INTRODUCTION:

COVID-19 was announced as a pandemic on 11 March 2020 by WHO.¹, leading to the rapid spread of novel coronavirus (COVID-19) into a pandemic responsible for the current global health crisis.² The actual number of infected cases is probably much higher due to asymptomatic cases that may be responsible for the development of the pandemic. In February 2021, there have been more than 117 million confirmed cases of COVID-19 and more than 2.6 million deaths worldwide, as reported by the WHO.³

The coronavirus outbreak was caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). SARS-CoV-2 is an RNA virus with a similar genetic structure to that of SARS-CoV or MERS-CoV.⁴ Protease which is encoded by the viral genome, plays a crucial role in the production of viral proteins, and controlling the function of the replicase complex, which is required for virus replication and infection, makes it the perfect target for designing antiviral therapies. Acute respiratory syndrome (SARS-CoV) coronavirus enzymes are one of the most promising targets for the discovery of anti-SARS drugs because of their key role in the life cycle of the virus.⁵

This analysis aims to present historical data on the antiviral activity of a specific herbal medicine against SARS-CoV-2. This will promote the use of herbal medicine as complementary COVID-19 prevention therapies, given the current absence of an effective drug or vaccine against SARS-COV-2. Many other doctors and researchers have already tried clinical trials with herbal medicines to suppress SARS-CoV-2.⁶

Structure of SARS-CoV-2:

As a novel betacoronavirus, SARS-CoV-2 is one of the viruses that belong to coronaviruses. It is a positive single-strand RNA virus (+ssRNA) belonging to the order Nidovirales, family Coronaviridae, and subfamily Orthocoronavirinae.⁷ This specific coronavirus is categorized into four genera: α, β, γ, and δ. Each genus is further subdivided based on subtype, genome, and phylogenic clustering characteristics. Humans are actually infected with six distinct forms of coronavirus. As a result, SARS-CoV-2 is now the seventh coronavirus capable of infecting humans. SARS-CoV and MERS-CoV (Middle East respiratory syndrome coronavirus) that infect humans belong to the β genus that is a predecessor for the SARS-CoV-2. The other forms of human coronaviruses are 229E and NL63 that belong to the α genus and also OC43 and HKU1 that belong to the β genus.^8,9

The RNA of this novel SARS-CoV-2 is ∼30 kb long, the same length as that of the SARS-CoV and MERS-CoV viruses that caused problems several years ago. SARS- CoV-2 shares 79% genome sequence identity with SARS- CoV and 50% with MERS- CoV.¹⁰ Its genome structure is similar to that of other betacoronaviruses. Replicase (ORF1a/ORF1b), spike (S), envelope (E), membrane (M), and nucleocapsid (N) are the six functional open reading frames (ORFs) organized in order from 5′ to 3′.¹¹SARS- CoV-2 shares more than 90% amino acid identity with SARS- CoV except for the S gene, which diverges.^10,12 Most of these SARS- CoV-2 non-structural proteins have greater than 85% amino acid sequence identity with SARS- CoV.¹¹

Coronaviruses have a pleomorphic, circular, or oval envelope. This virus measures 50–200 nanometers in diameter.^7,9 SARS-CoV-2 has a peculiar spike projection on its surface that resembles a solar corona.^7,9This newly discovered coronavirus encodes four large structural proteins that are spike (S), membrane (M), envelope (E), and nucleocapsid (N). The most important structure capable of binding to the receptor is the S protein. This glycoprotein, which is found on the virus's surface, is responsible for the virus's attachment to the receptor on the host cell.^9,13 In this virus, this protein also serves as the virus's primary antigenic structure.⁸This virus's S protein is a trimeric S glycoprotein, a class I fusion protein that mediates binding to the receptor of the host cell.¹⁴

The S protein of SARS-CoV-2 can interact strongly with the host cell via the ACE2 receptor as same as SARS- CoV, angiotensin-converting enzyme 2 (ACE2). This interaction poses a risk of human transmission to public health.^7,8 After the binding of s protein of the virus with ACE2, the envelope of virus fuse with the host cell membrane and enter the host cell.^7,13,15

Table 1. Epidemiology, Clinical sign, Pathogen and Diagnosis of COVID-19

Epidemiology:

· A recent travel to or residence in epidemic regions within 14 days.

