A Brief Review on Medicinal Plants-At-Arms against COVID-19

COVID-19 pandemic caused by the novel SARS-CoV-2 has impacted human livelihood globally. Strenuous efforts have been employed for its control and prevention; however, with recent reports on mutated strains with much higher infectivity, transmissibility, and ability to evade immunity developed from previous SARS-CoV-2 infections, prevention alternatives must be prepared beforehand in case. We have perused over 128 recent works (found on Google Scholar, PubMed, and ScienceDirect as of February 2023) on medicinal plants and their compounds for anti-SARS-CoV-2 activity and eventually reviewed 102 of them. The clinical application and the curative effect were reported high in China and in India. Accordingly, this review highlights the unprecedented opportunities offered by medicinal plants and their compounds, candidates as the therapeutic agent, against COVID-19 by acting as viral protein inhibitors and immunomodulator in (32 clinical trials and hundreds of in silico experiments) conjecture with modern science. Moreover, the associated foreseeable challenges for their viral outbreak management were discussed in comparison to synthetic drugs.


Introduction
COVID-19 (Coronavirus disease 2019) caused by novel SARS-CoV-2 virus is an ongoing pandemic responsible for the loss of more than 6.8 million as of February 2023 till date [1][2][3]. It manifests from mild illness (fever, cough, sore throat, and vomit) to severe respiratory illness (pneumonia) [4]. Multiplying its high infectivity, COVID-19 has imposed unprecedented threats to human health and global economy, leading to a catastrophic crisis of the world. Globally, exceptional eforts have been employed to control, treat, and reduce the impact and spread of SARS-CoV-2. As of 2023 (three years after the WHO announced COVID-19 as a pandemic), there are at least 18 approved vaccines under mass immunization drive (Table 1 [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]). Furthermore, Food and Drug Administration (FDA) special program known as Coronavirus Treatment Acceleration Program (CTAP) also reports a single agent (antivirals, cell and gene therapy, immunomodulators, and neutralizing antibodies) and combination agents for COVID-19 treatment with nine authorized for emergency use [23]. Antiviral investigational drugs such as remdesivir (Veklury) have received emergency use authorization (EUA) for COVID-19 treatment meeting eligibility requirements [24]. Immunomodulators such as dexamethasone have also been recommended for signifcant reduction in mortality in hospitalized patients (requiring oxygen or on ventilation) [25]. Tough mass immunization drive, EUA drugs, convalescent serum, and monoclonal antibodies application are helping the world regain life normalization and confdence, there are certain high priority questions that remain unanswered in view of the longevity of the vaccine efect (requirement of booster doses; protection against mild to severe symptoms), impact of omission of long term safety assessment studies on frail, children and at-risk individuals, side efects, and above all loss in vaccine's potency against rapidly evolving and highly transmissible SARS-CoV-  [26][27][28][29]. Issues related to efectiveness, dosage, and storage related to vaccines under trial for COVID-19 were also reported (Table 1). Tus, quest for fnding a secure and efcient one-stop solution against SARS-CoV-2 and its variants will continue and we must be now prepared with the learning of our past experiences for what the future beholds. Plant-based compounds have already been used to modulate the immunity and treat diseases of humans and other animals, which is an age-old method adopted over other medical sciences [30,31]. Terefore, plant-derived compounds or phytochemicals have also been considered as potential compositions for the prevention or treatment of SARS-CoV-2. Current solutions against COVID-19 involve de novo drug/vaccine development that targets the human immune system or virus itself. Countering de novo drug/ vaccine development, target-based drug repurposing/repositioning has emerged as a fast-track advantageous alternative in terms of established safety, low cost, and knowledge acquired from previous viral outbreaks [32,33]. Medicinal plant-based traditional medicine has gained attention once again for utilization against the ongoing viral attack as evident from the increased demand of medicinal plants (e.g., ginger and turmeric) for boosting immunity in countries like the US and China [34]. Tus, in the absence of everlasting and safety issue of therapeutic modality for COVID-19, plant-based medicines (e.g., phytopharmaceuticals, plant derived secondary metabolites) explored and validated to show efective results in the past viral epidemic outbreak should be taken into prophylactic consideration.

