coronavirus (MERS‑CoV), severe acute respiratory syndrome corona‑ virus 2
(SARS‑CoV‑2), OC43, NL63, 229E and HKU1. COVID-19 shows various unspecific
symptoms ranging from mild to severe, among infected individuals [4]. Certain percentage of
fatal cases have been reported in which infected individuals experiencing progressive
respiratory failure due to the damage of the alveolar epithelialc cells by viruses. Virus
initiates this damage through the receptor-binding domain (RBD) bind to the angiotensin-
converting enzyme-2 (ACE2) receptor, present in respiratory tract [5].

Mainly, Corona virus starts its infection through two pathway that are angiotensin converting
enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPSS2) on host cell membrane.
Patients are mainly die due to two reason one acute respiratory distress syndrome and
another severe cytokine release syndrome[6]. Viruses infecting humans can lead to
inflammatory processes and secrets numerous proinflammatory cytokines that are responsible
for the clinical appearance of inflammation. IL-2, IL-7, IL-10, G-CSF, IP-10, MCP-1, MIP-
1a, and TNF-α, are some major proinflammatory cytokines that are highly elevated in the
blood of severely infected COVID-19 individuals [7].

Till now, there is no specific treatment for COVID-19. No vaccine or right treatment for
COVID‑19 has been reported and only personal protection, supportive care, early diagnosis
and isolation to reduce the spread and violence of the infection. Scientists are trying to find
the best way to cure or prevent COVID-19, including using natural products and
nutraceuticals therapy. Since the immune status of patients plays an vital role in COVID-19
infection, an herbal medicine which has immunomodulatory effect, have possible preventive
measure and even therapeutic agent for COVID-19 infected individual [8] [9]. The clinical
efficacy of these treatments, however, warrants further approval. Experimental therapy with
antibiotics (such as vancomycin, ceph‑ alosporins, azithromycin, quinolones, tigecycline and
carbapenems), antivirals (such as remdesivir, ritonavir, lopinavir, and oseltamivir) and
corticosteroids (as well as methylprednisolone and dexamethasone) has thus been used for the
treatment of patients with COVID‑19 [10].

Natural products play a vital role in the development and treatment of several diseases
through human evolution[11]. The impressive source of bioactive metabolites are essential

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oils and extracts deraived from plants. Bioactivities of natural products have being
extensively used in ethnobotany and pharmaceutical industry, including cancer,
inflammation, oxidative process and viral infections [12] [13] [14] [15]. Several antiviral
bioproducts have already been described by the activity against HIV, Coronavirus, Hepatitis
B, Dengue virus, Enterovirus and Influenza virus. So, natural products could be effective in
the fight against SARS-CoV-2, through developing of specific chemotherapies against
COVID-19. Some metabolites of arachidonic acid and EPA, induce inflammation, such as
leukotrienes, thromboxanes, and prostaglandins, whereas other metabolites of EPA and DHA,
such as protectins, maresins, resolvins and lipoxins, inhibit inflammation, enhance the T‑cell
response, modulate wound healing processes, augment phagocytosis and decrease microbial
load [16]. A recent research revealed that both DHA and EPA, from fish oil, enhance
breathing for asthma patients. The intravenous and oral administration of DHA or EPA
potentially promote the recovery of COVID‑19 patients [17] [18].

In this review paper, we focused to provide a new outlook regarding therapeutic treatment of
Covid-19 and its prevention based on natural products. we provide insights on the potential of
natural products, herbal medicines and Nutraceuticals therapy against COVID-19 . We
summarized lately reported experimental prophylactics. Then, we discussed both the natural
products inhibiting human coronavirus and the herbal medicines proven effective in
alleviating respiratory distress syndrome. Ultimately, this review aims to offer another
conceptual scaffolding for COVID-19 prevention and profound insight into this pandemic.

2. Historical aspects of using natural product in disease prevention:

Although records of herbal medicine or medicinal plants dated back 5000 years to the
Sumerians, outline the well-known uses of laurel, caraway, and thyme plants. It has been
shown that the herbal medicine practice started at eight thousands years ago at China and
sixty thousands years ago in Iraq. On clay tablets in cuneiform Mesopotamia (2600 B.C) the
records of natural products illustrated, which tabulated from Cypress (Cupressus
sempervirens) oils and Myrrh (Commiphora sp.) are still apply to treat colds, inflammation
and coughs [19]. Research on Papaver somniferum L. (opium poppy) resulted in the
extraction of several alkaloids including morphine, a important drug, first reported in 1803. It
was in the 1870s that crude morphine derived from the plant P. somniferum, was boiled in
acetic anhydride to isolate diacetylmorphine (heroin) and easily converted to painkiller
codeine [20]. Historically, it is documented that the Sumerians and Ancient Greeks used
poppy extracts medicinally, whilst the Arabs described opium to be addictive. Historically,
for treatment and prevention of many diseases and illness natural products have been used
from the beginning. Medicine for any diseases, natural products used as the vital source
throughout the evolution. Our ancestors chewed on specific plant products to relieve pain,
and wrapped leaves of plant around wounds to cure. So, natural products used to treat
diseases and injuries since past decades [21].