· Contact with cases from other epidemicregions or symptomatic cases.

· Clustered cases or having contact with confirmed cases.

Clinical sign:

· Fever, Loss of taste and smell, difficulty in breathing.

· Dry cough, sore throat.

· Radiologic characteristics consistent with pneumonia.

· Normal or decreased leukocyte count at early stages, or lymphopenia.

Pathogen and Diagnosis:

· Detection of SARS-COV-2 or homology of SARS-COV-2 in the respiratory tract or blood specimens.

· Detection of the virus nucleic acid by real-time reverse transcription polymerase chain reaction (rRT-PCR), transcription-mediated amplification (TMA), or by reverse transcription loop-mediated isothermal amplification (RT-LAMP) from a nasopharyngeal swab.

Pathophysiology:

The spike glycoprotein-S bind to angiotensin converting enzyme -2 (ACE-2) receptors cells which help SSRNA to enter the host cell.¹⁶Where translation occurs and formation of polyproteins whichwill cleave by using TMPRSS2 (transmembrane protease serine 2) to make viral components along with SSRNA has potential to use another enzyme which is RNA dependent RNA polymerase to replicate the SSRNA.¹⁷ So, both replicated SSRNA and viral components joined to form virus (COVID- 19) which signals to release the macrophage upon tissue damage than the other inflammatory mediators (IL-6, IL-10, Tumour necrosis factors, granulocyte colony-stimulating factor, monocyte chemoattractant protein 1, macrophage inflammatory protein 1, are released from endothelium layer.¹⁸Which will cause the dilation of blood vessels by contraction of endothelium layer to increase the capillary permeability that causes alveolar edema leads to drowning out surfactant that responses to increases the surface tension the alveoli will collapse that tend to decrease the gaseous exchange that leads to hypoxemia and increase the work of breathing that causes dyspnea (shortness of breath).¹⁹

All inflammatory mediators bring neutrophils from blood to alveoli to destroy the virus by releasing reactive oxygen species (ROS)and protease which damages all cells including (ACE- 1 and 2) and the results sloughing off. Damage cells along with the consolidation of fluid accumulation, protein deposition, and cellular debris alter the gaseous exchange to promote hypoxemia. This causes septic shock the patient becomes hypotensive, decreased total peripheral resistance, blood pressure, and decreased perfusion of their organs.²⁰ it will also affect the liver to raise levels of AST, ALT, bilirubin, their response on the kidney is to increase the creatinine levels. SARS CoV-2 binds to host cells through the ACE2 receptor, which is expressed by epithelial cells of the lungs, intestine, kidneys, brain, and blood vessels.²¹ Which consequently promotes SARS-CoV-2 infection severity.^22,23

Ayurveda, being the science of life, propagates the gifts of nature in maintaining healthy and happy living. Ayurveda’s extensive knowledge base on preventive care, derives from the concepts of “Dinacharya” - daily regimes and “Ritucharya” - seasonal regimes to maintain healthy life. It is a plant-based science. The simplicity of awareness about oneself and the harmony each individual can achieve by uplifting and maintaining his or her immunity is emphasized across Ayurveda’s classical scriptures. One of best ayurvedic preparation is Kadha (Decoction).²⁴

Herbal drugs used in COVID-19:

