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Abstract

SARS-CoV-2 has been responsible for over 500 million cumulative cases all over the world since December 2019 and has marked the third introduction of a highly pathogenic virus after SARS-CoV and MERS-CoV. This virus is in a winning situation because scientists are still racing to explore effective therapeutics, vaccines, and event treatment regimens. In view of progress in current disease management, until now none of the preventive/treatment measures can be considered entirely effective to treat SARS-CoV-2 infection. Therefore, it is required to look up substitute ways for the management of this disease. In this context, herbal medicines could be a good choice. This article emphasizes the antiviral potential of some herbal constituents which further can be a drug of choice in SARS-CoV-2 treatment. This article may be a ready reference for discovering natural lead compounds and targets in SARS-CoV-2 associated works.

Keywords

SARS-CoV-2 herbal medicine natural product coronavirus pneumonia

Introduction

The recent eruption of β coronavirus (CoV-19) started in early December 2019 in Wuhan city of China. A large population of pneumonic patients was identified leading to the death of thousands of patients globally caused by CoV-19. The very popular name of CoV-19 by the World Health Organization is severe acute respiratory syndrome Corona virus-2 (SARS-CoV-2).¹ Till July 15th, 2022, over 565.5 million infected cases have been reported, of which, more than 6.3 million have lost their life.²

Coronavirus (CoVs) was identified for the first time in 1960 under the family Coronaviridae. Four types of CoVs have been discovered to date, among which α and β CoVs tend to circulate in mammalians and δ and γ CoVs in birds.^3,4 Till now six subtypes of human vulnerable CoVs have been recognized of which two CoVs, namely HCoV-229E and HCoV-NL63, belong to α CoVs while HCoV-HKU1, HCoV-OC43, SARS-CoV, and MERS-CoV are β CoV.⁵ All identified human susceptible CoVs have low pathogenicity, except SARS-CoV and MERS-CoV. Several deaths were recorded due to the outbreak of SARS-CoV⁶ and MERS-CoV⁷ in 2003 and 2012, respectively. Crossing the boundaries SARS-CoV-2 has represented a pandemic risk globally.

A report stated that SARS-CoV-2 has long genomes (up to 32 kb), which are in the same β CoVs clade as bat CoV RaTG13 (96.2% genomic similarity) and SARS-CoV (79.5% genomic similarity).⁸ SARS-CoV-2 is a positive sense single-stranded RNA. Several proteins, like spike (S), membrane (M), nucleocapsid (N), and envelope (E), are protected in the viral structure and characterized by their unique function. S protein is a surface protein that forms homotrimeric spikes on the virus surface which functionally regulate the binding and fusion of the virus into the host cell through their subunits S1 and S2. M and E proteins give the virus its shape and a matured viral envelope. Apart from this function, the E protein is also involved in the production of virus-like particles. Unlike other proteins, N protein is present inside the envelope and binds with RNA to make nucleocapsids.^9,10

Since the beginning of the SARS-CoV-2 outbreak, numerous studies have been conducted showing potential applications for the prevention and recovery management of the disease. Herbal medicines have shown appreciable results in improving the clinical condition associated with the disease, not only by regulating the pro- and anti-inflammatory cytokines, but also by showing alleviated antiviral activities.¹¹ Thus, the aim of this review article is to summarize some selected phytoconstituents which have been traditionally used to treat various infectious diseases, so that their application may be explored for the effective management of SARS-CoV-2 infection.

Mechanism of Viral Infection

SARS-CoV-2 uses its spike (S)protein to internalize with the human angiotensin-converting enzyme 2 receptor (hACE2), which is found on ciliated lung epithelia.⁸ The S proteins of the virus mediate the membrane fusion process through hACE2 to infect human cells (Figure 1). Further, the internalization of S protein and the hACE2 receptor facilitate the fusion and infection by bringing the viral and cellular membranes close.¹² After entering the cell, the envelope of SARS-CoV-2 is removed and virus RNA is released into the cytoplasm of the host cell.

Figure 1.

Schematic diagram of the viral infection process in lung epithelial cells.

RNA of SARS-CoV-2 directly enters into the ribosome of the host cell for translation. Therefore, it can directly produce the essentially required proteins to replicate in the host cell cytoplasm. The RNA-dependent RNA polymerase (RdRp) enzyme first transcribes the negative strand which is used to translate additional proteins and replication of new positive-stranded RNA genomes for the reproduction of newer viruses. The large polyprotein translated by the host ribosome is slashed by its own proteases into multiple proteins.¹³ The nucleocapsid protein N binds with the helical RNA and enters into the lumen of the endoplasmic reticulum, where it is enveloped by lipid, spike protein S, and envelope protein E. Further, these newly formed viruses in the host cell are transported to the cell membrane through Golgi vesicles and exocytosed into extracellular space to infect new cells.¹³ This process increases the viral load in the infected individual and the infected person starts showing symptoms and becomes a carrier of the virus also. Subsequently, the person-to-person spread of infection is initiated by contact with infected individuals.¹⁴ It is also evident that SARS-CoV-2 may be present in the feces of infected individuals and even after the patient is cured, thereby indicating a feco-oral route of viral transmission as well.¹⁵

Potential Antiviral Herbal Constituents

The application of phytoconstituents for antiviral indications is not new. Various published reports have shown the potential applications of herbal products in various diseases associated with viruses such as hepatitis, influenza, HIV, and SARS-CoV. Here, we summarize various phytoconstituents which have been explored against viral infection and further could be used for the effective management of SARS-CoV-2.

