Traditional Herbs against COVID-19: An Overview

By: Mr. Keyur V. Shastri

Assistant Professor (Department of Quality Assurance)

Vivekanand Education Society's College of Pharmacy

The world is suffering the Coronavirus infection 2019 (COVID-19) which has been declared to be a global pandemic by the World Health Organization (WHO) in March. The coronavirus pandemic has been argued as the greatest crisis globally as this pandemic has emerged as the greatest worldwide health crisis since the influenza pandemic. It caused more than 6.000.000 deaths all over the world. The causative agent is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is an enveloped beta-coronavirus that has non-segmented positive-sense RNA. SARS-CoV-2 has about 30 kb of genetic information that is 70% identical to the SARS-CoV. SARS-CoV-2 causes a disease in the respiratory tract of humans using the same receptor used by SARS-CoV: the angiotensin-converting enzyme 2. In severe cases, SARS-CoV-2 triggers an inflammatory immune response and the release of proinflammatory cytokines that result in many consequences. Cytokine storm, multi-organ dysfunction, and acute respiratory syndrome are some of such effects. There is no definite, consolidated, and efficient remedy for COVID-19 infections. Several types of vaccines are now available to hinder the COVID-19 pandemic nonetheless their delivery is still a challenge, especially for developing countries. Accordingly, the main concern for researchers is the innovation of reliable and effective antiviral therapeutics for SARS-CoV-2. Medicinal herbs may be an ideal gateway toward finding effective anti-COVID-19 therapeutics.

People worldwide, particularly from Asian countries including; Japan, India, and China, and also some African populations have employed herbs as remedies to alleviate symptoms of many diseases since the ancient age and are even up to date. This could be attributed mainly to the profound availability and relatively low cost of medicinal plants in these tribes. Thus, it could be possible to develop novel drugs with possible anti-COVID-19 efficacy from herbs and their bioactive components. Phytochemical metabolites, such as tannins, terpenoids, alkaloids, coumarins, flavonoids, and polyphenols, have shown efficacy against pathogenic microorganisms. This could be attributed to their ability to stop viral enzymatic and protein activities thus inhibiting viral entry and replication in the affected host cells. Accordingly, quite a lot of reports have recommended the efficacy of herbal bioactive compounds in reducing and managing the risk of SARS-CoV-2.

Evidence emphasizes that herbal medicine could be worthwhile in the  management  of  COVID-19.  Still, there is a shortage of information on the anti-COVID-19 agents derived from medicinal herbal extracts and their bioactivities. The National Health Commission of China has permitted the usage of herb-based medicines in combination with Western medicine as an alternate therapy for COVID-19 and has authorized some recommendations on the herbal therapy. At present, herbal remedies having antiviral activities work as an auxiliary treatment to stop SARS-CoV-2 infections as the conventional treatment is quite not thriving. Medication systems in various geographical zones use traditional medical herbs as the prime treatment for viral infections, including those triggered by the SARS-CoV. For instance, the leaf extracts of Toona sinensis suppress SARS-CoV replication. In addition, licorice has been recommended as a promising treatment for SARS-CoV. Besides, natural products such as diterpenoids, triterpenoids, sesquiterpenoids, and curcumin have shown their ability to impede SARS-CoV infection. Furthermore, dietary and herbal medicinal therapy may be efficient as an adjuvant against COVID-19. The bioactive ingredients in certain foods and herbs possess antioxidant, immunomodulatory, anti-inflammatory, and also antimicrobial activities. This could help in pre-and/or post-exposure prophylaxis by increasing the number and activity of cytokine suppressors, natural killer cells, lymphocytes, and macrophages. Consequently, the medicinal plant products could reduce the inflammation markers and respiratory disorders symptoms thus improving recovery. Hence, this review aims to present the most important medical herbs and their bioactive compounds, and some dietary supplements and functional foods that possess potential antiviral activities regarding COVID-19.

Herbal Therapeutic approaches against COVID

The lack of precise effective therapeutics against SARS-CoV-2 has encouraged some investigators to shift toward plant-based therapeutic approaches. This is due to the fact that numerous drugs are either plant materials or derived from their bioactive herbal constituents. Consequently, there is a remarkable interest in the detection of prospective anti-COVID-19 herbal medicines, since plant-based therapeutics exhibited encouraging efficiency against various viruses via reinforcing immunity.