Phytochemicals commonly used herbs in making Kadha Some of the commonly used herbs in the preparations of Kadha includes Tulsi (Ocimum sanctum), Haldi (Curcuma longa), Giloy (Tinospora cordiofolia), Black pepper (Piper nigrum), Ginger (Zingiber officinale), Clove (Syzygium aromaticum), Cardamom (Elettaria cardamomum), lemon (Citrus limon) and Ashwagandha (Withania somnifera).²⁵ A list of 108 phytochemicals present in herbs that are used in the preparation of Kadha or similar drinks were collected from the literature. Phytochemicals found in Ocimum sanctum (Oleanolic acid, Ursolic acid, Rosmarinic acid, Eugenol, Carvacrol, Linalool, Beta-caryophyllene, Estragole, Eugenic acid, Apigenin, Cirsimaritin, Isothymusin, Isothymonin, Vicenin, Orientin and Cirsilineol) (Pattanayak et al., 2010), Curcuma longa (Curcumin, Demethoxycurcumin, Bisdemethoxycurcumin, Ar-turmerone, Alpha-turmerone, Beta-turmerone, Atlantone, Cyclocurcumin, Calebin A, Trans-Ferulic acid, Vanillin and Vanillic acid) (Li et al., 2011), Tinospora cordiofolia (Magnoflorine, Berberine, Choline, Jatrorrhizine, Beta-Sitosterol, Tinosporide, Tinosporaside, Cordifolioside A, Tinocordioside, Cordioside, Tinocordifolioside and Tinocordifolin) (Sharma et al., 2019), Piper nigrum (Piperine, Piperamide, Piperamine, Pipericide, Sarmentosine, Sarmentine, Brachyamide B, Dihydropipericide, NFormylpiperidine, Guineensine, Pentadienoylpiperidine, Tricholein, Trichostachine, Piperettine, Piperolein B, Retrofractamide A, Chavicine, Isochavicine, Isopiperine, Nerolidol, b-caryophyllene and Piperic acid) (Damanhouri & Ahmad, 2014), Zingiber officinale (6-gingerol, 6-shogaol, 6-paradol, Zingiberene, Bisabolene, 1-dehydrogingerdione, 6- gingerdione, 10-gingerdione, 4-gingerdiol, 6-gingerdiol, 10- gingerdiol, Citral and Eucalyptol) (Bhattarai et al., 2018; Prasad & Tyagi, 2015), Syzygium aromaticum (beta-caryophyllene, Vanillin, Eugenol, Acetyl eugenol, Crategolic acid, Eugenin, Methyl salicylate, Kaempferol, Rhamnetin, Eugenitin, Oleanolic acid, Stigmasterol, Campesterol, Gallic acid and Flavonol glucosides) (Cortes-Rojas et al., 2014), Elettaria cardamomum (Protocatechualdehyde, Protocatechuic acid, Alpha-terpinyl acetate, 1,8-cineole, Linalool, Linalyl acetate, Limonene, 4-terpineol and Geraniol) (Noumi et al., 2018), Citrus limon (Eriodictyol, Quercetin, Hesperetin, Phloroglucinol, Umbelliferone, vitamin C (Vandercook & Stephenson, 1966; Rangel et al., 2011) and Withania somnifera (Withaferin A, Somniferine, Choline, Anaferine, Withanolide A, Withanolide B, Withanone and Withanolide) (Sangwan et al., 2004). 3D structures of these different phytochemicals were downloaded from PubChem (https://pubchem.ncbi.nlm.nih.gov) in structure-data file (SDF).²⁶ Preparation of Ayurvedic Kadha. There are specific Ayurvedic methods to prepare the Kadha. In India, variants of standard Kadha are also prepared using different combinations of herbs depending on the severity of disease/ailment and the availability of ingredients. The most common ingredients are Tulsi leaves (10–15 leaves or 1=4 teaspoon powder), Ginger (2–5 g rhizome or 1=4 teaspoon powder), Clove (4–5 pieces), Black pepper (4–5 pieces), Cardamom (4–5 pieces), Ashwagandha (2–5 g raw or 1=4 teaspoon powder) and Giloy (2–5 g raw or 1=4 teaspoon powder). To make the Kadha, these herbs are boiled in 200 ml water for 5–10 min, and jaggery or honey is added to make it sweet. The preparation is filtered and mixed with 1=4 teaspoon of lemon juice. In case, if all ingredients are not available, it can be prepared using locally available ingredients.²⁷

Curcumin:

Turmeric is a herbal plant also known as Curcuma longa (C. longa) belonging to the family Zingiberaceae and the Curcuma genus. It is widely known as a medicinal plant to treat various diseases and conditions. It contains carbohydrate (96.4%), protein (6.3%), fat (5.1%), mineral (3.5%) and moisture (13.1%). Its extract contains curcuminoids, which are curcumin (77.7%), demethoxycurcumin (DMC 17%) and bisdemethoxycurcumin (3%). The most common curcuminoid that is used as a medication is curcumin.²⁹ It is the yellow pigment of turmeric is widely used in our Indian Traditional herbal medicine to cure diseases associated with inflammation and infections for many decades. It is also reported that curcumin exerts antiviral activities.³²