Hesperidin

Hesperidin (formerly called vitamin P, C₂₂H₃₄O₁₅) is a bioflavonoid and a by-product of various citrus fruits like sweet orange (Citrus aurantium), lemon (C limon), grapefruit (Witis vinifera), mandarin (C unshiu), and Cala mansi (C mitis). In addition to citrus fruits, it is also present in sufficient quantities in non-citrus fruits like prickly ash (Zanthoxylumavicennae), indigofera (Indigoferatinetoria), and peppermint (Mentha piperita).¹⁶ Hesperidin is a glycoside composed of an aglycone (hesperetin) and a disaccharide (rutinose), thus called hesperetin 7-O-β-rutinoside¹⁷ (Figure 2a).

Figure 2.

Chemical structure of (a) hesperidin, (b) quinine methide triterpenoids, (c) emodin, (d) lycorine, (e) glycyrrhizic acid, and (f) betulinic acid.

Hesperidin has been of considerable interest due to its pharmacological activities. Garg et al proved its application for treating various diseases associated with increased permeability of blood capillaries and manifested in symptoms like edema, hypertension, and bleeding. Various reports support that hesperidin reduces capillary permeation and gives symptomatic relief in such diseases, including diabetes, hemorrhoids, scurvy, ulcer, bruising, and tuberculosis.¹⁸ Reports also suggest its application because of its anti-lipidemic,¹⁹ antihypertensive, diuretic,²⁰ and neuroprotective activities.¹⁶ Hesperidin also regulates the levels of various inflammatory markers like interleukin (IL) and tumor necrosis factor-α (TNF- α).^21,22

Hesperidin could be a choice of phytoconstituent to treat SARS-CoV-2 infection because of its capacity in controlling capillary permeation and inhibiting various inflammatory markers (IL and TNF-α). A recent report²³ has shown ACE2 receptor affinity of some flavonoids, including hesperidin, using molecular docking. The study implied that these flavonoids could play a potential role in SARS-CoV-2 treatment. A similar computational study²⁴ inferred that hesperidin might be a 3-chymotrypsin-like protease inhibitor. Using docking methodology, an interfering mechanism of S protein with ACE2 receptor was established. Another published report confirmed the low binding energy of hesperidin with the ACE2 receptor compared to Nelfinavir²⁵ and can be used against SARS-CoV-2 infection. In another study, the phytoconstituent was screened against the modeled structure of the receptor binding domain of the S protein and ACE2 receptor. The pharmacokinetic parameters of hesperidin were analyzed using various modelling software and showed good pharmacokinetics properties, minimal toxicity, and good bioavailability.²⁶ A report of a clinical study also confirmed that the application of 1 g hesperidin daily showed a reduction of 14.5% of symptoms associated with SARS-CoV-2 infection in 216 symptomatic non-vaccinated subjects.²⁷

Quinonemethide Triterpenoids

Quinonemethide triterpenoids (QMTs) are secondary metabolites present specifically in plants belonging to the family Celastraceae, which is comprised of approximately 90 tropical and subtropical genera of shrubs and lianes.²⁸ The name of this family (Celastraceae) is due to the presence of celastrol, an atripterine belonging to the quinine methides. In nature, QMTs are also considered a chemotaxonomic biomarker of the family. QMTs are the most common class of celastroloids, consisting of a quininemethide chromophore with a triterpenoid skeleton (Figure 2b).

To date, QMTs have been investigated for many therapeutic effects, such as anticancer, anti-inflammatory, and antileukemiaactivity.²⁹ A published report demonstrated the inhibitory activity of some QMTs (celastrol, pristimerin, and tingenone isolated from Triterygium regelii) against SARS-CoV. Molecular docking simulation was used to investigate the interaction of QMTs with the active site of SARS-CoV and their potential effectiveness was shown by low values for docking energy.³⁰ With the genomic similarity of SARS-CoV and SARS-CoV-2, QMTs may also be considered as potential therapeutic agents against SARS-CoV-2.

Emodin

Emodin [6-methyl-13,8-trihydroxyanthraquinone (Figure 2c)] is a natural anthraquinone derivative. It is isolated from different medicinal plants of Asian and European origin, namely, Aloe vera, Himalayan rhubarb (Rheum austral), buckthorn (Rhamnus species), rhubarb (Rheum barbarum, and R rhaponticum), Japanese knotweed (Reynoutria japonica syn. Polygonum cuspidatum), and Chinese rhubarb (Rheum palmatum).^31,32

Emodin has shown several therapeutic values including hepatoprotective, anticancer, and antimicrobial activities.³¹ Its antiviral activity against different viruses is well documented. Inhibitions of virus replication were studied on Hep-2 cells, using MTT and plaque reduction assays. Emodin exhibited potent inhibitory effects against both the selected viruses. However, it did not block the absorption of the virus into cells and could not inactivate the viruses directly.³³ In another work, the application of emodin against coxsackievirus B4 was shown.³⁴

A recent report stated the inhibition of SARS-CoV and HCoV-OC43 by emodin.³⁵ Batista et al have also proved the virucidal effect of emodin against the Zika virus. At a 40 µM concentration, emodin inhibited the infectivity by 83.3%.³⁶ Li et al, in a review article, have mentioned that emodin can be used against viroporin-like protein B2 of picornaviruses.³⁷ Rheum emodin was also reported to be active against enterovirus 71, which can cause encephalitis and acute flaccid paralysis.^38,39 A very recent study by Horvat et al also demonstrated the antiviral activity of emodin derivatives against human CoVs NL63.⁴⁰ However, longstanding use of emodin may cause renal toxicity, hepatotoxicity, and reproductive toxicity.³¹

