Medicinal Plants, Phytomedicines and Traditional Herbal Remedies for Drug Discovery and Development against COVID-19

By Mithun Rudrapal and Chukwuebuka Egbuna

This comprehensive reference explores medicinal plants, phytomedicines, and traditional herbal remedies as potential sources for the prevention and treatment of COVID-19. It features 9 chapters authored and edited by renowned experts.  The book specifically highlights the promising drug discovery opportunities grounded in bioactive compounds from medicinal plants and herbal medicines, offering insights into combatting SARS-CoV-2 infections and respiratory complications.
 
Key Highlights:
 
Drug Discovery Potential: Explores the vast potential of medicinal plants, phytomedicine, and traditional remedies against COVID-19, shedding light on groundbreaking drug discovery avenues.
Cutting-Edge Insights: Provides up-to-date insights into the use of medicinal plants, herbal drugs, and traditional medicines in the fight against COVID-19.
Natural Immune Boosters: Details the use of indigenous herbs, spices, functional foods, and herbal drugs for boosting immunity and preventing SARS-CoV-2 infections.
Drug Repurposing: Highlights innovative drug repurposing strategies using phytomedicine-derived bioactive compounds and phytochemical databases for COVID-19 drug development.
 
Additional features of the book include a reader-friendly introduction to each topic and a list of references for advanced readers. This timely reference is an informative resource for a broad range of readers interested in strategies to control COVID-19, including postgraduate researchers, and pharmaceutical R&D experts. It also serves as a handbook for professionals in clinical and herbal medicine.

• Language: English
• Publisher: Bentham Science Publishers
• Release date: Nov 5, 2023
• ISBN: 9789815049510

Mithun Rudrapal

Mithun Rudrapal is an Associate Professor and Head at the Department of Pharmaceutical Chemistry, Rasiklal M. Dhariwal Institute of Pharmaceutical Education and Research, Pune, India. Dr. Rudrapal has been actively engaged in teaching and research in the field of Pharmaceutical and Allied Sciences for more than 12 years. He has over 100 publications in peer-reviewed international journals to his credit and has filed a number of Indian patents. In addition, Dr. Rudrapal is the author or editor over a dozen published or forthcoming books or book chapters. Dr. Rudrapal works in the area of Medicinal Chemistry, CADD, Pharmacology, Drug Repurposing, Phytochemistry, Herbal Drugs and Nanophytotherapeutics. His research interests include discovery and development of drugs for infectious diseases, diabetes and inflammatory disorders from synthetic as well as plant sources.

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Phytoconstituents from Mother Nature against SARS-CoV-2/ COVID-19

Neelesh Kumar Nema¹, *, Swapnil Devidas Khamborkar¹, Smitha Sarojam¹, Baby Kumaranthara Chacko¹, Viju Jacob¹

¹ Nutraceuticals Division, C.V.J. Creative Centre-Bioingredients, Synthite Industries Pvt. Ltd., Synthite Valley, Kadayiruppu 682 311, Ernakulam, Kerala, India

Abstract

Coronavirus disease-2019 (COVID-19) is a pandemic disease due to the infectious virus Severe Acute Respiratory Syndrome-CoronaVirus-2 (SARS-CoV-2). Scientifically validated phytoconstituents sourced from Mother Nature are now an area of interest and targeted approach as a worldwide prophylactic measure against SARS-CoV-2. This section focuses on providing a clear understanding of the structure of SARS-CoV-2 as well as verified phytoconstituents from traditional medicine (TM) for addressing the virus with all feasible targets. Target-specific inflammatory pathways triggered by SARS post-infection include NLRP3, Metallopeptidase Domain 17, JAK-STAT, p38-MAPK, endocytosis pathways e.g. Clathrin, HMGB1 as well as associated interleukins and cytokines are primarily highlighted, which directly or indirectly trigger the immune system and play a significant role. Selected Indian medicinal herbs and their possible leads are detailed below, with the goal of focusing on specific routes with a high likelihood of preventing pandemics in the future.

Keywords: COVID-19, Coronavirus, Mother Nature, Phytoconstituents, SARS-CoV-2, Traditional Medicine.