In the field of herbal medicine research, a single plant species may have great medical importance as it may contain a wide array of bioactive phytochemicals. These phytochemical components  may  act  either  alone  or  in a combination with other constituents to produce the wished pharmacological impacts. The beneficial effects of medicinal herbs come from their bioactive secondary metabolites comprising; alkaloids, steroids, triterpenes, and glycosides. Studying the pharmacologic impacts of plants is a challenge.

Currently, the main concern of medical research is the development of innovative antiviral agents. On top of displaying direct antiviral effects, herbal drugs having anti-inflammatory activity can have a major role in COVID-19 treatment. This could be attributed to the cytokine storm; elevation of the inflammatory mediators as erythrocyte sedimentation rate (ESR), interleukin (IL)- 6, and C-reactive protein (CRP), which may cause severe disease with worse outcomes in COVID-19 patients.

Ayurvedic medicine to treat COVID-19

Ayurveda is the world’s ancient medicinal network that is assumed to be used in the management of various infections while having no adverse effects. Ayurveda is well-furnished with various treatment approaches for complicated deleterious ailments. Ayurveda health care experts have been aware of various microorganisms and the infections triggered by them. The Ayurveda and the Siddha rehearse initially began in India and are quite widely used to cure numerous infections. The identification, isolation, and characterization of bioactive phytochemicals in medical herbs might aid in the struggle with several infections. Thus, repurposing ancient medical plants possibly will provide a novel attitude for combating various viral contagions.

Ayurvedic Kadha

Ayurvedic medication and its extracts have been employed in the prevention and treatment of viral diseases. Kadha represents the earliest kind of medicine made by merging plant-based drugs and spices. It is an extract prepared from less juicy or dry constituents, such as herbs and spices from various Indian botanical drugs.

Making Kadha for oral consumption is an important Ayurvedic practice for augmenting the pharmacological effects of active components in botanic drugs. The Indian government recommended the usage of Kadha during the COVID-19 pandemic to improve the immune response and promote curing. The Ayurvedic Kadha- based phytochemical constituents possess a potent binding affinity with several viral and host targets. A fact that proposes their antiviral activity through regulating virus replication in their host cells Recently, the Ministry of AYUSH (Ayurvedic, Yoga, Naturopathy, Unani, Siddha, and Homeopathy) in India commended drinking Kadha as a booster immunity and also for depressing the tenderness during the COVID-19 crisis.

Guduchi Ghan Vati

Guduchi Ghan Vati is a traditional Indian remedy that is usually prescribed as an antioxidant and immunomodulatory therapeutic. Recently, its activity against the SARS- CoV-2 infections was also confirmed. The common Ayurvedic preparation, Guduchi Ghan Vati is itemized in the Ayurvedic Pharmacopoeia of India. It is prepared from an aqueous extract of Tinospora cordifolia. T. cordifolia (Lour.) Merr., generally recognized as “Guduchi”or “Giloe” is a big climbing tree that belongs to the family Menispermaceae. It exists in the tropical areas of both China and India. It has been historically used in traditional medicine.

Tinospora cordifolia and Piper longum

It is a herb present in India and China and belongs to the family of Menispermaceae. In the traditional Ayurvedic medication, this herb is  utilized  in  the  preparation of Guduchi Ghan Vati. In addition, it could be administered in combination with Piper longum L. (family Piperaceae). P. longum is one more common medical herb employed in Ayurvedic medicines. P. longum is commonly known as “Indian Long Pepper” and “Pippali”. Pippali is recognized as a traditional Ayurvedic complementary constituent, which improves the absorption and bioavailability of other bioactive constituents. It also has notable antiviral activities.

Plant Secondary metabolites against COVID-19 infections

Plant’s secondary metabolites (PSMs) are intermediate complexes formed as a result of stress exposure. PSMs can aid the host to interact and deal with various environmental stresses. They have strong antimicrobial, anti-fungal, and antiviral activities. Recently, researchers revealed that PSMs may have antiviral properties in humans. Reviewing the recently available data concerning the utilization of plant active metabolites in the prevention and/or treatment of COVID-19 revealed the activity of several bioactive phytochemical components on various diseases. The possible mechanisms include crucial immunomodulatory activities, affecting COVID-19 biomarkers, or modulating or halting the SARS-CoV-2 itself. There are four main PSMs groups: terpenoids/terpenes, phenolics and polyphenols, glycosides, and alkaloids. In this review, we discuss some of the newly published data as regards the application of plant bioactive metabolites in the prevention/management of COVID-19 infections.