Lycorine

Lycorine is a pyrrolophenanthridine alkaloid (Figure 2d) found in various Amaryllidaceae species.⁴¹ It was first isolated from Narcissus pseudo-narcissus and, therefore, initially called narcissia, but was later named lycorine. This alkaloid is reported to possess different pharmacological activities namely antiparasitic,⁴² antibacterial,⁴³ anti-inflammatory,⁴⁴ anti-tumor,⁴⁵ and antiviral.⁴⁶ Lycorine is reported for increasing the survival of mice infected with human enterovirus-71. The possible mode of action of lycorine is a viral replication inhibitory effect by blocking the elongation of the viral polyprotein.⁴⁷

Lycorine is also reported as a potent therapeutic substance against SARS-CoV and avian influenza (H5N1) virus.⁴⁸ Guo et al demonstrated the mechanism of 32 lycorine derivatives against the hepatitis C virus.⁴⁹ Another report also suggested that lycorine can interfere with the replication of poliovirus.⁵⁰ A cellular study conducted by Zhang et al, also confirmed the SARS-CoV-2 inhibitory activity of lycorine. However, only an extensive clinical study can confirm the application of lycorine in the management of the disease.⁵¹

Glycyrrhizic Acid

Glycyrrhizic acid, obtained from liquorice root (Glycyrrhiza glabra), is a saponin that is also known as glycyrrhizin or glycyrrhizinic acid. This is a well-recognized phytoconstituent from ancient times used for the treatment of several viral infections.⁵² This is an amphiphilic molecule (Figure 2e).⁵³

Wang et al have reported the activity of glycyrrhizic acid against coxsackievirus A16 and enterovirus 71. The antiviral activity was evaluated using Vero cells.⁵⁴ Glycyrrhizic acid has also been reported for the treatment of hepatitis C.^55,56 Viral entry and replication steps were blocked when treated with glycyrrhizic acid. An antiviral effect against porcine parvovirus has been reported by Li et al. A potent, dose-dependent inhibitory effect was seen when the virus was treated before infection.⁵⁷

Lin et al have published the inhibitory potential of glycyrrhizic acid and some other derivatives against Epstein-Barr virus infection.⁵⁸ The phytoconstituents also demonstrated an inhibitory effect against rotavirus replication.⁵⁹ Glycyrrhizic acid is also reported to inhibit many viruses infecting the respiratory system, namely influenza A, H1N1, and SARS-associated CoVs.^60–62 Glycyrrhizic acid and its derivatives showed potential against SARS-associated CoVs when tested against two clinical isolates.⁶² The above data showed good support regarding the potential application of glycyrrhizic acid in combating COVID-19. More randomized clinical trials will be required to obtain a precise conclusion.

Betulinic Acid

Betulin, a pentacyclic triterpene, is obtained from the outer bark of Betula species, family Betulaceae (Figure 2f). Betulinic acid,⁶³ which can be obtained from ethanolic and methanolic extracts of Betula species,⁶⁴ possesses various pharmacological activities like anticancer,^65,66 antibacterial,⁶⁷ antiplasmodial,⁶⁸ and antileishmanial.⁶⁹ Various studies have suggested the inhibitory activity of betulinic acid against many viruses, such as HIV-1NL4-3 and HIV-1JRCSF.⁷⁰ In one study, betulinic acid derivatives were used against the HIV virus.⁶⁵ In some other studies, the compound showed significant inhibitory potential against ECHO-6 virus,⁷¹ and A549 cells infected with influenza A/PR/8 virus.⁷² Some analogues of betulinic acid also display anti-Human Papilloma Virus type 11 activity.⁷³ A study conducted on the antiviral activity of natural products against CoVs suggested that betulinic acid may be considered active against SARS-CoV 3CLpro.⁷⁴ Molecular docking analysis was conducted on natural products and the study suggested that betulinic acid has the potential to inhibit the replication and 3CLpro target of 2019-nCoV with a binding energy of 4.23.^75,76 Considering the previous reports, these phytoconstituents may be future therapeutic agents against 2019-nCoV due to their additional anti-inflammatory action and significant activity against SARS-CoV.

Lectins

Lectins are naturally-occurring glycoproteins. Some foods with higher levels of lectins include beans, peanuts, lentils, tomatoes, potatoes, eggplants, vegetables, and wheat. Lectins protect plants during development.

Concanavalin A (ConA), a phytagglutinin detected in jack beans (Canavalia ensiformis), was found to be active against CoVs in previous studies. The plant is widely distributed in northeast India, south Asian countries, and North America. In India, this plant is cultivated for domestic use. ConA is responsible for the interim inactivity of the virus by binding glycosylated membrane proteins that enable viruses to recognize host cells.⁷⁷ The various biological features associated are related to the lectin's carbon binding characteristics. The Con A monomer is made from 237 amino acids (Mr ≈ 26500 Da) and is positioned in two anti-parallel b-sheets. This has high glucose/mannose carbohydrate empathy, especially in carbohydrates with a high level of 3,6-di-O-(α-D-mannopyranosyl)-D mannose. The tetramer Con A differentiates into its canonical dimer below pH 6.5. A high pH/metal ion binding is known to be the monomer–dimer–tetramer equilibrium, which indicates that there is a large decrease in the number of hydrogen intermediates bindings of Con A.⁷⁸

Carrington and collaborators (1985) found that ConA has up to 15% protein and a circular homology is evident in comparing the sequences of amino acids from different species.⁷⁸ ConA easily binds with the virus, and, after treatment with conA, the virus loses its hemagglutination properties and infectivity is transiently interrupted. The application of ConA is nevertheless limited by its extreme hepatotoxicity.⁷⁹ Ahmed et al (2022) demonstrated the role of various lectins exhibiting antiviral activities, especially against SARS-CoV. However, extensive clinical evidence is required to support the statement⁸⁰ (Table 1).