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* Corresponding author Neelesh Kumar Nema: Nutraceuticals Division, C.V.J. Creative Centre-Bioingredients, Synthite Industries Pvt. Ltd., Synthite Valley, Kadayiruppu 682 311, Ernakulam, Kerala, India; Tel: [phone]; Fax: [phone]; E-mail: [e-mail]

INTRODUCTION

SARS-CoV-2 (Severe Acute Respiratory Syndrome-Coronavirus-2) is the virus that causes the COVID-19 pandemic. This zoonotic virus is quite tiny (65-125 nm in diameter), but it affects people all over the world [1]. According to the International Committee on Taxonomy of Viruses (ICTV), SARS-CoV-2 belongs to the Coronaviridae family, and its genome is made up of a positive-sense single-stranded RNA [(+) ssRNA] virus with a size range of 30 kbs [2-5]. Out of the existing two major variants, L (~70%) is more aggressive and infectious compared to S type (~30%) [6]. Coronavirus replicates inside the host

cell and is responsible for severe health issues, especially for respiratory illness, e.g. severe pneumonia [7] further morbidity and also for mortality [8]. SARS-CoV-2 is more severe than other viruses in a similar category [1]. On the 31st of December, 2019, China officially declared instances of pneumonia related to an unknown cause for the first time [9]. From that day onwards, the numbers are increasing at an exponential level. Situations are still very complicated and even after the vaccination program, people are affected by this virus with a new variant, namely, Omicron. After almost 2 years of completion, 271,963,258 confirmed cases are reported from 224 countries, areas, or territories. Therefore far, a total 5,331,019 number of deaths are confirmed globally as per Worldometer- 17 December 2021 at 5.14 am [10].

Antiviral drugs [11] and clinically/FDA-approved vaccines against COVID-19 [12] are the primary and immediate solutions to manage this pandemic condition. Antimicrobial includes antibacterial and antiviral; antibiotic, antimalarial, anthelmintic, human amniotic fluid (hAF), Type 1 Interferons (IFNs), Monoclonal antibody (mAb), Convalescent plasma therapy and mesenchymal stem cells (MSCs), and various vaccination programms are some of the other prospective treatment alternatives that are in use and being researched [11], however other health-associated complications are also diagnosed, which can persist prolong and very difficult to normalize the patient. Not to forget, the recurring frequency of COVID-19 is also very high even after full vaccination with the proper dose recommended by the inventor companies and standard instructions released by WHO. In silico computational docking technologies are still being used by researchers to find and locate compounds of virtual ligands from chemical databases that already exist [12, 13]. Considering the pandemic situation and the alternative solutions, researchers are also considering preventive attitudes instead of curative approaches by which people can immunize their body system against this virus. Natural products and traditional systems of medicine could be an alternate source to answer this intricate problem. Plants may be the best source since they grow in Mother Nature's environment and habitat in a variety of extreme climates to survive their existence and nourishment. Some plants with high immunomodulatory properties and the ability to protect against infectious outbreak infection during sensitive seasonal changes must yet be studied scientifically to determine the mechanisms by which they function against this viral outbreak. To obtain an alternative source from Mother Nature and to brighten the dark, one must first comprehend the nature of the virus, its replication, pathophysiology, and implications on the bodily organs. This chapter provides a quick overview of viral structure, structural and nonstructural proteins, pathogenesis, and method of action, with a focus on potential targets for virus suppression and alternative treatments as preventative medicines. The findings from attentive knowledge were extracted using Elsevier Scopus database information about traditional medicine. Further, Indian medicinal plants recommended by the Government of India were also considered in this study [14]. In all, 20 plants are featured here, and via this strategy, the research community and scientists will receive access to information on plants that might be the key to a future solution to the SARS-CoV-2 outbreak.

MATERIALS AND METHODS

SARS-CoV-2 and Phytoconstituents Data Collection

The title SARS-CoV-2 was searched using Scopus, an online database tool from Elsevier https://www.scopus.com/home.uri with the language limit set to English only. The database was searched for published literature, which was then filtered using the subject matter keywords phytomedicine/phytoconstituents from medicinal plants as anti-SARS-CoV-2 treatments [15]. From an Indian perspective, some of the potential medicinal plants compiled by scientists at the National Medicinal Plants Board (NMPB), Department of AYUSH (Acronyms: Ayurveda, Yoga, and Naturopathy, Unani, Siddha, and Homeopathy), Government of India, are also taken into account in this study for naturally boosting the immune system [14].