3. Important natrural products and their function for respiratory disease

prevention

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Now a days, interest in plants as promising antiviral products are increasing for the failure of
many traditional drugs against viral infections combined with viral resistance. Nature created
an immense library of chemicals for the designing of drugs to treat many diseases including
viral infection. Since natural compounds, including flavonoids, ligans, phenolic acids,
terpenes, coumarins, alkaloids and proteins play a vital role in inhibiting viruses and acting as
supportive therapies against viral infections, we reviewed active natural products against
SARS-CoV-2 and other respiratory viruses such as influenza A, MERS etc. In Addition, for
the treatment of acute respiratory tract infection natural-based agents are used regularly,
mainly in children, because of insufficiency specific antiviral drugs and its low cost.
Flavonoids are widespread groups of natural products which are phenolic in nature. There are
ten major sub-groups of flavonoids, i.e. isoflavones, flavans, flavones, flavonols,
biflavonoids, catechins, chalcones, flavanones, flavanonols and aurones[22]. Among these
sub-groups some flavonoids have antiviral effects against different types of respiratory
infectious viruses such as influenza viruses. Three flavonoids, in 2018 including 6-
hydroxyluteolin 7-O-β-d-glucoside, nepitrin (1) and homoplantaginin were isolated from the
Salvia plebeian (Methanol extract). These phytochmicals were found to be active against
influenza virus neuraminidase H1N1A/PR/9/34. A flavonoid Matteflavoside G (2), isolated
from the rhizomes of Matteuccia struthiopteris. Tod (currently accepted name Onoclea
struthiopteris, Roth), exhibited important suppressive activity against the H1N1 influenza
virus neuraminidase. These compounds showed activity against H1N1 neuraminidase.
Flavonoids including quercetin (3), isoquercetin (4), and rutin (5), isolated from the methanol
extract of Capparis sinaica Veill demonstrated a reduction in the virus titer by 68.13%,
79.66% and 73.22% inhibition at a concentration of 1 ng/ml, respectively. Quercetin (3) and
rutin (5) are also inhibit the viral neuraminidase activities the influenza infection in animal
models and in vitro. From the hydroalcoholic extract of Humulus lupulus L Quercetin (3) and
rutin (5) were isolated. This extract was found to inhibit replication of various viral strains,
in different stage of infection[23]. Sanggenon G (11) and sanggenol A (6) are two prenylated
flavonoid derivatives found to act as dual inhibitors of both bacterial NAs and viral.
Interestingly in contrast to the approved NA inhibitor oseltamivir, these compounds inhibited
planktonic growth and also biofilm formation of pneumococci. In the screening of natural
products for anti-influenza potential, two chalcones named echinantin (7) and
isoliquiritigenin (8) revealed strong inhibitory action against various neuraminidases
originating from the influenza viral strains H1N1, H9N2, novel H1N1 (WT), and oseltamivir-
resistant novel H1N1 (H274Y) expressed in 293T cells. Echinantin was identified as the most
active compound against NA derived from the novel H1N1 influenza with an IC50 of 2.49 ±
0.14 μg/ml. Some biflavonoids act successfully as potential NA inhibitors like ginkgetin (9),
hinokiflavone (10), and 4′-Omethylochnaflavone (11)[24] .

4. Natural products against SARS CoV-2

Heat Shock Protein A5 is one of the host-cell receptors that has been discovered to be
recognised by viral S protein (HSPA5, also known as BiP or GRP78). HSPA5 is upregulated
and translocated to the cell membrane when a cell is infected, where the SARS-CoV-2 spike
recognises it and starts the infection process. It used molecular docking and molecular
dynamics simulations to evaluate various natural product molecules against the HSPA5
substrate-binding domain (SBD) [25]. HSPA5 has proximal binding affinities for
phytoestrogens (Daidzin, Genistein, Formononetin, and Biochanin A) and estrogens. SARS-
CoV-2 adhesion to host cells may be hampered by these substances.

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A B

C D

E F

G H

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No. Compound type Isolated from References
A. Glycyrrhizin Euphorbia neriifolia [26]
B. Isotheaflavin-3-gallate Black tea [27]
C. Tannic acid Black tea [28]
Scutellarein (4)
Scutellaria
D. Quercetagetin (5) [29]
Myricetin (6)
Robinetin (7)
E. Isolinoleic acid Mucuna pruriens [30]
F. Ethanol extract/Lycorine Lycoris radiata [29]
Leukamenin (1)
Glaucocalyxin (2) Lactuca sativa
G. [29]
Pseurata (3)