Terpenes (Essential Oils)

Terpenes are a large group of natural organic compounds present in plants. They are lipophilic compounds found in many plants’ essential oils. Terpenes possess a strong odor that safeguards the plants from various pathogens. Terpenes remain the principal secondary metabolites in more than 36,000 species. They could be used as anti-cancer, anti-inflammatory and antiviral, antioxidant, and also antibacterial. Recently, terpenes have extended specific interest owing to their prominent anti- viral activities. Terpenes can incorporate with the lipid bilayer of the virus disturbing its structure. Therefore, terpenoids are considered specific inhibitory compounds against viruses. Certain terpenes such as celandine-B, betulinic acid, and ursolic acid have displayed vigorous antiviral effects (IC₅₀: 1–20 g/mL). Besides, the  research discloses that terpenes have advanced binding affinities and strong inhibition with all coronavirus diversities and could be highly active against COVID-19. The outer spiky lipid layer of COVID-19 is important for its attachment to the host’s cell membrane. Terpenes can destroy the lipid layer of COVID-19 and inhibit its binding characteristics.

Moreover, coronavirus consists of a single-stranded RNA. This RNA strand acts as an RNA messenger. Once it enters the host cells, it triggers the formation of two polyproteins that are further consisted of new replication and transmission complexes which regulate the RNA synthesis and structural proteins formation and also enhance protease enzyme activity. The protease enzyme plays a major role in the disintegration of the polyprotein. The recent antiviral therapeutic strategies involve identifying inhibitors of protease enzymes from natural products. Among these, terpenes have a particular impact because of their diverse accessibility in plants and microorganisms and their little IC₅₀.

Glycyrrhizin

Glycyrrhizin is a triterpene saponin that has several biologic activities and pharmacologic properties. Recent studies have discussed the therapeutic potential of glycyrrhizin for the management of COVID-19. Glycyrrhizin has many activities as binding to angiotensin-converting enzyme II (ACE2), hindering the accumulation of intra-cellular reactive oxygen species (ROS), down regulating the proinflammatory cytokines, hindering thrombin, preventing the overproduction of airway exudates, and stimulating endogenous interferon. Recently, it was reported that the combination of glycyrrhizin /and boswellic acids is valuable in the treatment of COVID 19 due to its multi-target mode of action. It is efficient in preventing mortality, shortening the recovery time, and improving the prognosis.

Phenolics and polyphenols

Plant metabolites that have aromatic rings and one or more hydroxyl groups are called phenolics and polyphenols. In addition, they are known as polyhydroxy phenols due to the presence of multiple phenol structural units. They are considered valuable in the therapeutic field. Polyphenols include flavonoids, tannins, and rosemerinic acids. The hydroxyl group of polyphenols can interact with the positively charged amino groups of proteins thus resulting in their inhibition via destroying the 3-D structure of proteins. This unique intercalation with proteins caused the active inhibitory effects of polyphenols against various microbes and viruses. Likewise, polyphenols can react with both the virus’s protein and also DNA/RNA causing cell death. Consequently, numerous polyphenols are generally considered antiviral agents. Concerning their antiviral, anti-inflammatory, and antimicrobial significance, polyphenols may also be a valuable source of research against COVID-19 infections.

Quercetin

Quercetin originates from the Latin word “Quercetum” meaning the oak forest. Quercetin is chemically belonging to the flavones. It is the chief polyphenolic flavonoid, which could be obtained from several fruits and vegetables, such as berries, onions, apples, dill, lovage, capers, and cilantro. It could also be artificially received from supplementary tablets inclosing quercetin or some of its synthetic derivatives.

Quercetin displays major antiviral, pro-metabolic, and anti-inflammatory activities. Furthermore, researchers have discovered that quercetin supplements can support antioxidant, anti-inflammatory, anti-viral, and immune-protective activities. Recent studies have proposed the possible mechanisms by which quercetin can display its anti-COVID-19 properties. This includes (a) disturbing SARS-CoV-2 S protein interaction with ACE2, which can inhibit viral entry into its host cells. (b) Pre- venting the SARS-CoV-2 replication. Nguyen et al. have reported the inhibitory effects of quercetin against 3C-like protease (3CLpro), which is vital for SARS- CoV replication, with an IC₅₀ of 73 μM. Besides, it was verified that quercetin interacts strongly with the SARS- CoV-2 Mpro, which is a protease assisting the virus RNA translation. (c) Decreasing the cytokine storm owing to its anti-inflammatory activity.