Information Evaluation

The information is summarized as follows:

Structure of SARS-CoV-2 and it’s replication; possible potential targets and also phytoconstituents-alternative as a preventive medicine.

RESULTS

SARS-CoV-2 and Ethnomedicinal Plants

To conclude the study, global publications on pandemic SARS-CoV-2 including medicinal herbs and their phytoconstituents were reviewed and downloaded from the Elsevier Scopus database. Scientists and academicians from various countries, including the United States, India, the United Kingdom, Italy, and China, have been observed to publish the greatest number of articles with their co-authors for the keywords SARS-CoV-2 in conjunction with phytochemical, herbs, spices, phytomedicine, phytotherapy, and phytoconstituents.

Medicinal plants that have been utilized in the Indian System of Medicine (ISM) since antiquity [16] and that are prevalent in the list of plants advised combating COVID-related disorders are chosen based on publications, cost-effective affordability, and stress-free availability, and are explained in detail. i.e., Andrographis paniculata (Burm. f.) Wall. ex Nees, Azadirachta indica A. Juss, Cinnamomum verum Presl, Clerodendrum serratum (L.) Moon, Curcuma longa L., Cymbopogon jwarancusa (Jones) Schult, Glycyrrhiza glabra L., Hedychium spicatum Sm., Inula racemosa Hook.f., Justicia adhatoda Medick., Illicium verum Hook.f., Ocimum basilicum L., Ocimum tenuiflorum L., Phyllanthus emblica L., Pichrorhiza kurroa Royle ex Benth., Swertia chirata Buch.-Ham. ex Wall., Syzygium aromaticum (L.) Merr. & L.M.Perry, Tinospora cordifolia (Willd.) Miers. Withania somnifera (L.) Dunal, Zingiber officinale Roscoe. These plants are summarized in Table (1).

Table 1 Medicinal plants and associated active phytoconstituents for boosting immunity and protecting from viral infections (COVID-19) [14].

To better comprehend how these medicinal plants and their derivatives operate, the morphological aspects of SARS-CoV-2 and its pathogenesis are outlined.

SARS-CoV-2 Morphological Features and Structure

Fig. (1) shows the anatomy and genetics of SARS-CoV-2. Like other viruses, SARS-CoV-2 has two separate sections that comprise structural protein and functional genomic proteins. The 5'-untranslated regions (UTR) of all beta coronavirus genomes contain roughly sixteen (16) open reading frame (ORF) genes associated with nonstructural proteins (NSPs) and ten (10) open reading frame (ORFs) genes associated with structural proteins (SPs). ORF1a encodes 1-11 NSPs for polypeptide pp1a translation, whereas ORF1b encodes 12 to 16 NSPs for polypeptide pp1ab translation. The structural core consists of four operational proteins: spike (S protein with 180-220 kDa), envelope (E protein with 9-12 kDa), membrane (M protein with 23-35 kDa), and distinct protein nucleocapsid (N protein with 50-60 kDa-inside the structural envelope), as well as a large number of unknown non-structural genes at the 3'UTR [42]. All three S, M, and E structural proteins aid in the development of a viral structural coat, whereas N protein aids in the packing of the RNA genome and the transmission of genetic information to other virions [13].

Fig. (1))

Coronavirus and associated genomes (Structural and nonstructural proteins responsible for virus replication).

In the replication process, each structural protein has a distinct function and purpose. This virion particle has a club-shaped surface projecting spikes on the outer coat that give it a crown or coronet-like look, thus the name coronavirus [26]. Virion-cell membrane fused to the host cells via a highly glycosylated trimeric spike protein [43] that is composed of two subunits that are S1 and S2 [1]. These proteins help virus cells in attaching, replicating, and exiting from the host cells [44].

SARS-CoV-2 Replication in the Host Cells

Adhesion and invasion occur on the host cell's surface, whereas endocytosis, biogenesis, development, and release (all phases of viral reproduction) occur within the host cell. Fig. (2) depicts the CoV life cycle in the host cell.