H. Iguesterin Celastrus orbiculatus [29]

Table 1: Anti-SARS-CoV-1 natural metabolites

Besides S protein and PLpro, the other promising drug target for combating the infection of
SARS-CoV-2 is 3-chymotrypsin-like protease (3CLpro, also known as main protease). The
conserved 3CLpro controls virus replication. Screen a series of alkaloids and terpenoids
derived from African plants as potential inhibitors of 3CLpro using molecular docking and
absorption, distribution, metabolism, excretion, and toxicity (ADMET) virtual analysis by the
SuperPred webserver [31]. The results revealed that 10-Hydroxyusambarensine,
Cryptoquindoline, 6-Oxoisoiguesterin, and 22-Hydroxyhopan-3-one might be potent
inhibitors with greatest drug-likeness against SARS-CoV-2 3CLpro [32].
By molecular docking and molecular dynamics simulations, have shown that with an one
derived from Ashwagandha leaves (Withania somnifera ) could bind and stably interact at the
catalytic site of TMPRSS2 (His296, Asp345 and Ser441). In addition, they have confirmed
that withanone significantly downregulated TMPRSS2 in MCF-7 cells, suggesting its dual
potential to ramp down TMPRSS2 function [33].

Abd El-Aziz et al. investigated the potential of eight natural polyphenols (quercetin,
naringenin, caffeine, oleuropein, ellagic acid, benzoic acid, resveratrol, and gallic acid
polyphenols) as inhibitors of SARS-CoV-2 RdRp by molecular docking assay. The studied
polyphenols formed hydrogen bonds with the nucleotide triphosphate (NTP) entry channel
amino acids (ARG 555, ARG 555, LYS 545) in SARS-CoV-2 RdRp (except caffeine and
oleuropein) [34]. Binding to NTP may inhibit the entry of the substrate and subsequently
repress the enzyme activity. The results suggested that gallic acid and quercetin exhibited
high binding affinity to RdRp. The NSP12 is an important RdRp for the coronavirus
replicative machinery, which binds to co-factors NSP7 and NSP8 to activate its ability to
replicate long RNA [35]. A recent study has established two homologous models for virtual
screening. Cepharanthine, an alkaloid tetrandrine isolated from Stephania (Stephania
tetrandra S. Moore), has been reported to have anti-inflammatory and antioxidant activities
[36].

Koshak et al. from King Abdulaziz University will investigate the effects of Nigella sativa
seed oil with immunomodulation and antiviral activity in hospitalized adult patients
diagnosed with COVID-19.The researches mentioned above are all still in preliminary stages

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of drug development although they have shown great potentials against SARS-CoV-2 using
computer-based screening [37]. Further pre-clinical studies have to be performed to examine
the anti-viral effects of those lead compounds. In the meanwhile, great number of clinical
trials have registered to investigate the potentials of natural product to halt disease
progression [38].

Fig: Schematic illustration of keypoints on the application of natural products as anti-Covid-19

5. Differential mode of actions of natural product against SARS CoV-2

5.1. ACE2 Inhibitors:

In humans, the major receptor of SARS-CoV-2 viruses is ACE2, and researchers are working
to understand its mechanism of action and control as a way to combat the virus. The main
function of ACE2 as part of the renin-angiotensin system is to convert angiotensin II, a potent
vasoconstrictor, to angiotensin I. (structural forms I, III, IV, V, VI and VII), a vasodilator that
contributes in the maintenance and reduction of the blood pressure by counter-regulating
ACE [39]. Despite it being an analogue of ACE, their similarity is only approximately 42%.
An issue regarding ACE2 and coronaviruses infections is that most of the chronic treatment
of hypertension and diabetes involves the use of ACE inhibitors. These substances are also
known to cause the expression of ACE2 to be upregulated, putting the patient in the risk
group of COVID-19 [40][41]. In fact, most of the COVID-19 confirmed patients that
presented severe or fatal forms of the infection had comorbidities, hypertension or diabetes in
particular. Meanwhile, common ACEIns included in hypertension medications such as
perindopril, enalapril, and losartan have no effect on ACE2. The limited ability of ACEIn to
cleave angiotensin I is thought to be the cause of ACE2 overexpression. As the concentration
of angiotensin I rises as a result of ACE inhibition, ACE2 mRNA increases to compensate
[42].

Several natural products present ACE inhibition activity and are extensively used in
ethnobotanics, and in some cases are deeply rooted in the human diet. The application of

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bioproducts, like ACE inhibitors, is widespread, primarily because the synthetic substances,
such as enalapril, were developed using a natural metabolite as a scaffold. This demonstrates
their reliability as a new medicine sources; they present less side effects than synthetic drugs;
and, in some cases, even natural extracts can present lower IC50 values [43][44].