Table 1.

Possible Mechanism of Action of Various Phytoconstituents as Antiviral Agents.

Phytoconstituents	Possible mechanism of action	Reference
Hesperidin	Prevents SARS-CoV-2 internalization with the host cell by showing affinity to the three main protein receptors of SARS-CoV-2 (SARS-CoV-2 protease domain, the receptor binding domain of the spike glycoprotein, and the receptor binding domain of ACE2 at the protease domain	⁸¹
Quinonemethide triterpenoids	3C-like protease (3CLpro) inhibitor	³⁰
Emodin	Inhibits the ion channel formed by the 3a protein and thus prevents virus release	³¹
Lycorine	Although the exact mechanism is unclear, the antiviral effect may be due to the reproduction inhibition by hindering viral polymerase activity or extension of the viral polyprotein during protein synthesis	⁴⁷
Glycyrrhizic acid	Inhibition of virus replication in the host cell. It also inhibits adsorption and penetration of the virus in the early steps of the replicative cycle	⁶²
Betulinic acid	3C-like protease (3CLpro) inhibitor	⁷⁶
Lectins	They bind with SARS surface proteins, which are heavily glycosylated, and inactivate them from binding to host cells.	⁷⁹

Anti-Malarialphytoremedies

According to an international study by thousands of doctors, anti-malarial medicines are the best CoVs treatment currently available. From 30 countries, and about 2000 doctors surveyed, 37% said that they were the most efficient virus therapy. Doctors in Europe, the USA, and China were given permission to prescribe hydroxychloroquine to SARS-CoV-2 patients when the epidemic was spiralling and there was no treatment at all. Some phytoremedies can also be looked at for the treatment of CoVs when considering the potential of anti-malarial medicines.

Artemisinin, which is obtained from Artemisia annua leaves, is perhaps the most powerful natural anti-malarial source. Artemisinin is only used in conjunction with other anti-malarial drugs consisting of Artemisinin Combination Therapy, owing to weak pharmacokinetic properties and careful attempts to curtail monotherapy resistance. In the developing world, Artemisinin involves a small return on the plant and higher costs for secondary anti-malarial drugs in Legislation. Apparently, this is the only way to treat the malaria parasites with increased drug resistance such as chloroquine and hydroxychloroquine.^82,83 Data obtained from a randomized and controlled clinical study revealed the efficacy of artemisinin-piperaquine for the treatment of COVID-19, with 10.6 ± 1.1 days mean time to reach an undetectable viral RNA level for the treatment group and 19.3 ± 2.1 days for the control group.⁸⁴

Chinese Remedies Against SARS-CoV

Some Chinese herbs are known for their antiviral effects and have, therefore, been investigated for their potential function against SARS-CoV75.⁸⁵ Many studies showed that they decrease the expression of inflammatory markers and regulate the TLR7/NF-κB pathway to show antiviral effects.⁸⁶ Gao et al studied the anti-inflammatory and immunoregulatory potential of Yupingfeng powder. The study showed that the formulation was effective against external pathogens such as SARS-CoV infection. Furthermore, humoral and cellular immune function in mice with immunosuppression also improved with the formulation.⁸⁷ Another Chinese formulation, named Lianhuaqingwen capsule, is one of the most prescribed Chinese formulations to treat respiratory tract infections. This formulation effectively suppresses the inflammatory cytokines and thereby may be a promising option for controlling the influenza virus.⁸⁸ A clinical trial conducted on COVID-19 infected patients revealed the effectiveness of Lianhuaqingwen by showing rapid recovery as compared to the control group.⁸⁹

A large number of herbal extracts show efficiency against SARS-CoV, some of them being Lycoris radiata, Artemisia annua, Pyrrosia lingua, and Lindera aggregata. Lycoris radiata extract was the most active. Bioassay-guided chromatographic separation of the extract led to the isolation of lycorine, which inhibited SARS-CoV at a concentration of 15.7 nM. Lycorine showed a high specificity index against HepG2 cell lines.⁹⁰ Another work, reported by Lau and coworkers, shows the inhibition of two main SARS-CoV proteins (3CLpro and RdRp) by the aqueous extract of Houttuynia cordata. Additionally, the extract also increased the cell count of CD4 + and CD8 + , indicating its immune/stimulation function.⁹¹ Recent results indicate that three alkaloids, tetrandrine, fangchineoline, and cephoranthine substantially prevent viral-induced cell death. The replication of HCoV-OC43, along with S and N protein expressions, was significantly suppressed by alkaloidal treatment.⁹² A total of 221 phytochemicals were screened for SARS-CoVantiviral activity; 10 diterpenes, 2 sesquiterpenes, 2 triterpenes, five lignans, and curcumins were shown to have an inhibitory activity.⁷⁶

Here we have summarized some of the previously reported phytoconstituents being used as antivirals for other CoVs infections. The inhibitory mechanisms of these phytoconstituents may also be replicated for the prevention of COVID-19. However, extensive research and clinical evaluation are required to establish these phytoconstituents as effective tools against COVID-19 infection.

Conclusion

Herbal drugs have been useful in various viral infections. Many phytoconstituents have exhibited excellent antiviral properties and the mechanism of their action against different viruses has been reported. In the case of the outbreak of the COVID-19 pandemic, a situation for which there were no available drugs, and completely effective vaccines, many herbal molecules that have shown potent anti-SARS-CoV activity may find application. However, clinical studies of some phytoconstituents, such as hesperidin, emodin, artemisinin, lycorine, and lianhuaqingwen, have shown exciting anti-SARS-CoV efficacy. However, still more phytoconstituents should be studied through proper clinical trials to find more effective anti-SARS-CoV treatments.

