BACKGROUND

Over the centuries, plants and herbs are used as an important source of medicines1 According to WHO, traditional medicines have always been the major source of treatment in primary healthcare system of communities. Right from the evolution of human civilization, the practice of use of medicinal plants have been documented for the purpose of curing human ailments2. The use of medicinal plants take us 5000 years back, providing the primitive evidence of use of traditional medicines in Indian, Chinese, Egyptian, Roman, Greek and Syrian texts3. The vast knowledge of the medicinal values of plants today is the result of long evolution through trials and error when everything was based on experimentations due to which man learned the healing properties of medicinal plants in barks, seeds, fruiting bodies and other parts of plant4. The use of traditional medicines depend on local availability of natural resources and their indigenous knowledge5. About 80% of the health needs of the world’s population is facilitated by herbal medicine, and that too in rural areas of developing countries6. In majority of the developing countries, herbal medication has sustained its popularity, as modern medications are limited in those regions7. According to the reports of WHO, 80% of the population in Africa depends on traditional medicines for health care.

India has always been a land of plants and possesses a rich history of traditional healing system, especially the use of plants and herbs. India has the rich diversity of medicinal plants and Indian herbs are extensively used for the medicinal properties throughout the world8. Forests of India are the major source of therapeutic medicinal plants, contributing to about 90% of the herbs and medicinal plants, with Gujarat, Haryana, Rajasthan, Andhra Pradesh, Uttrakhand and Tamil Nadu being the leading producers of herbal plants in India8. The ancient literatures of India, such as Rigveda, Charak Samhita, Atharvaveda and Sushruta Samhita, talk about the practices of medicinal plants to treat diseases3. In India, around 17,000-18,000 flowering species are found, among which 6,000-7,000 species are considered to have medicinal values3. Apart from the medicinal uses, herbal plants are the source of livelihood to a large section of population of India9. Around 70% population of rural India depends on medicinal plants as a source of treatment of various diseases10. Indians have been using medicinal plants to cure several diseases, treating the wounds and inflammation. Medicinal plants possess several properties and are known to cure some common prevalent diseases, such as malaria, tuberculosis, diarrhoea, asthma and pneumonia11. During the outbreak of epidemic diseases, such as malaria, cholera, small pox in the colonial era, traditional plants were continued to be used in India for medicinal purposes1. Medicinal plants are used against diseases like diabetes, intestinal disorders, parasitic infections, skin disorders, gastrointestinal disorders, neurological disorders, piles, skeletal diseases, viral infections .12. Infectious diseases across the world are the major causes of mortality and are increasing alarmingly within the last few years13. Viral diseases have become a major health concern throughout the world and the emergence of COVID-19 in late 2019 has resulted in a global pandemic.

The Indian Traditional System of Medicines is one of the ancient medical practice in the world14. There are several medicinal plants native to India, which are used as antiviral and immune stimulant14. Various plants, such as . are known to possess the antiviral and immunomodulatory properties which boost the immune system15, 16, 17. The phytochemicals found in plants and the compounds specific to plants, such as flavonoids, saponins, alkaloids, quercetin, catechins and polysulphates play an important role in the inhibition of viral entry of viruses, which further inhibits their replication, causing damage to their nucleocapsid and genetic material16. Therefore, with the help of traditional practices of Indian medicinal plants, new treatment methods can be developed to combat the effects of COVID-19.

A BRIEF OVERVIEW OF CORONAVIRUS

Coronavirus disease 2019 (COVID-19) originated in Wuhan, Hubei Province, China in late December, 201918. It is a positive, single-stranded virus, appearing in a crown shape when seen under an electron microscope, as it has spike glycoprotein on the envelope19. Coronavirus comes under the broad realm of Riboviria, having a total of 39 species20 (Figure 1).

The virus has the largest genome (26.4-31.7kb) among all the RNA viruses known till date21. It has a 5’-cap structure and 3’poly A tail with 14 open reading frames (ORFs) which encode 27 proteins22. There are four structural proteins of the virion, known as S (Spike), E (Envelope), M (Membrane) and N (Nucleocapsid); the S, E and M proteins together constitute the viral envelope, while the protein N holds the RNA genome23. The viral envelope plays a major role in the assembly and release of virus, promoting viral pathogenesis24.