According to recent research, the SARS-COV2 virus, like the original SARS-CoV, infects human host cells by attacking the Angiotensin Converting Enzyme 2(ACE2) membrane receptor, which is a coronavirus entry site. The viral S protein binds to the ACE2 receptor on the mucus membrane, allowing for viral and membrane fusion and subsequent viral replication in the host.^32,33 ACE2 expression was found in nasal epithelial cells, pulmonary alveolar epithelial type II cells (AECII), and the luminal surface of intestinal epithelial cells, according to a recent report. Angiotensin-converting enzyme 2 (ACE2), a homologue of ACE with 61 percent sequence similarity to the ACE catalytic domain, hydrolyses Angiotensin II to Angiotensin (1–7) and attenuates Angiotensin II-ATIR axis mediated vasoconstriction effects, lowering blood pressure via vasodilation.³⁴

In line of the growing evidence of curcumin's therapeutic properties, they propose a hypothetical treatment strategy in which curcumin is used as:

1) A possible inhibitory agent blocking the host viral interaction (viral spike protein—ACE2 receptor) at a human entry site.

2)As a COVID19 attenuator, it reduces respiratory discomfort by modulating the proinflammatory effects of Angiotensin II-AT1 receptor-signalling pathways.

Curcumin's function in the control of RAAS (Renin Angiotensin Aldosterone System) components, through which it is known to exert antioxidant, anti-inflammatory, and antihypertensive effects, has also been extensively researched. Curcumin has been linked to a reduction in the expression of ACE and AT1R receptors in brain tissue and vascular smooth muscle cells in animal studies.

Inhibition of the symptoms of hypertension and oxidative stress induced by Angiotensin II-AT1R in animals. Previous research has found high levels of AT2R and ACE2 expression in myocardial cells treated with curcumin, indicating that curcumin can protect the heart by modulating the effects of the Angiotensin II receptors AT1R and AT2R. Upregulation of AT2R causes AT1R expression to be suppressed, resulting in anti-inflammatory effects mediated by Angiotensin II-AT2R, including inhibition of NF-B activity and oxidative stress. As a result, curcumin therapy reduced the proinflammatory effects of the Angiotensin II-AT1R axis, resulting in substantial reductions in proinflammatory cytokines TNF-, IL-6 and reactive oxygen species.^32,35

Cinchona:

Cinchona officinalis (Cinchona, Quinine), a member of the Rubiaceae family and the Genus Cinchona, has been prized for its antimalarial properties for decades. Jesuit's bark, Peruvian bark, Cinchona bark are all synonyms for the cinchona. Cinchona bark contains approximately 30 different forms of quinoline alkaloids. Quinidine, quinine, cinchonine, and cinchonidine are the most common alkaloids found in cinchona bark. Quinine alkaloids make up 30-60% of the cinchona's composition. Cinchona trees (Cinchona L., Raiatea) from the Andean mountain forests have several advantages, as a basic component of the trees contains bioactive compounds that can help to cure fever. Jesuit missionaries were the first to notice this beneficial influence, which spread across the world over time.³⁶

To treat COVID-19, quinine sulphate has been one of the most sought-after drugs in society. State officials and physicians made insensitive remarks, causing widespread pandemic. As a result, people searched out competitively quinine-containing drugs. Because of the high incidence and mortality rate of COVID-19 globally, the people's behaviour was caused by a spontaneous reaction. This section will go into how quinine can be used as an antiviral and immunomodulator in a virus-related disease. Also, the potentially adverse effects of quinine in people with or without COVID-19 will be discussed. Quinine gained popularity as a substitute for the antimalarial medication chloroquine. Malaria medications were gradually repurposed as potent inhibitors of viral infection, rather than as antimalarial drugs. According to a large amount of evidence, many antimalarial drugs had been studied and found to have some benefits against viral infection.³⁷