Methods
Papers published over the past three years (i.e., from January 1 st , 2020, to February 2 nd , 2023) in public databases, including ScienceDirect, PubMed, and Google Scholar, were searched by terms "medicinal plants," "SARS-CoV-2," and "COVID-19" (Figure 1). Te published year was set to post-2020 to ensure their novelty, and the results were limited to the top 50 on ScienceDirect, PubMed, and Google Scholar to guarantee their relevance. Ten, the abstracts of each article were reviewed to assess if the articles were relevant to the topic. Te references of each article were also gone over in order to fnd additional technical approaches. Based on abovementioned inclusion criteria, the most appropriate articles were selected for review and discussion. For each article and case study included, were classifed into 3 categories: (1) reported methodology; (2) target sites; and (3) plant-based antiviral compounds (Table 2).

Status on Registered Clinical Trials with Plant-Based
Medicines and Drug Supplements. Over 8800 studies related to COVID-19 of clinical trials were ofcially reported in ClinicalTrials.gov, including 32 studies based on plantderived compounds. To provide an overview on drug supplements, with herbal and botanicals and plant-derived secondary metabolites candidates under clinical trials as the therapeutic agent against COVID-19, we mapped and analyzed two registration databases (i.e., the World Health Organization's International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov). ClinicalTrials.gov listed privately and publicly funded clinical studies conducted around the world [61]. Similarly, ICTRP is a central database containing the trial registration data submitted by the sixteen listed registries in the WHO [62]. Data  Search by ScienceDirect using the terms " medicinal plants "," SARS-CoV-2", and " antiviral compound " Search by PubMed using the terms " medicinal plants "," SARS-CoV-2" Search by Google Scholar using the terms " medicinal plants "," SARS-CoV-2", and " antiviral compound "   In silico analysis (i) Higher binding afnity with targets (i) Silybin [41] In silico analysis (i) Angiotensin-converting enzyme 2 (i) Baicalin (ii) Scutellarin (iii) Hesperetin (iv) Nicotianamine (v) Glycyrrhizin [42] 4 Interdisciplinary Perspectives on Infectious Diseases In silico analysis Molecular docking Molecular docking Molecular docking Molecular docking  [52] Interdisciplinary Perspectives on Infectious Diseases 5 Molecular docking Molecular docking Molecular docking Interdisciplinary Perspectives on Infectious Diseases supplements, and vitamins. For our study interest and comparative analyses of ClinicalTrials.gov with ICTRP, we reclassifed the data into fve major categories of amino acids, herbal and botanicals, secondary metabolites, vitamins, and minerals as shown in Figure 2(a). Studies registered under herbal and botanicals (63) and plant derived secondary metabolites (17) [63] support the curative potential of plant-based medicine against COVID-19.