Footnotes

Authors’ Contributions

NS, GTK, ANB, SS: conceptualization, data collection/curation, analysis, writing, reviewing the first draft. NS, LS, AS, KD, RK: analysis, writing the first draft. NA, KR: reviewing, editing.

Authors’ Note

Kamal Dua, Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW, Australia; Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Ethical Approval

This study does not directly involve humans or other organisms as it is a review study.

Consent for Publication

All authors consented to submitting the manuscript to Natural Product Communications.

ORCID iDs

Khalid Raza

Nitin Sharma

References

Guo

Y-R

Cao

Q-D

Hong

Z-S

, et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status. Military Med Res. 2020;7(1):11. doi:10.1186/s40779-020-00240-0

WHO Situation Report. https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200428-sitrep-99-covid-19.pdf?sfvrsn=119fc381_2

Woo

PCY

Lau

SKP

Lam

CSF

, et al. Discovery of seven novel mammalian and avian coronaviruses in the genus Deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus. J Virol. 2012;86(7):3995‐4008. doi:10.1128/JVI.06540-11

Qazi

Sheikh

Faheem

Khan

Raza

. A coadunation of biological and mathematical perspectives on the pandemic COVID-19: a review. Coronaviruses. 2021;2(9):e030821190295. doi:10.2174/2666796702666210114110013

Yin

Wunderink

. MERS, SARS and other coronaviruses as causes of pneumonia: MERS, SARS and coronaviruses. Respirol. 2018;23(2):130‐137. doi:10.1111/resp.13196

Chan-Yeung

R-H

. SARS: epidemiology. Respirology. 2003;8(s1):S9‐S14. doi:10.1046/j.1440-1843.2003.00518.x

Zaki

Van Boheemen

Bestebroer

Osterhaus

ADME

Fouchier

RAM

. Isolation of a novel coronavirus from a man with pneumonia in Saudi arabia. N Engl J Med. 2012;367(19):1814‐1820. doi:10.1056/NEJMoa1211721

Zhou

Yang

X-L

Wang

X-G

, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270‐273. doi:10.1038/s41586-020-2951-z

Schoeman

Fielding

. Coronavirus envelope protein: current knowledge. Virol J. 2019;16(1):69. doi:10.1186/s12985-019-1182-0

10.

Ashour

Elkhatib

Rahman

Elshabrawy

. Insights into the recent 2019 novel coronavirus (SARS-CoV-2) in light of past human coronavirus outbreaks. Pathogens. 2020;9(3):186. doi:10.3390/pathogens9030186

11.

Eftekhari

Enayati

Doustimotlagh

Farzaei

Aneva

. Natural products in combination therapy for COVID-19: qT prolongation and urgent guidance. Nat Prod Commun. 2021;16(9):1‐3. doi:10.1177/1934578X211032471

12.

Xia

Liu

Wang

, et al. Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion. Cell Res. 2020;30(4):343‐355. doi:10.1101/2020.03.09.983247

13.

Masters

. The molecular biology of coronaviruses. Adv Virus Res. 2006;66:193‐292. doi:10.1016/S0065-3527(06)66005-3

14.

Carlos

Dela Cruz

Cao

Pasnick

Jamil

. Novel wuhan (2019-nCoV) coronavirus. Am J Respir Crit Care Med. 2020;201(4):P7‐P8. doi:10.1164/rccm.2014P7

15.

Yeo

Kaushal

Yeo

. Enteric involvement of coronaviruses: is faecal–oral transmission of SARS-CoV-2 possible? Lancet Gastroenterol Hepatol. 2020;5(4):335‐337. doi:10.1016/S2468-1253(20)30048-0

16.

Agrawal

Blunden

. Pharmacological significance of hesperidin and hesperitin, two citrus flavonoids as promising antiviral compound for prophylaxis against and combating COVID-19. Nat Prod Commun. 2021;16(10):1‐15. doi:10.1177/1934578X211042540

17.

Devi

Rajavel

Nabavi

, et al. Hesperidin: a promising anticancer agent from nature. Ind Crops Prod. 2015;76:582‐589. doi:10.1016/j.indcrop.2015.07.051

18.

Garg

Zaneveld

LJD

Singla

. Chemistry and pharmacology of the citrus bioflavonoid hesperidin. Phytother Res. 2001;15(8):655‐669. doi:10.1002/ptr.1074

19.

Monforte

Trovato

Kirjavainen

, et al. Biological effects of hesperidin, a Citrus flavonoid. (note II): hypolipidemic activity on experimental hypercholesterolemia in rat. Farmaco. 1995;50(9):595‐599.

20.

Galati

Monforte

Kirjavainen

, et al. Biological effects of hesperidin, a citrus flavonoid. (Note I): antiinflammatory and analgesic activity. Farmaco. 1994;40(11):709‐712.

21.

Iskender

Dokumacioglu

Sen

Ince

Kanbay

Saral

. The effect of hesperidin and quercetin on oxidative stress, NF-κB and SIRT1 levels in a STZ-induced experimental diabetes model. Biomed Pharmacother. 2017;90:500‐508. doi:10.1016/j.biopha.2017.03.102

22.

Chen

Xie

Lei

Xiang

. Hesperidin protects against IL-1β-induced inflammation in human osteoarthritis chondrocytes. Exp Ther Med. 2018;16(4):3721‐3727. doi:10.3892/etm.2018.6616

23.