Symptoms of SARS-CoV-2 includes fever, coughing and shortness of breath, but in severe infection, it can lead to pneumonia, multi-organ failure, severe acute respiratory syndrome and even death25, 26. Clinical reports reveal that the most distinctive comorbidities of SARS-CoV-2 were hypertension and diabetes mellitus27. SARS-CoV-2 binds to the host cells through the ACE 2 receptor (Angiotensin converting enzyme 2), which is facilitated by spike glycoprotein, and the process is set with the help of a protease called TMPRSS228, 29. After further endocytosis followed by uncoating, components of SARS-CoV-2 with the aid of host cell machinery produce new viruses. As a result of stimulation of SARS-CoV-2, the host immune system releases cytokines following inflammation through activation of dendritic cells, NK cells, macrophages, and neutrophils, which can result into sepsis, multiple organ failure, septic shock and even death30. The expression of ACE 2 is high in heart, kidney, blood vessels, lungs and intestine31. Multiplication of viruses induce cellular responses comprising of innate and adaptive immune cells32, 33. Neutrophils produces injury to lungs and adaptive immune cells, mainly the T cells (Cytotoxic CD8 T cells), which not just kill the virus, but also causes injury to lungs34, 35. This triggers the progression of systemic inflammatory response called cytokine surge, in which there is an extensive increase in the number of cytokines (TNF-α, IL1, IL6, IL10 .) which thereby causes inflammation and cell death of Type 1 and Type 2 cells in the alveoli36. This causes the interruption in transportation of oxygen, resulting in apoptosis in alveoli of the lungs and hence causes Acute Respiratory Distress or Syndrome (ARDS)37. Transmission of SARS-CoV-2 virus occurs from human to human through respiratory droplets during coughing and sneezing38.The high affinity of S-protein of SARS-CoV-2 to bind ACE 2 is 10 - 20 fold greater than S protein of SARS-CoV, due to which SARS-CoV-2 spreads rapidly31.

In the race to curb the spread of the novel Coronavirus, several strategies and measures are being implemented from social distancing to drugs and vaccine discoveries. In addition, traditional herbal medicines are also being explored side by side as there is still huge dependence on medicinal plants as complementary medicines39. As we know that SARS-CoV-2 affects weak, immune compromised people, herbal medicines can play a potential role in boosting the immune system and possess antiviral properties which can curb the effects of COVID-19, lowering down the death rates worldwide40.

STATUS OF MEDICINAL PLANTS OF INDIA

Humans depend on nature and its source for survival and sustenance. Plants have been one of the important sources of medicines, and in India, curative properties of plants take us back to the age of the Rigveda (2500 to 1600 B.C.)1. Traditional herbal medicines hold a long history in treating various infectious diseases due to the presence of anti-bacterial, anti-viral, anti-inflammatory and immunomodulatory properties, which make them effective against a wide array of diseases41, 39, 42. India has a rich traditional healing system, and the oldest printed book on Indian Medicinal Plants, enlists the use of the medicinal plants. The most ancient written evidence of usage of medicinal plants for the preparation of medicine has been found from Nagpur on Sumerian clay slab, which dates back to 5000 years ago4. In India, there are more than 1.5 million practitioners who use traditional medicine system for healthcare, and more than 1500 herbal formulations are sold as dietary supplements10, 43. 1000 species of medicinal plants are reported in India, among which 540 species are herbs, 100 are shrubs, 160 climbers, 200 species are trees, orchids are 15 species and ferns and conifers are 2044. 70% of Indian medicinal plants are found in tropical forests of Eastern and Western Ghats, Himalayas, Aravali Vindhya range and Chota Nagpur Plateau45.

Despite the progress of modern medical and pharmaceutical research, the use of medicinal plants are still significant and common, and the Indian Traditional System of Medicines (Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homeopathy (AYUSH)) uses herbs and plants for treatment of various diseases1 (Table 1). Studies reveal that plant derived compounds (Phytoconstituents), extracts of parts of plant such as roots, stems, barks, flowers, fruits and seeds, help in treating common to rare infections15 (Figure 2).

National Medicinal Plant Board (NMPB), established in India in November 2000 by Government of India, acts as a primary board for coordinating all matters related to medicinal plants, their growth, export, conservation and cultivation. This board is located in Department of AYUSH of Ministry of Health and Family Welfare, Government of India3.

ANTIVIRAL ACTIVITY OF INDIAN MEDICINAL PLANTS

Earth contains around 10 viruses, and they are ubiquitous even in the marine environment, as nearly 5000 viral genotypes are present in every 200 L of water62, 63. Viral diseases are increasing throughout the world and are a matter of great concern64. They enter the body and redirect body’s metabolism to produce multiple copies of their genome and proteins65. Plants contain a variety of bioactive constituents, such as alkaloids, phenolic compounds, saponins, flavonoids, lignans and other bioactive components which make them a suitable treatment option against viral infections66, 67, 64. Studies reveal that compounds, such as andrographolide, glycyrrhizic acid, curcumin as well as extracts of have antiviral activities68. Antiviral activities of plants like , , are well known65. Antiviral activities of 38 Indian plants have been reported in 32 papers to be effective against human immunodeficiency virus (HIV)68. In another study by Mehrotra .69 neutralizing activity of has been reported against hepatitis virus. Ahmed and Verma70 studied the genus (Euphorbiacae) and worked on plants namely which showed pharmacological and phytochemical properties of the genus exhibiting diverse biological activities such as antihepatotoxicity, anti-HIV, anti-carcinogenic and anti-inflammatory properties. Indian plants, such as (Family-Fabaceae), (Family-Avecennaceae), (Family-Vitaceae), (Family-Convolvulaceae), (Family-Aristolocheaceae), (Family-Fabaceae), (Family-Mimosaceaeare), (Family-Zygophyllaceae) and (Family-Capparidaceae) are found to possess antiviral properties against pox viruses 59 (Table 2).