Te Efect of Medicinal Plants on SARS-CoV-2. It was found that the medicinal plants efectively inhibited SARS-
CoV-2 in fve aspects: life cycle, immune responses, associated pathophysiology, role of medicinal plants, and their secondary metabolites. We have summarized the stages involved in the life cycle of SARS-CoV-2 followed by immune response developed by the host cell upon viral infection and development and associated pathophysiological response that lead to medical complications to identify the potential targets for action by medicinal plants and their secondary metabolites [75][76][77][78] (Figure 4). Basically, the life cycle of SARS-CoV-2 involves ten steps from (i) viral entry through the binding of spike (S) protein to ACE 2 (angiotensin-converting enzyme (2) receptor and priming of S protein by cellular serine proteases (TMPRSS2), (ii) membrane fusion; endocytosis and viral genome release, (iii) translation of viral protein, (iv) processing of viral polyproteins, (v) RNA replication, (vi) genomic and subgenomic transcription, (vii) genomic replication, (viii) translational of structural proteins, (ix) the formation of mature virion, and (x) its release via exocytosis. Medicinal plants and their secondary metabolites can act as spike protein, ACE2, TMPRSS 2, RdRp, 3CL Pro, and PL pro inhibitors. Synchronous to the viral life cycle progression, the host cell undergoes pryoptosis and releases damage associated signals that triggers generation of proinfammatory cytokines and chemokines leading to infammatory responses and ultimately to creation of proinfammatory feedback that causes medical complications such as pneumonia, cardiac dysfunction, acute renal injury, multiorgan dysfunction, or acute respiratory distress syndrome. Medicinal plants having antioxidant, antitussive, anti-infammatory, and immunomodulatory properties can be utilized for ailments of physiological response generated by SARS-CoV-2. Direct virus-mediated cytotoxic efect, dysregulation of the RAAS (renin-angiotensin-aldosterone system) due to downregulation of ACE2 related to decreased cleavage of angiotensin I (ANG1) and angiotensin II (ANG 2) and dysregulation of the immune response and hyperinfammation can be proposed as mechanisms for COVID-19 [76,79]. In China, the application of TCM has been acclaimed for COVID-19 prophylaxis. Trough both the network pharmacological and the literature review, Huang et al. [33] recently summarized the top fve ingredients, targets, and potential mechanisms underlying the actions of TCM (medicine/decoctions). Tey reported the role of TCM on viral protein binding and replication, suppression of cytokine storm, alleviation or elimination of excessive immune response, and organ protection. COX-2, CASP3, IL-6, MAPK1, MAPK14, MAPK8, and RELA were identifed as top fve targets in the their analyses followed by IL-17, arachidonic acid metabolic pathway, HIF-1, NF-κB, Ras, and TNF as the top fve prospective signaling pathways.

In Silico Approach: Traditional Active Compounds Can Act as Immunomodulators against SARS-CoV-2.
With the tremendous progress of computer power and artifcial intelligence, in silico approaches have been broadly adopted in the treatment of pandemic health emergencies. Sahoo et al. [80] systematically tested the potential combinations in anti-HIV drugs and vitamin C derivatives through bioinformatic tools, which implied possible less toxic regimens for the treatment against COVID-19. Tere is an urgent need for the involvement of an in silico approach in pandemic health emergencies. Chen and Du [42] concluded that baicalin, hesperidin, nicotine, and glycyrrhizin have the potential to bind to ACE2 and block the entry of COVID-19. Rudrapal et al. [81] identifed six bioactive phytomolecules with a promising anti-SARS-CoV-2 potential by in silico screening. Bharathi et al. [82] identifed fve compounds: acteoside, verbascoside, kanzonol V, progeldanamycin, and rhodoxanthin, which acted efectively against the target residues in the receptor-binding domain (RBD) and signifcantly against the Indian delta variant of COVID-19 compared with ceftriaxone. Raugh studied 65 bioactive compounds in tea leaves to provide a lead compound for NSP16 against SARS-CoV-2. Trough in silico (molecular dynamics simulation) analysis, Singh et al. [83] found that favin compounds exhibited lower binding free energy than the standard molecule sinefungin.

Challenges and Opportunities.
Synthetic drugs are often associated with treating disease symptoms and not the root cause. In fact, no less than 100,000 people each year die due to these toxicities and about 8% of hospital admissions in the