Alkaloids

Alkaloids are a wide group of secondary metabolites (≥ 12.000 compounds) that have  at  least  one  nitrogen atom in a negative oxidation state. Alkaloids can be advantageous in our search for anti-COVID-19 to manage this pandemic. Alkaloids are mostly present in flowering plants, fungi, bacteria, and certain animal species. They are categorized according to their biosynthetic pathway as tropanes, quinolines, indoles, purines, isoquinolines, imidazoles, pyrrolidines, pyrrolizidines, pyridines, and other types. The pharmacological effects of these bioactive metabolites include antioxidant, antifungal, antimalarial, antibacterial, and antiviral activities.

Recent studies demonstrated the prospective effects of some alkaloids to be used either on their own or in combination with further medications for the management of the COVID-19 pandemic. The compounds reported with the greatest inspiring antiviral effects against SARS-CoV-2 that could be further explored by in vitro assays and clinical trials were: papaverine, caffeine, berberine, colchicine, crambescidin 786, cryptospirolepine, deoxynortryptoquivaline, cryptomisrine, 10-hydroxyusam- barensine, emetine, ergotamine, camptothecin, lycorine, nigellone, norboldine, and quinine.

Colchicine is lipid soluble, a tricyclic alkaloid. It is currently used as an anti-inflammatory drug for gout, Adamantiades–Behçet’s disease, and other auto-inflam- matory ailments, such as familial Mediterranean fever. Besides, colchicine is explored against COVID-19 infection owing to its ability to interfere with inflammatory immune responses. In addition to its influence on neutrophil activity, colchicine has resulted in a decline in the production of superoxide free radicals, reduction in tumor necrosis factor, and indirect blocking of the NLRP3 inflammasome. The NLRP3 inflammasome is a, which senses the threat and triggers local and/or systemic inflammatory responses through enhancing the pro-inflammatory cytokines, as the IL-1β. Particularly, colchicine reduces the production of cytokines to manage the inflammatory activity and stop the cytokine storm.

In addition, colchicine is considered a microtubule disassembling agent as it hinders tubulin protein polymerization. This causes disastrous effects on microtubule polymerization. Coronaviruses depend on microtubules and the cytoskeleton to enter their host cells, and also to help in the transcription and replication of viral genome. Theoretically, colchicine can inhibit the entry of coronavirus into the host cells, since the entry necessitates spike protein interaction with the cytoskeletal proteins, especially tubulin. It can further interfere with the coronavirus replication, because the microtubules are crucial to forming the double membrane vesicles in host cells, along with the assembly and the transfer of spike proteins into the virions, which are significant stages in the virus replication.

Various nations are suffering multiple waves of COVID-19 with growing stress on the health care system. Investigating plant-based therapeutic approaches including traditional medicines, bioactive metabolites, and functional foods to combat the SARS-COV-2 could provide massive achievements in our battle against the COVID pandemic. The significant therapeutic contributions of herbs and/or their active metabolites in the past made several recent research suggest their use as valuable therapies for COVID-19. They may be used alone or as complementary or alternative medicines to be able to combat COVID-19 infections. Our review indicates that many promising bioactive metabolites, plant-based herbal preparations, nutraceutical products, and functional foods showed encouraging anti- COVID effects, and they are in various stages of clinical trials to allow their use in the treatment of COVID-19. These herbal remedies may not prevent viral infection but can enhance the patient’s welfare by supporting immune system preservation. Still, the evaluation of the effectiveness and safety of these phytochemicals and herbal preparations is crucial to exploit their therapeutic properties for the management of COVID-19 patients. As a final point, COVID-19 is challenging human beings all over the world. Dealing with this pandemic necessitates efforts of each individual and global cooperation of researchers, experts, and authorities. Besides traditional herbs, numerous functional foods, healthy lifestyle choices, and dietary supplements can considerably lessen the financial strain of COVID-19 suffering patients and the death rates across the world during this pandemic.