Chloroquine, for example, had antiviral activity against the SARS-CoV infection.³⁸ Seeleretal was the first to study the quinine effect as an anti-influenza virus infection treatment.³⁹Furthermore, Baronietal identified quinine's antiviral activity.Quinine sulfate suppresses viral infection in indirect ways, for example, by inducing a heat shock protein response, disrupting multiple pathways during virus replication, and inhibiting NF-kB by blocking gene expression, according to a study that evaluated quinine sulphate on infected HSV-1 HaCat cells.⁴⁰Viruses infecting host cells cause viral RNA to be released, disrupting normal protein synthesis. However, associate degree expression of an infective agent recognition receptor (PRR) called RIG-I within the infected host cell will increase minimally to promote the IFN-I signaling pathway instead of elevating organic phenomenon of IFN-stimulated genes (RNase L, PKR) that inhibit the synthesis of the protein, thereby block microorganism replication.⁴¹ In virus-infected cells, the RNase L pathway can remove ssRNA, while PKR inhibits translation and interferes with signaling.⁴² Infected host cells' genome replication and translation are inhibited, and RIG-I and IFN are increased. IFN is the cytokine secreted by host cells to combat viruses, according to research.⁴³

Quinine sulphate works as an antiviral agent by boosting RIG-I and IFN-alpha production. Both will then activate PKR to prevent viral mRNA translation and RNAse to degrade viral poly mRNA (L) As a result, there is no viral protein produced. Since available data show that quinine prevents the release of TNF- α, the most important cytokine in determining the severity of COVID-19 symptoms, CSS does not appear in COVID-19 after quinine administration.^44,45 Since quinine inhibits TNF- α expression at the mRNA transcription level, as measured by northern blot, it will reduce rather than promote inflammation in microbe-infected people.⁴⁴While the cinchona tree extract does not cause CSS directly, Lilesetal found that quinine can cause immune-mediated and toxic reactions.

In 2009, a Belgian research group reported the efficacy of chloroquine in eradicating lethal viral infections caused by the human coronavirus OC43, which is closely linked to the human coronavirus. Through injecting the drug into the mother's milk, SARS was able to spread around the world.⁴⁶ In terms of the efficacy of chloroquine against SARS-CoV-2, a recent study involving hundreds of COVID-19 patients found that the chloroquine-treated group was superior in terms of reducing the duration of the disease progression of the condition, strengthening lung imaging results, and pneumonia a deterioration and an increase in virus-negative seroconversion Compared to the placebo group, there were no side effects.⁴⁷ The drug was given in a 500 mg dose twice daily in this first clinical trial against COVID-19. A multicenter collaboration committee of the Department of Science and Technology and the Health Commission of the United States released an expert consensus on February 20, 2020. Chloroquine phosphate tablets are produced in the province of Guangdong.500 mg twice a day for ten days is prescribed as a starting dose. mild, moderate, and serious cases of SARS-CoV-2 pneumonia.⁴⁸ Treatment victimization chloroquine might enhance the treatment success rate, shorten the hospital keep, and lowers the mortality related to COVID-19.⁴⁹

Ashwagandha:

Withaniasomnifera (Ashwagandha) is known to inhibit SARS-Cov 2's main protease (Mpro or 3Clpro). Somniferine and Withanoside V were found to inhibit SARS-CoV-2 activity. The main proteases of SARS-CoV-2 were studied as a potential macromolecular target for COVID-19 management using active phytoconstituents from Ayurvedic scriptures. Ayurveda, also known as "The Science of Life," is an ancient Indian philosophy of medicine based on the holistic concept of life, wellness, and healing. The ayurvedic text describes a group of rejuvenation methods that provide biological nourishment to body tissues.⁵⁰ It describes several medicinal plants with a wide range of therapeutic potential in treating respiratory illnesses, one of which is Withania Somnifera (Ashwagandha). Which acts as an immunomodulator and helps the body fight infections.