Interdisciplinary Perspectives on Infectious Diseases
United States of America are due to adverse or side efects of synthetic drugs. On the contrary, deaths or hospitalizations due to herbs are so rare that the National Poison Control Centers of the United States does not have a database for side or adverse efects of herbs. Medicinal plant mechanisms are often complicated and not straightforward [84]. Compared to the synthetic inhibitors, plant-based drugs have less toxicity and are much safer to use. It has been demonstrated that a combination of isolated active compounds is not able to mimic the whole plant efects. Tis is perhaps the reason why medicinal plants usually tend to have several broad complementary or synergistic actions on physiological systems simultaneously, usually in the same general therapeutic direction and often nonspecifc. COVID-19 remains a new disease with limited information available on its pathophysiology. Tus, prospective plant-based drug molecules must be analyzed in silico, in vitro (cell lines based assays), and in vivo (animal models) before clinical trials with a strong pharmacokinetic profle to address issues related to their efcacy potential and poor bioavailability. Di Matteo et al. [85] argued that the characterization of potential drug candidates through computer studies can improve the efciency of clinical trials. Furthermore, to amplify their chances towards qualifcation for designation as a drug molecule, novel formulation(s) must be developed in combination analyzed for their administration. Key attractions of plant-based medicines lies in their low cost, prospects for scalability, and safety; however, issues in maintenance of the quality of raw material, limited information on mechanism of action, and efcacy due to multiple components are the bottlenecks. Plant-based medicines ofer to developing countries that have limited resources to cope up with the current pandemic situation. Similarly, this situation also exists with developed countries; however, reformation/amendments in their existing regulatory policies are required. Further facilitation and incentive for interdisciplinary research in the feld of medicinal plants are also required. To highlight the current strength, weakness, opportunities, and challenges of medicinal plant vs. synthetic drugs against COVID-19, we have represented a summary of the short analysis in a SWOT format (Table 3).

Te Hidden Hands of Asymptomatic Subjects.
It is estimated that 1 in 4 of the corona patients may be asymptomatic [86]. Te fnding suggests that isolation of symptomatic subjects alone is futile and will not stop the ongoing spread of SARS-CoV-2. One of the main tasks in pandemic control and elimination would therefore be to invest in the identifcation of the largely undetected asymptomatic subjects (and hence the huge reservoirs of the virus). Terefore, "false negative" cases are not uncommon, given that the biomarkers (e.g., antigen or antibody) may fall beyond the thresholds of the limit-of-detection of each   technology. Current diagnostic approaches fall largely into two categories, i.e., polymerase chain reaction (PCR) and rapid antibody test (RDT) based. First, the PCR antigen test which detect the presence of the viral acid nucleic in the body. Second, the RDT is to detect the early immune response to the infection. If a subject is infected, their blood will contain antibodies to the virus. However, none of this is ideal, with the PCR and RDT sufering from long procedural time and specifcity problems, respectively. Mass screening is the expensive way to go and may seem to be the only way. It has been done multiple times in China. Qingdao, for example, is testing its entire population of nine million people for COVID-19 over a period of fve days. Wuhan was earlier reported to have tested over nearly 11 million of its entire population [87]. On the other hand, the devil's advocate may propose running a medicinal plant diets campaign rendering the needs for mass screening instead (or at least as complementary measure). Tis may be one of the acid tests placed highly in postlockdown pandemic management.

Te Trone of Personalized Medicine.
One of the Holy Grails to speed up the translational use of medicinal plants is through the active employment of modern spectrometers to check on the herbal authenticity (or otherwise its toxicity) and the metabolism of the herbs in a highly regulated and reproducible manner. Not until the 1960s, structural elucidation of natural products used to be a time-consuming complicated process requiring technical skill. It relied almost entirely on degradative chemistry or elemental analysis of the crystallized material. With the advent of spectroscopic techniques (e.g., nuclear magnetic resonance (NMR), ultraviolet, and infrared) and mass spectrometry, new structural biology is solved typically within hours (if not days).
Of those four modern techniques, NMR is the most rapid (in minutes), robust, and relatively high sensitivity, requiring only submilligram quantities of amorphous products [56]. It provides detailed information both on the frequency domain (e.g., chemical shift) [88] and time domain (e.g., relaxometry) [88,89] from a whole range (library of pulse sequences) of highly informative two-and multidimensional spectra. 2D NMR-based metabolomic (coupled with multivariate analysis) can be used to extract information on targeted compound analysis, metabolic profling, metabolomics fngerprinting, and metabolic analysis.
It is worth noting that the administration of active compounds (in the form of pure chemical) and that of a plant extract containing the same chemical entity is essentially diferent in their bioavailability as well as mode-of-actions [90]. Humans are faced with the reality that life forms and living organisms are in general complex. Tus, the rise of functional assays (e.g., functional genomics, functional proteomics) in the era of postgenomics is not an unexpected one.
Recent reports on functional phenotyping using low-feld NMR-based micro scanner (e.g., malaria [90][91][92][93], diabetes mellitus, hemoglobinopathies, and trauma-emergency) on live biological cells/tissues (ex vivo) obtained directly from patients open up new opportunities in in vitro diagnosis in personalized manner [94][95][96][97]. NMR-based microscanner is the scaled down version of a large and expensive MRI machine which is being used clinically to map out the human body noninvasively. Te same noninvasive technology can be used to map a single drop of blood using much simpler and compact hand-held instrumentation [98]. Miraculously, a single drop of blood contains enormous amounts of untapped complex information (and yet patient-specifc and time-unique) at the molecular level akin to unique molecular QR-code (or "molecular fngerprint") [95] as the attribute of various physiological and pathological states. Te complex signatures were extracted using two-and multi-dimensional time-domain NMR correlation spectroscopy and deciphered with the help of machine learning for disease classifcation [95,99,100] (e.g., diagnosis and prognostic) is making fast in-road into medical research and the clinical translational stage [99,100].