There are at least 300 plants show ACE inhibitors activity, including some popular medicinal
and food species, such as cinnamon (Cinnamomum zeylanicum Blume or Cinnamomum
verum J. Presl.), pepper (Capsicum spp.), olive (Olea europaea L.), hawthorn (Crataegus
pinnatifida Bunge), black nightshade (Solanum nigrum L.), passion fruit (Passiflora
edulis Sims) and grape (Vitis vinifera L). ACE inhibitors from natural products belong to
several phytochemical classes, including flavonoids, xanthones, alkaloids, peptides, terpenes,
and tannins [45]. Some compounds have presented both AceIn and ACE2 inhibitor activity,
for example, phenolic compounds like myricetin and quercetin glycosylated derivates. The
ability to inhibit both, ACE and ACE2, is caused by their closely related active sites, which
are distinct mainly in terms of the smaller intramolecular size of ACE2 sites. Briefly, ACE2In
natural metabolites are of the same chemical classes of ACEIn and can be readily obtained in
medium polarity extracts of angiosperms species such as roots and barks [46].

ACE and ACE2 inhibitors present amphiphilic molecular structures usually with an aromatic
moiety, in order to enable their interaction with the protein, a similar pattern to the observed
with SARS-CoV-1 inhibitors. Pharmacophere analysis of suggested natural metabolites
capable to inhibit SARS-CoV-2 through ACE2 inhibitions usually have structural features in
accordance with Lipinski's rule with molecular weight lower than 500 Da, less than 5
hydrogen bond donors and a log P under 5 [47] [48]. The number of hydrogen bond acceptors
were more variable among suggested phytochemicals against COVID-19, ranging until
20. For instance, ACEIn peptides have as first residue an aromatic amino acid, and the third
is a hydrophobic one. The sequence trending necessary for peptides to be ACEIn was
extensively exploited [49].
The first in silico screening for anti-SARS-CoV-2 natural metabolites was within traditional
chinese herbs, such as species of the Citrus genus. The virtual molecular docking of Chinese
herb metabolites with the ACE2 against SARS-CoV-2 suggested 11 natural products capable
of inhibiting it. The natural metabolites suggested as possible bioactive substances against
within Chinese medicinal botanic species includes baicalin (baicalein-7-O-glucuronide),
scutellarin (scutellarein-7-glucuronide), hesperetin, nicotianamine, glycyrrhizin, naringin,
naringenin, hesperidin, neohesperidin, and nobiletin [50]. Similar to ACEin natural ACE2
inhibitors screened to combat SARS-CoV-2 are classified as alkaloids, flavonols, flavanones,
terpenes, limonoids, lignans, terpenoids, tannins, phenolic acids and fatty acids. Disregarding
the distinct software's and molecular docking models, the class with major representatives
and better affinity results are within flavonoids.

Fig: Toxic alkaloids of Veratrum with antiviral activity

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Although the first in silico study of anti-COVID-19 natural products emphasizes flavanones
with lower distribution on flora, such as naringin and naringenin, recent finds indicates
glycosylated derivates of quercetin to present promising inhibition activity with lower
binding energy than −8.3 kcal mol−1. These flavonoids, described by Joshi et
al. (2020) includes quercetin-3-glucuronide-7-glucoside and quercetin 3-vicianoside, which
can be found in Indian long pepper (Piper longum L.), turmeric (Curcuma longa L.) and
wormwood (Artemisia absinthium L.) Considering inhibition of COVID-19 through ACE2
the flavolignan silybin have presented the lowest binding affinity until end of 2020 May.
Silybin is one of the major metabolites obtained from milk thistle seeds (Silybum marianum),
a plant with traditional usage in chemopreventive, anti-inflammatory agent and in the
treatment of digestive disorders [51].
There are two crucial factors to remember about flavonoids' anti-SARS-2 activity:
(1) Glycosylated forms are more active than their non-glycosylated counterparts.
(2) Extracts and fractions outperform isolated substances by a large margin. [52].
Although most of promising natural metabolites against SARS-CoV-2 binding to
ACE2 are within flavonoids, cases within other classes, such as limonoids
(tetranortriterpenoids) and alkaloids deserts attention. Alisha and Tripti (2020) demonstrated
that the limonoid 6-α-acetoxygedunin has an even lower binding affinity to ACE2 than any
flavonoid. Limonoids are major compounds produced by Meliaceae family, mainly within the
genus Carapa, such as C. guianensis, an Amazonian species known as andiroba, widely
consumed as an anti-inflammatory [53][54]. The presence of anti-COVID-19 within well-
known species is promising on the development of chemotherapies as their exploitation is
already stablished.
Molecular docking in the chromatographic fingerprint of a Chinese medicinal plant applied
in the treatment of COVID-19 has also characterized extracts and alkaloids of the Veratrum
nigrum L. as ACE2 inhibitors of SARS-CoV-2. Most of the suggested alkaloids are typical of
the Liliaceae genera, such as hupehemonside, pseudojervine, and imperialine [56][44].
However, Veratrum species are known to be toxic when consumed after decoction due the
occurrence of a specific group of alkaloids, which are either major or minor compounds in
their chemical profile, though, the incidents of human intoxication is rare and usually
accidental. One of the alkaloids reported through molecular docking as anti-SARS-CoV-2 is
an analogue of jervine , a toxic alkaloid. Thus, despite the presence of several possible anti-
COVID-19 alkaloids, special care needs to be take when considering the use
of Veratrum species [48].