Cheng

Zheng

, et al. Citrus fruits are rich in flavonoids for immunoregulation and potential targeting ACE2. Nat Prod Bioprospect. 2020;12(1):4. doi:10.1007/s13659-022-00325-4

24.

Liu

Yang

, et al. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharmaceutica Sinica B. 2020;10(5):766‐781.

25.

Utomo

Ikawati

Meiyanto

. Revealing the potency of citrus and galangal constituents to halt SARS-CoV-2 infection. Preprints 2020:2020030214. doi:10.20944/preprints202003.0214.v1.

26.

Bhowmik

Nandi

Kumar

. Evaluation of flavonoids as 2019-nCoV cell entry inhibitor through molecular docking and pharmacological analysis. Heliyon. 2021;7(3):e06515. doi:10.1016/j.heliyon.2021.e06515

27.

Dupuis

Laurin

Tardif

, et al. Fourteen-days evolution of COVID-19 symptoms during the third wave in non-vaccinated subjects and effects of hesperidin therapy: a randomized, double-blinded’ placebo-controlled study. MedRxiv. 2021:1‐29. doi:10.1101/2021.10.04.21264483

28.

Pina

Coppede

Contini

SHT

, et al. Improved production of quinone-methide triterpenoids by Cheiloclinium cognatum root cultures: possibilities for a non-destructive biotechnological process. Plant Cell Tiss Organ Cult. 2017;128(3):705‐714.

29.

Yan

Sun

, et al. Anticancer effects of pristimerin and the mechanisms: a critical review. Front Pharmacol. 2019;10:746. doi:10.3389/fphar.2019.00746

30.

Ryu

Park

S-J

Kim

, et al. SARS-CoV 3CLpro inhibitory effects of quinone-methide triterpenes from Tripterygium regelii. Bioorganic Med Chem Lett. 2010;20(6):1873‐1876. doi:10.1016/j.bmcl.2010.01.152

31.

Dong

Yin

, et al. Emodin: a review of its pharmacology, toxicity and pharmacokinetics. Phytother Res. 2016;30(8):1207‐1218. doi:10.1002/ptr.5631

32.

Lin

, et al. Traditional usages, botany, phytochemistry, pharmacology and toxicology of Polygonum multiflorum Thunb.: a review. J Ethnopharmacol. 2015;159:158‐183. doi:10.1016/j.jep.2014.11.009

33.

Liu

Zhong

Yang

. Antiviral effect of emodin from Rheum palmatum against coxsakievirus B5 and human respiratory syncytial virus in vitro. J Huazhong Univ Sci Technol Med Sci. 2015;35(6):916‐922. doi:10.1007/s11596-015-1528-9

34.

Liu

Wei

Chen

L-J

, et al. In vitro and in vivo studies of the inhibitory effects of emodin isolated from Polygonum cuspidatum on coxsakievirus B4. Molecules. 2013;18(10):11842‐11858. doi:10.3390/molecules181011842

35.

Schwarz

Wang

Sun

Schwarz

. Emodin inhibits current through SARS-associated coronavirus 3a protein. Antiviral Res. 2011;90(1):64‐69. doi:10.1016/j.antiviral.2011.02.008

36.

Batista

Braga

Campos

, et al. Natural products isolated from oriental medicinal herbs inactivate Zika virus. Viruses. 2019;11(1):49. doi:10.3390/v11010049

37.

Zou

Jiang

Huang

Liu

. Biological function and application of picornaviral 2B protein: a new target for antiviral drug development. Viruses. 2019;11(6):510. doi:10.3390/v11060510

38.

Zhong

Zhang

Wang

, et al. Rheum emodin inhibits enterovirus 71 viral replication and affects the host cell cycle environment. Acta Pharmacol Sin. 2017;38(3):392‐401. doi:10.1038/aps.2016.110

39.

MM-L

Chu

JJH

. Developments towards antiviral therapies against enterovirus 71. Drug Discov. 2010;15(23–24):1041‐1051. doi:10.1016/j.drudis.2010.10.008

40.

Horvat

Avbelj

Durán-Alonso

, et al. Antiviral activities of halogenated emodin derivatives against human coronavirus NL63. Molecules. 2021;26(22):6825. doi:10.3390/molecules26226825

41.

Roy

Liang

Xiao

Feng

Liu

. Lycorine: a prospective natural lead for anticancer drug discovery. Biomed Pharmacothe. 2018;107:615‐624. doi:10.1016/j.biopha.2018.07.147

42.

Abbassy

el-Gougary

el-Hamady

Sholo

. Insecticidal, acaricidal and synergistic effects of soosan, Pancratium maritimum extracts and constituents. J Egypt Soc Parasitol. 1998;28(1):197‐205.

43.

Casu

Cottiglia

Leonti

, et al. Ungeremine effectively targets mammalian as well as bacterial type I and type II topoisomerases. Bioorg Med Chem Lett. 2011;21(23):7041‐7044. doi:10.1016/j.bmcl.2011.09.097

44.

Park

. Synthesis and characterization of norbelladine, a precursor of Amaryllidaceae alkaloids, as an anti-inflammatory/anti-COX compound. Bioorg Med Chem Lett. 2014;24(23):5381‐5384. doi:10.1016/j.bmcl.2014.10.051

45.

Jimenez

Santos

Alonso

Vazquez

. Inhibitors of protein synthesis in eukaryotic cells. Biochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis. 1976;425(3):342‐348. doi:10.1016/0005-2787(76)90261-6

46.

Vrijsen

Vanden Berghe

Vlietinck

Boeyé

. Lycorine: a eukaryotic termination inhibitor? J Biol Chem. 1986;261(2):505‐507.