Recent Development of Medicinal Plant in the Post-Pandemic Era.
As the governments around the world have liberalized the control of the pandemic, great outbreak seems have pasted. However, there are still possibilities of another virus mutation and consequent widespread infection. Strenuous eforts are still of need for seeking the treatment method, including the medicinal plant-based way.
According to TCM, the clinical manifestations of COVID-19 infections fall into two categories, one being respiratory symptoms and the other being digestive symptoms. During the recovery period, if the patient's lung and spleen functions have not fully recovered, the patient will sufer from weakness and shortness of breath; if the patient has a defciency of the spleen and liver wood, the patient will sufer from insomnia. Furthermore, there will be a legacy of taste and smell disorders if the functions of the lungs and spleen of the patients are not fully restored, as the lungs are associated with the nose and the spleen with the mouth. Abovementioned has shown that treatment during the recovery period is mainly directed at the two organs, the lung and the spleen; thus, the clinical treatment can be based on formulas that promote the lung, moisten the lung, strengthen the spleen, and resolve dampness. Luo et al. [65] stated that the most frequently used medicinal plant included Radix astragali (Huangqi), Radix glycyrrhizae (Gancao), and Radix saposhnikoviae (Fangfeng). In South America, Arun Dev Sharma found eucalyptus (Eucalyptus globulus Labill.) to be an efective antiviral agent against SARS-CoV-2. Janenone, a vital essential oil from Eucalyptus globulus oils, can penetrate nonspecifcally into the lipid bilayer of the virus and alter the fuidity of the membrane and has antiviral efects against the main protein of SARS-CoV-2 [101,102]. Safa et al. [103] administered a 1000 mg dose of ginger tablets three times a day for three months to COVID-19 infected patients and found clinical improvement in symptoms including fever, dry cough, and malaise.

Conclusion
In short, COVID-19 outbreak is unfortunately not the frst viral outbreak or the last one. Tis pandemic which came (and went) like a storm had left many of us pondering about the fate of humanity with respect to disaster control. Can we ever learn to live in harmony with Nature? Or made to eat the humble pie in the name of economic progress? Medicinal plants have been in existence as long as human beings have existed on this planet earth. It is said that there is a natural cure for every disease on earth. We humbly appeal to the authority, researcher, and society at large to look seriously into the huge potential of medicinal plants and their secondary metabolites. With intensifed efort to develop this platform into evidence-based medicines, what was once an "alternative medicine" can work in synergy with "mainstream medicine." Human society can utilize current COVID-19 adversity as a window of opportunity for change and an hour to adapt plant-based medicine for a new era of sustainable health.

Data Availability
Data used to support the fndings of this study are available upon reasonable request from the corresponding author.

Conflicts of Interest
Te authors declare that there are no conficts of interest.