Fig: Metabolites virtually screened as ACE2 and TMPRSS2 inhibitors of SARS-CoV-2.

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5.2. TMPRSS2 inhibitors:

Despite molecular docking indicating it as a method in COVID-19 treatment, TMPRSS2

inhibitions search is the lowest among the major replication proteins. TMPRSS2 has
previously been linked to influenza virus inoculation and replication, cancer, and the SARS-
CoV-1 virus [56][57]. TMPRSS2 natural inhibitors includes flavonoids, terpenes and
peptides. For instance, the flavonoids baicalein and baicalin , which have already been
reported as a down-regulators of the TMPRSS-2 expression, were also indicated on in
silico studies against COVID-19. It's worth noting that molecular docking studies have
suggested that baicalein is also an ACE2 inhibitor. Indeed, it would be excellent if the
candidate metabolite could be used to interact with several virus binding sites in order to
boost its bioactivity in vivo [58].

Fig: Mechanism of action through TMPRSS2 and ACE2

Virtual molecular screening can be used to find anti-COVID-19 natural metabolites, and
baicalin and baicalein are suitable examples. Following its promising results in molecular
docking, enriched fractions containing both compounds were evaluated in vitro and shown to
have antiviral activity comparable to that of the repurposed medication. In vitro tests were
performed by fluorescence resonance energy transfer protease assay and with Vero E6 cells
contaminated with COVID-19. Within both assay, baicalein had the most promising results
with IC50, EC50 and selectivity index (SI) to the SARS-CoV-2 3CLpro of 0.94 μM, 1.69 μM
and 118, respectively, while baicalin presented the values 6.41 μM, 10.27 μM and 19,
respectively. For instance, chloroquine EC50 was 1.13 μM, with a SI of 88. This
data confirms that in silico experiments, such as those obtained for baicalein, can give
promising insights on possible anti-COVID-19 natural metabolites [59]. The major natural

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source of baicalein are Scutellaria and Oroxylum genera, mainly in the roots of S.
baicalensis and the seeds of Oroxylum indicum. Both flavonoids have therapeutic properties
as neuroprotective, antioxidant, anti-inflammatory, renal protector and anticancer. In
addition, these flavonoids also presented remarkable activity as inhibitors of viruses, such as
the Zika virus [51][47].

In addition to already know human TMPRSS2 inhibitors, Rahman et al. (2020) demonstrated
by in silico studies that iridoids, diterpenes and lignans are promising anti-SARS-CoV-2
through TMPRSS2 interaction. The inhibition of TMPRSS2 requires similar structural
features as those previously described for ACE2 inhibitors, presence of hydroxy moieties for
hydrogen binding and presence of aromatic rings. Rahma and coworkers suggested 12 natural
metabolites with binding energy with TPMRSS2 ranging from −11.06 to −14.69 kcal mol−1 .
The natural metabolite with greater inhibition potential was the geniposide, an iridoid found
in Gardenia genus (Rubiaceae) and endemic in Central America and China. Such values are
higher than any molecular docking focused on ACE2 inhibition. Natural source of the 12
metabolites suggested as anti-COVID-19 by Rahma and coworkers included marine soft
corals (Formosan gorgonian and Alcyoniidae family), free-floating algae
from Sargassum genus, mushrooms of Paxillus genus and several species of angiosperms,
such as magnolia-vine (Shisandra sphenanthera) green tea (Camellia sinensis) and the
branched asphodel (Asphodelus ramosus) [58].

Fig: Bioactive natural products against Human Corona Virus.

5.3. RNA polymerase inhibitors

Anti-SARS-CoV-2 treatment is taking a new path thanks to RNA polymerase inhibitors,

which block viral multiplication in a very particular way. ACE2 or TMPRSS2 inhibitors,
which attach to the host cell, are likely to be less hazardous than metabolites having this
feature. Although RNA polymerase inhibitors are less hazardous, their utility in the treatment
of coronaviruses is still limited still rare. Only two compounds, remdesivir and a synthetic
1,4-diazepane derivate (IC50 of 0.45 M), are found in the literature that inhibit coronavirus
RNA translation [59]. Four commercial medications were also recommended by molecular
docking, but their efficacy has yet to be verified. Natural inhibitors of SARS-CoV-2 RNA
polymerase screened in essential oils thus far showed docking values lower than commercial
inhibitors, despite their potential in viral treatment. Because natural inhibitors of the RNA
polymerase of the Dengue and Chikungunya viruses have been discovered in natural extracts,
it is likely that natural metabolites capable of inhibiting SARS-CoV-2 RNA translation are
still unknown [60].