Fig. (2))

Attachment of the viral S protein to host receptors, endocytosis, release of the genetic sequence ssRNA(+) into the host cytoplasm, replication and generation of new ssRNA(+) genomes, and exocytosis are all part of the CoV life cycle in host cells.

Interactions with the Host Cell

Bats were shown to be the carriers of major alpha and beta-CoV species, according to studies. It spreads from the bat to human populations mostly through respiratory secretions [2]. The virus's spike protein interacts to the surface receptors of the host cell through angiotensin-converting enzyme 2. (ACE2) [4], especially in human lungs leading to pulmonary edema [45]. Spike proteins interact with host cells through two different surface receptors: ACE2 and dipeptidyl peptidase 4 (DPP4) [46]. Through a receptor recognition pattern, ACE2 aids in the binding of coronavirus to host cells. It causes chemical changes in the host membrane, allowing virion particles and their genetic sequences to pass through. The N-terminal domain of spike protein S1 plays an important function in the contact phase with the host cell, whereas the C-terminal region of spike protein S2 assists in changing the conformation and inclusion of the virion genome into host cells. When comparing the SARS-CoV and SARS-CoV-2 gene sequences, it was observed that the amino acids serine and proline in SARS-CoV-2 are replaced with glycine and isoleucine in SARS-CoV at positions 723 and 1010, respectively, in transmembrane helical sections, especially ORF1a [47]. SARS-CoV-2 is spreading rapidly as a result of the foregoing modifications. This material will need to be looked into further to fully comprehend and explain the mechanics of viral transmission.

Fusion of Genomes

The viral S protein consists of an ectodomain, transmembrane anchoring, and a short intracellular tail. The lysine encoding human ACE2, or G protein-coupled receptor, binds to virion particles. The Ang II type 1 receptor (AT1-R) is connected to cardiovascular and renal functions, whereas the Ang II type 2 receptor (AT2-R) is related with binding affinity [48]. Following effective binding, protein Trans-Membrane Serine Protease 2 (TMPRSS2) began a series of enzymatic changes [11]. The operation of viral membranes to merge with the host plasma membrane is required for this conformational shift, allowing genomes to enter host cells. Replication mechanisms begin in the host cytoplasm after the nucleocapsid is liberated [49]. This is a crucial target-concerned stage for governing and managing the virus's entry into the host cells.

Replication (Transcription and Translation)

Open reading frames ORF1a and ORF1b create the pp1a and pp1b replicase polyproteins (PPs) [49]. Both pp1a and pp1b are lengthy polypeptides that help build the replication transcription complex (RTC). They share the instruction to host ribosomes for translation via the Replication-Transcription Complex (RTC) mechanism, allowing them to produce virus-transcribed proteinases e.g. papain-like protease (PLpro) required for functional replicase and chymotrypsin-like proteins (CLpro) for disruption of proteins into distinct amino acids. This proteinase cleaved its polypeptides to make viral surface proteins. Aside from the aforementioned, one of the RNA-dependent RNA polymerase (RdRp) enzymatic proteins also generates the Replication Transcription Complex (RTC), which copies the viral genome and creates a total number of sixteen predicted non-structural proteins (NSPs1-16) while also assisting in the synthesis of (-)ssRNA. This pattern carried genetic information as well as structural protein knowledge, which was then translated to single-standing RNA [50].

Exit from the Host Cell

The endoplasmic reticulum (ER) Golgi intermediate compartment (ERGIC) complex receives structural proteins. Replicated genomes attach to the N protein and form ribonucleoprotein (RNP) complexes in parallel. Finally, the ERGIC body aids in the formation of a predeveloped virion particle by assisting in the association of all necessary and needed proteins. The resulting particles then enter the Golgi complex, where they develop smooth wall vesicles. Exocytosis occurs when fully formed virion particles contact with the plasma membrane and come out from the host cell's intracellular matrix. This process is repeated inside the host cell, and the virion particles can make many copies of the infectious particles.

Targets for Therapeutic Intervention

Bats carry SARS-CoV, an unanticipated human illness. Bats, to their surprise, are immune to coronavirus protein-mediated reactions [51]. Because of the bat's extended life expectancy and high CoV resistance, researchers are currently concentrating their efforts on determining what site-specific targets may be used as a prophylactic measure against SARS-CoV-2. To contract the virion particle and regulate the effects, there are two sorts of focused techniques.