(Family- Rhizophoraceae) was assessed for its antiviral activities against Human immunodeficiency virus (HIV) cell culture system and the polysaccharide extracted from the bark of was found to be inhibiting the viral cycle as it protected MT-4 cells from HIV induced cytopathogenicity and inhibited expression of HIV antigens71. Fiore 72 reported antiviral activity of spp. (Licorice) against HIV-1, SARS related Coronavirus, hepatitis B virus, vaccinia virus and vesicular stomatitis virus, as it reduces transportation of the virus to the membrane and sialyation of surface antigen of hepatitis B virus inhibits fusion of the viral membrane of HIV-1 with the cell by reducing membrane fluidity. It also induces interferon gamma in T cells and inhibition of phosphorylating enzymes in the infection by vesicular stomatitis virus.

commonly known as neem (Family- Meliaceae), native to Indian subcontinent, is another promising plant having active component azadirachtin and other constituents such as nimbidol, sodium nimbinate, gedunin, salannin, quercetin, nimbolinin, nimbin and nimbidin, and holds a long history of use in traditional medicines throughout the world73. Extracts of neem have shown antiviral activity on viruses such as vaccinia, Buffalo pox, chikunguniya, herpes, measles 68.

Central Drug Research Institute, Lucknow (CDRI) screened top 11 families for their pharmacological activities, and the rank of 11 families on the basis of their antiviral activities were found to be in this order: Euphorbiaceae > Fabaceae > Asteraceae > Fagaceae > Myrtaceae > Rubiaceae > Rosaceae > Caesalpineaceae > Lamiaceae > Lauraceae > Anacardiaceae68.

INDIAN MEDICINAL PLANTS EFFECTIVE AGAINST COVID-19

Medicinal plants are known to have antiviral properties and several health benefits and their bioactive constituents may provide help in designing novel alternative and supplementary treatment for COVID-1974. Due to less cost, easier availability and no side effects, majority of the Indian population rely upon herbal medicines40. Several plants of Indian origin have been quoted to possess antiviral activity against SARS-COV-275. Certain medicinal plants have been recommended by India for prevention and prophylaxis of coronavirus, such as , , , and 76. The medicinal drugs for coronavirus can be derived from turmeric, ginger, tulsi, fenugreek, cloves, cinnamon and fennel seeds77.

As per the study conducted by Srivastava.78, 18 different species of Indian herbal plants were assessed in the pursuit of potent COVID-19 inhibitors through and the inhibition potentials of the plant were in order as follows: harsingar > aloevera > giloy > turmeric > neem > ashwagandha > redonion > tulsi > cannabis > black pepper, on the basis of lipophilicity, aqueous solubility and binding affinity. Molecular docking study against Mpro and ACE 2 showed that phytochemicals present in plants, such as have better binding energy with Mpro and ACE-2 as studied by Joshi .79.

In another research done by Maurya and Sharma80, phytochemicals and bioactive compounds present in tulsi, haldi, giloy, ginger, cloves, lemon, ashwagandha and ginger were assessed using molecular docking approach against SARS-CoV-2. The compounds in herbs were docked with viral capsid spike and protease to study their antiviral activities, and the phytochemicals were found potentially efficient in inhibiting different stages of SARS-CoV-2 infection and its target proteins. As studied by Shree 81, the compounds obtained from , and could bind to SARS-CoV-2 Mpro and was found to decrease the viral transcription and replication serving as a potential inhibitors .

CONCLUSION

India has always been known for its rich biodiversity and extensive varieties of plants, which are found from Himalayas to the marine and desert to the rain forests. The present study revealed the status of medicinal plants and herbs of India and their various therapeutic benefits. Use of herbal medicines is not only safe and cost-effective, but it is also free from side effects. AYUSH system of medication emphasizes on simple natural remedies for the improvement and development of strong immune system.

Efforts should be made to explore and promote the knowledge of healing through such medicinal plants. The proper use of medicinal plants against COVID-19 could safeguard lives of several people reducing the risks of infection, thereby minimizing the rate of mortality.

Abbreviations

3CLpro: 3- Chymotrypsin Like Protease

ACE 2: Angiotensin converting enzyme 2

ADMET: Absorption, Distribution, Metabolism, Excretion, and Toxicity

ARDS: Acute Respiratory Distress or Syndrome

AYUSH: Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homeopathy

DCG: Desacetylgedunin

DFT: Density Functional Theory

DTQ: Dithymoquinone

NMPB: National Medicinal Plant Board

PLpro: Papain Like Protease

RBD: Receptor Binding Domain

ROS: Reactive Oxygen Species

TIM: Traditional Indian Medicines

TMPRSS2: Transmembrane Protease Serine 2

TNSS: Total Nasal Symptom Scores

Acknowledgments

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Author’s contributions

All authors equally contributed in this work. All authors read and approved the final manuscript.

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The authors declare that they have no competing interests.