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5.4. 3CLpro Inhibitors

Fig: Structure of SARS CoV-2 3CLpro

Natural products have long played an important role in the creation of drugs to treat a variety
of disorders. As a result, traditional herbs from various geographical regions and habitats
should be explored as possible sources of novel medications to treat viral infections, such as
those caused by SARS-CoVs and their variants [61]. For ages, the medicinal plant Isatis
tinctoria L. (Brassicaceae) has been prized for its therapeutic and cosmetic properties, as well
as its indigo-blue colouring properties in Europe, Central Asia, and TCM. All parts of this
plant are used in complementary and alternative pharmaceutical formulations to treat eruptive
epidemic disorders such as pharyngitis, laryngitis, hepatitis, fevers of various kinds, and
influenza and viral skin diseases [62]. Currently, the therapeutic qualities of I. tinctoria root
are recognised in European phytotherapy, mostly due to its antiviral effects. During SARS-
CoV epidemics in China, Hong Kong, and Taiwan, Isatis tinctoria L. and other phenolic
herbs were frequently utilised to combat the virus. Phytochemicals are found in the root of I.
tinctoria L. such as indigo, indirubin, indican, β-sitosterol, sinigrin and γ-sitosterol. Seven
other compounds from various sources, namely aloe-emodin, hesperetin, quercetin,
naringenin, daidzein, emodin and chrysophanol were also tested for their SARS-CoV-
3CLpro inhibitory effect. Among these, aloe-emodin, sinigrin and hesperetin reportedly
inhibited cleavage activity of the 3CLpro in a cell-based assay in dose-dependent manner
[63][64].

Fig: Working mechanism of Natural products for COVID-19 prevention and treatment(different
pathways)

Page No. - 13
Fig: Chemical structures of compounds active against SARS-CoV-2-3CLpro

Page No. - 14
6. Nutraceuticals against SARS CoV-2
6.1. Vitamins:
For enhance the resistance to COVID‑19 infection 20‑50 µg intake (daily) of vitamin D was
recently recommended for healthcare workers, obese individuals and smokers. Patients
suffering from normalized pulmonary function and acute bronchiolitis increased immunity
Supplementation with vitamin D needed. Vitamin D intake also reduces developing
respiratory infections [65][66]. The high dose of vitamin C (1,000‑6,000 mg) administration
has also been reported to decrease their length of stay in an intensive care unit and also
decrease the time spent by critically ill patients on mechanical ventilation by 25%. Often, in
reducing the effectiveness of asthma induced by the common cold, vitamin C plays a
important role [67].

6.2. Dietary minerals:

Selenium: For optimal immune function the importance of selenium has been emphasized in
the literature. Through the redox antioxidant properties and homeostasis selenium provides
resistance against viral infections. Dietary selenium can be effectively used in the current
pandemic COVID‑19 and also boost the immunity against the lethal H1N1 influenza virus
infection [68].
Zinc: Zinc deficiency is one of risk factor for the development of pneumonia among the old
people. Zinc salts inhibit cell‑to‑cell spread in human epithelial type 2 (HEp‑2) cells and also
prevent the replication of respiratory syncytial virus, a in vitro study proved this. Zinc has an
anti-inflammatory and antioxidant activities, along with it can regulate tight junction proteins,
such as Zonula occludens‑1 and claudin‑1 and it is essential for the respiratory epithelium. In
a separate study, the length of cilia at the bronchial epithelium of zinc‑deficient rats was
shown to be improved by zinc supplementation [69]. In vitro experiments reported the ability
of zinc to improve mucociliary clearance by increasing the beat frequency of cilia. Zinc ions
also inhibit the RNA‑dependent RNA polymerases of rhinoviruses, hepatitis C virus (HCV)
and influenza virus, and to impair the activity of the RNA‑synthesizing machinery of
nidoviruses, the order of viruses to which SARS‑CoV‑2 belongs [70].
Iron: Iron deficiency can reduce host immunity and increase suscepti‑bility to infections
whereas excessively high serum concentrations of iron can cause oxidative stress and lead to
viral mutations. The dysregulated homeostasis of iron, which change serum concentrations,
associated with several respiratory diseases including cystic fibrosis, asthma, COPD,
idiopathic pulmonary fibrosis, acute respiratory tract infections and lung cancer. A standard
serum iron concentration results a favorable clinical outcomes for COVID‑19 patients [72].
N‑acetyl‑cysteine (NAC): NAC, which is derived from cysteine, naturally occurring amino
acid. The mucolytic and anti‑oxidant effects of NAC have been reported to significantly
reduce COPD exacerbations and improve the function of airways. NAC treatment has also
been reported to reduce mucus releaseand to inhibit the RSV infection of human alveolar
epithelial (A549) cells. It would promote clearance of mucus and alleviate oxidative stress
and inflammation. Taken together, these results demonstrate the clear potential of NAC as an
adjuvant supplement for COVID‑19 patients [73].