Pre-Viral Infection Targeted Approaches

The genes that code for structural protein S subunits S1 and S2 might be a potential target for preventative medicine [52]. Other potential benchmark targets for building novel medications and supporting treatments are proteolytic processing mechanisms [13]., such as 3CLpro, PLpro, and RdRp [53]. Approaches against COVID-19 include antiviral formulations that block virus absorption or attachment to host cells, which work on upper and lower respiratory tract infection [54, 55].

Post-Viral Infection Targeted Approaches

Inflammatory Oriented Targets

The principal and prominent mechanism against SARS CoV and MERSCOV infection is the inhibition of the NLR family pyrin domain containing 3 (NLRP3) pathway. Infection activates this pathway by causing a triggering protein to be produced [56]. Surprisingly, even in the face of high viral strain, this protein is suppressed in bats compared to humans and mice [51]. Bats have a longer lifetime and a stronger capacity to live in the presence of numerous viral reservoirs without any infection [57, 58], which is a subject of research. Scientists can block this route and discover a COVID-19 alternative.

Pathogen Associated Molecular Patterns (PAMPs) bind to TLR3/4 and affect the total recordable injury frequency (TRIF) and Myeloid differentiation primary response protein (MDPRP) pathways individually (MyD88). MyD88 then activates p68, p50, and an inhibitor of kB (Ikb), before sending a message to NF-kB and Mitogen-activated protein kinases (MAPKs) for a subsequent reaction. These chemicals cause the synthesis of cytokines like Pro-IFN-1 and Pro-IFN-18 by activating the modulator of extracellular signal-regulated protein kinase (ERK1) pathways [59, 60]. The ATP-dependent NLRP3 inflammasome transforms these two pro-signaling proteins Pro-IFN-1 and Pro-IFN-18 into the active metabolite form IFN-1 and IFN-18 with the help of Apoptosis-associated speck-like protein containing a CARD (ASC) and controlled caspase-1 proteins [61].

Through the MyD88 pathway, active cytokines further stimulate the NLRP3 inflammasome and generate interleukins, such as IL-1., Fig. (3) illustrates the NLRP-3 and other associated pathways.

SARS-CoV-2 REPLICATION

Inflammatory cytokines released by T and B cells regulate the NLRP pathway in the lungs [62].

The activation of NLRP3 and its mechanism are complexes [60], however, NLRP3 might be a target for SARS-CoV-2 prevention because this pathway is more active in bats than in humans [58]. The p38 MAP kinase pathway may be the target for developing a promising COVID-19 therapy approach [63]. Angiotensin-Converting Enzyme 2 (ACE2) converts to ACE 1-7 on the normalized cell surface. Because the ACE2-associated p38 MAPK pathway could not activate as a result of this conversion, proinflammatory cytokines including IL-6, TNF-α, and IL-1 could not be released. This conversion is disrupted during the virus's entrance. The Ang II-dependent p38 MAPK pathway is triggered when Ang II levels rise, triggering a flood of proinflammatory cytokines. To normalize and to counter-balance, Ang 1-7 inhibits the release of the cytokine; however, during viral entry, it reverses and activates the linked cytokines [64]. Chloroquine (CQ), an antimalarial drug, functions similarly by blocking the p38 MAPK ERK activators [65]. This elaborative fact suggests that inhibiting the p38 and ADAM17 pathways might be a new possible target for avoiding this virus, and researchers are currently working to develop a formula that inhibits the same process without interfering with other essential pathways.

Fig. (3))

Inflammatory mechanisms that may exist during the post-infection period; Virus-infected alveolar epithelial cells respond by activating p38-MAPK and TLR4 pathways, among others. HMGB1 pathways that are reliant on DAMP and PAMP.