47.

Liu

Yang

, et al. Lycorine reduces mortality of human enterovirus 71-infected mice by inhibiting virus replication. Virol J. 2011;8(1):483. doi:10.1186/1743-422X-8-483

48.

Yang

Zhang

, et al. Tandem mass tag-based quantitative proteomic analysis of lycorine treatment in highly pathogenic avian influenza H5N1 virus infection. PeerJ. 2019;7:e7697. doi:10.7717/peerj.7697

49.

Guo

Wang

Cao

, et al. A conserved inhibitory mechanism of a lycorine derivative against enterovirus and hepatitis C virus. Antimicrob Agents Chemother. 2016;60(2):913‐924.

50.

Hwang

Chu

Yang

Chen

Yates

. Rapid identification of inhibitors that interfere with poliovirus replication using a cell-based assay. Antiviral Res. 2008;77(3):232‐236. doi:10.1016/j.antiviral.2007.12.009

51.

Zhang

, et al. Gemcitabine, lycorine and oxysophoridine inhibit novel coronavirus (SARS-CoV-2) in cell culture. Emerg Microbes Infect. 2020;9(1):1170‐1173. doi:10.1080/22221751.2020.1772676

52.

Shibata

. A drug over the millennia : pharmacognosy, chemistry, and pharmacology of licorice. Yakugaku Zasshi. 2000;120(10):849‐862. doi:10.1248/yakushi1947.120.10_849

53.

Selyutina

OYU

Polyakov

. Glycyrrhizic acid as a multifunctional drug carrier – from physicochemical properties to biomedical applications: a modern insight on the ancient drug. Int J Pharm. 2019;25(559):271‐279. doi:10.1016/j.ijpharm.2019.01.047

54.

Wang

Chen

Wang

, et al. Glycyrrhizic acid as the antiviral component of Glycyrrhiza uralensis Fisch. against coxsackievirus A16 and enterovirus 71 of hand foot and mouth disease. J Ethnopharmacol. 2013;147(1):114‐121. doi:10.1016/j.jep.2013.02.017

55.

Ashfaq

Masoud

Nawaz

Riazuddin

. Glycyrrhizin as antiviral agent against hepatitis C virus. J Transl Med. 2011;9(1):112. doi:10.1186/1479-5876-9-112

56.

Matsumoto

Matsuura

Aoyagi

, et al. Antiviral activity of glycyrrhizin against hepatitis C virus in vitro.Polyak SJ, editor. PLoS ONE. 2013;8(7):e68992.

57.

Zou

Ren

Zarlenga

Ren

. Antiviral effect of diammonium glycyrrhizinate on cell infection by porcine parvovirus. Curr Microbiol. 2015;69(1):82‐87. doi:10.1007/s00284-014-0540-9

58.

Lin

J-C

Cherng

J-M

Hung

M-S

, et al. Inhibitory effects of some derivatives of glycyrrhizic acid against Epstein-Barr virus infection: structure–activity relationships. Antiviral Res. 2008;79(1):6‐11. doi:10.1016/j.antiviral.2008.01.160

59.

Hardy

Hendricks

Paulson

Faunce

. 18 β-Glycyrrhetinic acid inhibits rotavirus replication in culture. Virol J. 2012;9(1):96. doi:10.1186/1743-422X-9-96

60.

Wolkerstorfer

Kurz

Bachhofner

Szolar

OHJ

. Glycyrrhizin inhibits influenza A virus uptake into the cell. Antiviral Res. 2009;83(2):171‐178. doi:10.1016/j.antiviral.2009.04.012

61.

Lidia A

Zarubaev

Baltina Lia

, et al. Glycyrrhizic acid derivatives as influenza A/H1N1 virus inhibitors. Bioorg Med Chem Lett. 2015;25(8):1742‐1746. doi:10.1016/j.bmcl.2015.02.074

62.

Cinatl

Morgenstern

Bauer

Chandra

Rabenau

Doerr

. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet. 2001;361(9374):2045‐2046. doi:10.1016/s0140-6736(03)13615-x

63.

Tsai

J-C

Peng

W-H

Chiu

T-H

Lai

S-C

Lee

C-Y

. Anti-inflammatory effects of Scoparia dulcis L. and betulinic acid. Am J Chin Med. 2011;39(05):943‐956. doi:10.1142/S0192415X11009329

64.

Yogeeswari

Sriram

. Betulinic acid and its derivatives: a review on their biological properties. CMC. 2005;12(6):657‐666.

65.

Theo

Masebe

Suzuki

, et al. Peltophorum africanum, a traditional South African medicinal plant, contains an anti HIV-1 constituent, betulinic acid. Tohoku J Exp Med. 2009;217(2):93‐99.

66.

Fulda

. Betulinic acid: a natural product with anticancer activity. Mol Nutr Food Res. 2009;53(1):140‐146.

67.

Chowdhury

Mandal

Mittra

, et al. Betulinic acid, a potent inhibitor of eukaryotic topoisomerase I: identification of the inhibitory step, the major functional group responsible and development of more potent derivatives. Med Sci Monit. 2002;8(7):BR254‐BR265.

68.

Haque

Nawrot

Alakurtti

, et al. Screening and characterisation of antimicrobial properties of semisynthetic betulin derivatives.Panepinto J, editor. PLoS ONE. 2014;9(7):e102696.

69.

Laavola

Haavikko

Hämäläinen

, et al. Betulin derivatives effectively suppress inflammation in vitro and in vivo. J Nat Prod. 2016;79(2):274‐280.

70.