6.3. Amino acids

Arginine: Arginine has been reported to act synergistically with, such as high temperatures
and acidic pH levels, and can thus potentially inactivate enveloped viruses. Arginine
associates with multiple sites on viral particles, thereby affecting glycoprotein‑lipid
interactions on the viral envelope. A study demonstrated the possible use of an intranasal
spray containing an aqueous solution of arginine to inhibit influenza A infection in vivo

Page No. - 15
because it has low cytotoxicity of arginine. In a NC/Nga mouse model of asthma, arginine
was found to contribute to improved asthmatic symptoms by reducing airway inflammation
in lung tissue and altering L‑arginine metabolism [74].
Glutamine (GLN): In the human body, GLN is one of the most abundant free amino acid. In
a murine model of asthma, demonstrated that, at therapeutic doses, GLN inhibiting the
recruitment of neutrophils into the respiratory tract that is suppress the inflammation. In a
ventilator‑induced lung injury (VILI) mouse model, in which the lungs of mice are acutely
injured by acid aspiration, the administration of GLN was reported to reduce the destruction
of lung tissue, lung edema, cytokine production and neutrophil recruitment to the lung. Thus,
GLN may provide therapeutic benefits to patients with COVID‑19 [75].
β‑glucans: β‑glucans, which are important catalyst of immune cells, including macrophages,
natural killer cells and neutrophils,show a favorable effect on the host defense system.
β‑glucans have also been shown to exhibit antiviral activity against HSV‑1 and influenza
virus. Recently suggested, β‑glucans can help to reduce mortality and morbidity of
COVID‑19 [76].

6.4. Fatty acids

Omega‑3 fatty acids: Fat plays a important role in health and nutrition, essential part of our
diet which classified as saturated and unsaturated. It participate in cell communication and
signalling, key source of energy, also play plasma membrane structural role. In case of URTI
complication patients omega‑3 fatty acids have significant health benefits. In hospital it
shorten the length of stay of severely ill patients. omega‑3 fatty acids act as bronchodialator,
effectively reduced airway inflammation and also works efficiently against viral infections.
Omega-3 fatty acids usage against COVID‑19 warrants further investigation [77].

6.5. Probiotics
For patients suffering from airway infections, probiotics as nutritional supplementation has
effective role. Probiotic stain such as Bifidobacterium bifidum W23, Lactobacillus brevis
W63, Enterococcus faecium W54, Lactobacillus acidophilus W22, and Bifidobacterium lactis
W51 helped to prevent the of upper respiratory tract infections. Probiotic strain, Lactobacillus
casei Zhang has anti‑inflammatory, immunomodulatory and anti‑oxidative effects and also
maintain gastrointestinal health. Probiotic strains, including Lactobacillus gasseri SBT2055
and Lactobacillus rham‑ nosus CRL1505 reduce RSV infection [78]. A recent study
suggested, probiotics use as a dietary supplement to prevent infection of susceptible
populations with SARS‑CoV‑2. It has negligible side‑effects if use in correct doses.

Page No. - 16
Fig: Schematic diagram illustrating the potential beneficial effects of nutraceuticals and herbal extracts in the
management of COVID‑19

7. Available herbal medicine against SARS CoV-2

In this situation, in which the preventive and therapeutic agents have not been established and
recommended for administration to patients, herbal medicines are frequently used by many
people in the community. According to the characteristics of the SARS-CoV-2 virus, a
molecular mechanism of the host is involved inthe immune response.

Echincea purpurea: Echinacea purpurea (E. purpurea) is a known herbal medicines in Europe and
North America because it exhibits positive effects against viral infections. Purple coneflower is the
common name [79]. The preparation of E. purpurea can be made in the form of extracts, sprays,
tinctures and teas. Most of the Native Americans use this type of herb for respiratory infections. It
contains many bioactive compounds such as caffeic acids and chicoric acid, polysaccharides and
alkyl amides. The use of E. purpurea extracts for the treatment of viral diseases spread in the
community after some studies reported that it had advantages as antiviral activity. No clinical trial is
available to present evidence on the efficacy and safety profiles of Echinacea administration to
COVID-19 patients. The in vitro study showed a beneficial effect of Echinacea as avirucidal agent.
However, whether it has harmful effects or not must be further researched clinically [80].

Page No. - 17
Xanthorrhizol: Java turmeric or Curcuma xanthorrhiza Roxb (C. xanthorrhiza) is an herbal plant
that is widely used in Southeast Asian countries. This plant belongs to the Zingiberaceae and
Curcuma genus. Java turmeric originates from Indonesia and has been spread and grown wild in
Thailand, Malaysia, Sri Lanka, and Philippines. It also has been used as a food additive to increase
the flavour of food. In addition, this plant has been utilised in the medicine world, and its benefits
have been scientifically proven. This plant is used to treat some diseases and as a supplement.
Xanthorrhizol is an immunosuppressant and it has ability to inhibit proinflammatory cytokines that’s
why it may be used as a treatment for COVID-19. Patients with COVID-19 are susceptible to CRS.
So, the use of Xanthorrhizol may lower the proinflammatory response in a patient with COVID-19
with or without CRS. However, the administration of Xanthorrhizol needs to be done carefully and
with consideration because at present, no study has been conducted with Xanthorrhizol in COVID-
19 [81]. There is still a chance that the administration of Xanthorrhizol may worsen the conditions of
patients with COVID-19. Using Xanthorrhizol for treatment and prevention in COVID-19 still
requires more evaluation, especially in the clinical trial setting.