Immunomodulatory Targets

SARS-CoV-2 uses the surface receptor ACE2 to infect alveolar epithelial type 2 cells (AEC2). Host cells produce an excessive number of pro-inflammatory cytokines in response to viral infection, resulting in a 'cytokine storm.' T lymphocytes, particularly CD4+ T and CD8+ T lymphocytes, regulatory T (T reg) cells, antigen-specific T cell (memory T cells), natural killer cells, and B lymphocytes (B cells) are all affected by virus-mediated responses following SARS-CoV-2 infection [6]. JAK3, on the other hand, regulates lymphocyte function and is connected to hematopoietic activity. SARS-CoV-related activities are controlled by interferon factors such as IFN-β and IFN-γ,which modulate the Tyk2 and JAK2 pathways. JAK inhibitors (JAKinibs), which block the JAK-STAT subfamilies and type I/II cytokine receptors, are another option for preventing and regulating the 'cytokine storm,' as depicted in Fig. (4) [48]. Except for JAk-STATE, AP2-associated protein kinase-1 (AAK1; Adaptor-associated protein kinase 1) and cyclin G-associated kinase (GAK), which is mediated by clathrin-mediated endocytosis (CME) [66], are also involved in lung cell regulation. This might be a one-of-a-kind target for therapeutic development in the fight against SARS-CoV-2 infections [67]. Suppression of High-Mobility Group Box 1 (HMGB1), particularly activates the innate immune system and stimulates severe pulmonary inflammation, including COVID-19 [68], is another intriguing and new potential treatment. Several herbal remedies have been shown to successfully suppress HMGB1 secretion [69]. Furthermore, the NF-κB is found to regulate the creation of several pro-inflammatory cytokines, either directly or indirectly as a consequence of T helper cell activation. At an infection site, the cytokines IL17 restore monocytes and neutrophils and initiate a cascade of cytokine and chemokine cascades, including IL1, IL6, IL8, IL21, TNF (lymphotoxin-alpha), and Monocyte Chemoattractant Protein-1, a member of the C-C chemokine family (MCP-1) [70].

Fig. (4))

JAK/STAT Pathway; JAK/STAT-Mechanism and possible targets for inhibiting it.

T cells are required for adaptive defense against viral infections. CD4+ helper T cells (Th) aid B cells in the production of virus-specific antibodies, whereas CD8+ cytotoxic T cells (Tc) can kill virus-infected host cells. Infected individuals showed significantly higher levels of proinflammatory cytokines that are critical to COVID-19 patients. Total lymphocytes were found to be very low, although IL-6 and IL-10 both were found to be enormously high and contributed a vital part in the cytokine storm [71].

These findings suggest that targeting cytokines as a treatment strategy against the COVID-19 epidemic might be beneficial and preventative. High levels of proinflammatory cytokines, such as IFN-α and IFN-γ, lead to the spread of infectious and serious illnesses. IL-6 and IL-10 were also observed to be abundant in other studies [62, 63, 72, 73] suggesting that these interleukins are notable and might be the primary targets for inhibiting and reducing the infection associated with SARS-CoV-2 patients. COVID-19's humoral immune response has received little investigation thus far [74].

Remedies involving IgG and/or IgM antibodies might be a priority for COVID-19 researchers. In one investigation, 285 SARS-CoV-2 patients with virus-specific immunoglobulins IgG and/or IgM were found to be positive nineteen days after the first symptom appeared [75, 76]. Antibodies (IgG and IgM) were found to be high in 338 hospitalised patients in a similar study, however, the elevated levels of immunoglobulins were not sustained over time. In most patients, IgM levels rose after the first week of SARS-CoV-2 infection and peaked after two weeks. Only 1 week later, it was decreased to its original levels, and the level was maintained for a long time [74].

Because bats have a high tolerance for virus-related illnesses and because interferon has been shown to protect bats from virus-related infections, there is potential for developing strategies that are closely linked to the generation of immunoglobulins as a medicine for preventative care against this virus [77]. Natural immunomodulators derived from medicinal plants and their phytoconstituents [78] might be a valuable source for developing SARS-CoV-2 preventative medication, based on the aforementioned findings.

Solutions for the Treatment

Antiviral and antimalarial medications, as well as other possible treatment approaches such as anthelmintic, human amniotic fluid (hAF), Type 1 Interferons (IFNs), Monoclonal antibody (mAb), Convalescent plasma therapy and mesenchymal stem cells (MSCs), and various vaccination programms are in use and being researched to address this significant disease [11]. Ribavirin interacts with and binds the RdRp target site; Sofosbuvir suppresses nucleotide polymerase enzyme; Lopinavir and Ritonavir controls protease enzyme