Sousa

Varandas

Santos

, et al. Antileishmanial activity of semisynthetic lupane triterpenoids betulin and betulinic acid derivatives: synergistic effects with miltefosine.cavalli A, editor. PLoS ONE. 2014;9(3):e89939.

71.

Tang

Jones

Jeffery

, et al. Synthesis and biological evaluation of macrocyclized betulin derivatives as a novel class of anti-HIV-1 maturation inhibitors. The Open Med Chem J. 2014;8(1):23‐27.

72.

Pavlova

Savinova

Nikolaeva

, et al. Antiviral activity of betulin, betulinic and betulonic acids against some enveloped and non-enveloped viruses. Fitoterapia. 2003;74(5):489‐492.

73.

Hong

E-H

Song

Kang

, et al. Anti-influenza activity of betulinic acid from Zizyphus jujuba on influenza A/PR/8 virus. Biomol Ther. 2015;23(4):345‐349.

74.

Kazakova

Giniyatullina

Yamansarov

Tolstikov

. Betulin and ursolic acid synthetic derivatives as inhibitors of Papilloma virus. Bioorganic Med Chem Lett. 2010;20(14):4088‐4090.

75.

Wen

C-C

Kuo

Y-H

Jan

J-T

, et al. Specific plant terpenoids and lignoids possess potent antiviral activities against severe acute respiratory syndrome coronavirus. J Med Chem. 2007;50(17):4087‐4095.

76.

Zhang

Deng

Peng

. In silico screening of Chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus. J Integr Med. 2020;18(2):152‐158.

77.

Van Dongen

Heck

AJR

. Binding of selected carbohydrates to apo-concanavalin A studied by electrospray ionization mass spectrometry. Analyst. 2000;125(4):583‐589.

78.

Carrington

Auffret

Hanke

. Polypeptide ligation occurs during post-translational modification of concanavalin A. Nature. 1985;313(5997):64‐67.

79.

Mitchell

Ramessar

O’Keefe

. Antiviral lectins: selective inhibitors of viral entry. Antiviral Res. 2017;142:37‐54.

80.

Ahmed

Jahan

Nissapatorn

Wilairatana

Rahmatullah

. Plant lectins as prospective antiviral biomolecules in the search for COVID-19 eradication strategies. Biomed Pharmacother. 2022;146:112507. doi:10.1016/j.biopha.2021.112507

81.

Man

M-Q

Yang

Elias

. Benefits of hesperidin for cutaneous functions. Evid Based Complement Alterna Med. 2019:1‐19. doi:10.1155/2019/2676307

82.

Elfawal

Towler

Reich

, et al. Dried whole plant Artemisia annua as an antimalarial therapy.snounou G, editor. PLoS ONE. 2012;7(12):e52746.

83.

Agrawal

Blunden

. Artemisia extracts and artemisinin-based antimalarials for COVID-19 management: could these be effective antivirals for COVID-19 treatment? Molecules. 2022;27(12):3828.

84.

Yuan

, et al. Safety and efficacy of artemisinin-piperaquine for treatment of COVID-19: an open-label, non-randomised and controlled trial. Int J Antimicrob Agents. 2021;57(1):106216. doi:10.1016/j.ijantimicag.2020.106216

85.

Yang

Islam

Wang

Chen

. Traditional Chinese medicine in the treatment of patients infected with 2019-new coronavirus (SARS-CoV-2): a review and perspective. Int J Biol Sci. 2020;16(10):1708‐1717.

86.

Y-J

Yan

Y-Q

Qin

H-Q

, et al. Effects of different principles of Traditional Chinese Medicine treatment on TLR7/NF-κB signaling pathway in influenza virus infected mice. Chin Med. 2018;13(1):1‐16.

87.

Gao

Shao

, et al. Antiinflammatory and immunoregulatory effects of total glucosides of Yupingfeng powder. Chin Med J. 2009;122(14):1636‐1641.

88.

Ding

Zeng

, et al. The Chinese prescription Lianhuaqingwen capsule exerts anti-influenza activity through the inhibition of viral propagation and impacts immune function. BMC Complement Altern Med. 2017;17(1):130.

89.

Yan

. Randomized controlled trial assessing the efficacy of Lianhua Qingwen as an adjuvant treatment in patient with mild symptoms of Covid-19. https://clinicaltrials.gov/ct2/show/NCT04433013

90.

Shen

Niu

Wang

, et al. High throughput screening and identification of potent broad-spectrum inhibitors of coronaviruses.Gallagher T, editor. J Virol. 2019;93(12):e00023‐19.

91.

Lau

K-M

Lee

K-M

Koon

C-M

, et al. Immunomodulatory and anti-SARS activities of Houttuynia cordata. J Ethnopharmacol. 2008;118(1):79‐85.

92.

Kim

Min

Jang

, et al. Natural bis-benzylisoquinoline alkaloids-tetrandrine, fangchinoline, and cepharanthine, inhibit human coronavirus OC43 infection of MRC-5 human lung cells. Biomolecules. 2019;9(11):696. doi:10.3390/biom9110696

Therapeutic Options for the SARS-CoV-2 Virus: Is There a Key in Herbal Medicine?

Abstract

Keywords

Introduction

Mechanism of Viral Infection

Potential Antiviral Herbal Constituents

Hesperidin

Quinonemethide Triterpenoids

Emodin

Lycorine

Glycyrrhizic Acid

Betulinic Acid

Lectins

Anti-Malarialphytoremedies

Chinese Remedies Against SARS-CoV

Conclusion

Footnotes

Authors’ Contributions

Authors’ Note

Declaration of Conflicting Interests

Funding

Ethical Approval

Consent for Publication

ORCID iDs

References