Cinchona sp: Cinchona trees (Chincona L., Raiatea) from the Andean mountain forests have
benefits as a particular component of the trees contains bioactive compounds that can cure fever.
This beneficial effect was first discovered by Jesuit missionaries and gradually expanded throughout
the world. The bark of the trees produces quinine alkaloids, which used for effective treatment of
malaria for more than several centuries. Quinine has a mode of action that same as chloroquine, a
synthetic anti-malaria agent to treat malaria. Thus, it is known as a chloroquine analogue. Nowadays,
quinine sulphate has become one of the most wanted drugs in the society for COVID-19 treatment.
Inappropriate statements had been made by state officials and doctors that caused public panic. So,
people looked for quinine-containing drugs competitively. The behaviour of the people was
triggered by a spontaneous reaction because of the high incidence and mortality rate of COVID-19
worldwide. This section will explain the potential of quinine to act as an antiviral agent and function
as an immune modulator in a disease caused by a virus. Further explanation will also discuss the
potentially harmful effects of quinine in individuals with or without COVID-19 [82][83].
chloroquine showed an antiviral effect against the SARS-CoV infection. A clinical trial proved that
hydroxychloroquine improves the SARS-CoV-2 viral load in COVID-19 patients when combined
with azithromycin. From this evidence, quinine as a chloroquine analogue might be predicted to
have beneficial effects in eliminating the COVID-19.

Curcumin: Turmeric is an herbal plant known as Curcumalonga (C. longa) also called rhizomatous.
It is a plant that has got much interest in the scientific and medical fields. Turmeric belongs to the
ginger (Zingiberaceae) family and the Curcumagenus. Turmericis mostly used as an important spice,
a natural food colouring, and as food flavour. For many years, turmeric has been widely known as a
medicinal plant to treat various diseases and conditions. The treatment with turmeric has been
investigated in preclinical and clinical studies. This evidence raises concerns about the administration
of Curcumin as a treatment for COVID-19. Some patients with COVID-19 show a
hyperinflammatory and hypercytokinaemia known as CRS or a cytokine storm. Administration of
Curcumin may increase the production of proinflammatory cytokines that may worsen the condition
of COVID-19 patients with acytokinestorm [84]. Afurther and more detailed investigation is
urgently needed to clarify the effect of curcumin in the treatment and prevention of COVID-19.

8. Therapeutic benefits of natural products for respiratory diseases

The use of natural products and phytochemicals for the treatment of various diseases draw a
worldwide attention. Before the discovery of antibiotics, herbal extracts played an important role in

Page No. - 18
the treatment of diseases, and purified natural products and herbal extracts now provide a lots of
compounds for the designing of novel antiviral drugs [85][86]. Lin et al summarized the antiviral
activity of various natural products and herbal medicines against some important viral pathogens,
such as dengue virus, RSV, immunodeficiency virus (HIV), measles virus, influenza virus, human
HSV, HCV, hepatitis B virus, enterovirus 71, coxsackievirus and coronavirus. Firstly, it stimulated
cell‑mediated immunity and then it attenuated viral replication by inhibiting pivotal viral enzymes
(3CL protease and RNA‑dependent RNA polymerase) play vital role in the replication process.
Black seed (Nigella sativa), has emerged as a ‘miracle’ herb, with effective bronchodilatory,
antidiabetic, antioxidant, anticancer, anti‑inflammatory, immunomodulatory and
pulmonary‑protective activities [87]. Medicinal mushrooms Cordyceps have important potential role
to strengthen the immune systems, respiratory and cardiovascular, and also have significant antiviral
and antioxidant properties [88]. Recently, the medicinal and health promoting attributes of
therapeutic fungi have drawn significant attention in the field of COVID‑19 research.

9. Colclusion:

The purpose of this review was to highlight the potential of several herbal extracts and
nutraceuticals as potential COVID19 therapies. We conclude that these natural products may have
the ability to regulate the synthesis and release of proinflammatory cytokines, interfere with the
virus's development in host cells, and affect certain molecular pathways associated to the RAA
system, based on the previous explanation. Herbal agents might be useful as treatments to fight
COVID-19. A guideline for the physician is that, even if the patient is well, the administration of
these herbal remedies should be done with caution. This is due to the fact that there has been a lot of
conflicting information about these agents. As a result, there's a chance that these therapies are linked
to the development of negative side effects. Furthermore, preclinical and clinical trial evaluations of
these herbal medicines for COVID-19 have not been done, therefore more research is needed.

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