W. Somnifera (WS), also known as Ashwagandha, is a Rasayana (rejuvenator) that has been shown to improve physical and mental well-being, rejuvenate the body in weakened conditions, and increase longevity [40]. Anti-inflammatory, anti-diabetic, antimicrobial, analgesic, anti-tumor, anti-stress, neuroprotective, cardioprotective, rejuvenating, and immunomodulatory properties have been identified.^51,52,53,54Withanolides are an active ingredient that includes steroidal saponin, alkaloids, and steroidal lactones. Withaferin-A and Withanolide D, as well as new Withanolide Glycosides Withanoside I–VII, contribute the majority of biological action.⁵⁵ Previous research has shown that certain phytoconstituents from medicinal plants interact with SARS CoV-2 Mpro and other COVID-19 target proteins (S, E, and N). These phytoconstituents include Withaferin A, Withanolide B, Somniferine A, Withanolide, glucoside, and Withanone.⁵⁶

Ayurvedic formulations can play an important role in the production of healthy and nontoxic therapeutic moieties. An attempt was made to identify new active and stable inhibitors against novel coronavirus main protease using in silico molecular docking and molecular dynamic simulation studies, from a total of 102 active phytoconstituents from a medicinal plant. As a result, viral translation into functional polyproteins, which is necessary for virus replication, is inhibited, and host physiological/biological functions are disrupted.

Lianhuaqingwen (LH):

Lianhuaqingwen (LH) is a patented Chinese medicine product that has been developed for the treatment of cold and influenza.^57,58 Nowadays it is widely used as an antiviral agent in clinical practice, especially for various respiratory virus infections on a series of influenza viruses by inhibiting viral replication and regulating immune function, and has achieved similar therapeutic effectiveness with Oseltamivir in reducing the course of H1N1 virus infection.^57,58,59 Although LH significantly relieved the clinical symptoms of the COVID-19, the underlying mechanism of antiviral effects on coronavirus, especially in the SARS-COV-2 is by inhibiting virus replication and reducing the cytokine release from host cells.⁶⁰This is useful in the therapeutic use of LH in combination with current drugs for the treatment of COVID-19. However, the pharmaceutical components and pharmacological mechanism of LH in fighting COVID-19 are still largely unexplored.

LH has the functions of clearing away heat and detoxifying the lungs, and thus it is also clinically used to treat patients with the symptoms of fever and stagnation of the lung.⁶¹ In comparison to oseltamivir, LH had a stronger effect on the relief of fever, cough, sore throat, and fatigue in an anti-influenza A (H1N1) trial. Furthermore, it showed comparative therapeutic effectiveness in the reduction of illness duration and viral shedding duration.^58,62

LH inhibits the spread of influenza viruses from different strains in vitro, with a 50% inhibitory concentration (IC50) ranging from 0.35 to 2 mg/ml. It could also suppress the virus-induced nuclear factor κB (NF-κB) activation and reduce the virus-induced gene expression of interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-α (TNF-α), interferon-γ-inducible protein-10 (IP-10), and monocyte chemoattractant protein-1 (MCP-1).⁵⁷ Using a similar in vitro study, it has been shown that LH exerted anti-SARS-CoV-2 activity by inhibiting virus replication and reducing cytokine release from host cells. by using network pharmacology, it is found that there are 15 active components in LH and 61 related targets and the active components of LH might inhibit cytokine storms by regulating various inflammatory signal pathways.⁶³

Lianhuaqingwen capsule has been confirmed to show therapeutic effects by clinical research and observation.^60,64The course of treatment is from 7 to 10 days, indicating the effectiveness of LH in treating COVID-19.

Fig 1. Mechanism of action of Herbal drugs

CONCLUSION:

Current findings and the recent knowledge about SARS-CoV and SARS-CoV-2 pathology, profess the use of Ayurvedic Kadha in the prevention and management of COVID-19. The phytochemicals found in the Kadha have a significant binding affinity with the different CoVs proteins (Scheme 1), indicating that they may control viral infection and multiplication in the host cells. Molecular docking study with human inflammatory mediators predicts that many of the phytochemicals present in this preparation have significant anti-inflammatory property. Most of the phytochemicals found in the herbs Ashwagandha, Giloy, Tulsi, Clove and Black pepper have the potential to interact with most of the druggable proteins selected in this study. In conclusion, regular consumption of ayurvedic Kadha in consultation with an ayurvedic practitioner may decrease the inflammatory response, boost the individual’s immunity and reduce the risk of CoVs infection including SARS-CoV-2.

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