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Review

COVID-19 Prophylaxis Efforts Based on Natural Antiviral Plant Extracts and Their Compounds

by
Oksana Sytar
1,2,*,
Marian Brestic
1,3,*,
Shokoofeh Hajihashemi
4,
Milan Skalicky
3,
Jan Kubeš
3,
Laura Lamilla-Tamayo
3,
Ulkar Ibrahimova
5,
Sayyara Ibadullayeva
5 and
Marco Landi
6,*
1
Department of Plant Physiology, Slovak University of Agriculture, A. Hlinku 2, 94976 Nitra, Slovakia
2
Department of Plant Biology, Institute of Biology, Kiev National, University of Taras Shevchenko, Volodymyrska, 64, 01033 Kyiv, Ukraine
3
Department of Botany and Plant Physiology, Faculty of Agrobiology, Food and Natural Resources, Czech University of Life Sciences Prague, Kamycka 129, 16500 Prague, Czech Republic
4
Plant Biology Department, Faculty of Science, Behbahan Khatam Alanbia University of Technology, 47189-63616 Khuzestan, Iran
5
Institute of Molecular Biology and Biotechnology, Azerbaijan National Academy of Sciences, Matbuat Avenue 2A, Az 1073 Baku, Azerbaijan
6
Department of Agriculture, Food and Environment, University of Pisa, 56126 Behbahan, Italy
*
Authors to whom correspondence should be addressed.
Molecules 2021, 26(3), 727; https://doi.org/10.3390/molecules26030727
Submission received: 18 December 2020 / Revised: 27 January 2021 / Accepted: 27 January 2021 / Published: 30 January 2021
(This article belongs to the Special Issue Antiviral Properties of Natural Products)
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Abstract

:
During the time of the novel coronavirus disease 2019 (COVID-19) pandemic, it has been crucial to search for novel antiviral drugs from plants and well as other natural sources as alternatives for prophylaxis. This work reviews the antiviral potential of plant extracts, and the results of previous research for the treatment and prophylaxis of coronavirus disease and previous kinds of representative coronaviruses group. Detailed descriptions of medicinal herbs and crops based on their origin native area, plant parts used, and their antiviral potentials have been conducted. The possible role of plant-derived natural antiviral compounds for the development of plant-based drugs against coronavirus has been described. To identify useful scientific trends, VOSviewer visualization of presented scientific data analysis was used.

Graphical Abstract

1. Introduction

COVID-19 was characterized and announced as a pandemic on 11 March 2020. The novel coronavirus was first reported in Wuhan, Chinaand spread around the world from there. On 12 February 2020, the WHO announced a name for the new coronavirus disease: COVID-19, which became the fifth recorded pandemic since the 1918 influenza outbreak [1,2,3]. Across the world, governments supported safety by minimizing human contact through country-wide lockdowns of public places, limiting gatherings, imposing quarantines. and mandating mask wearing in public and social distancing. These measures did help to slow the spread of SARS-CoV-2 [4,5]. Major efforts were undertaken to develop vaccines and to find effective drugs and therapies to reduce infectivity. At time of writing, there are more than 50 vaccine candidates under development [6,7], and the WHO has already listed the Pfizer-BioNTech vaccine for emergency use. At the same time, antiviral extracts and compounds with the potential to limit virus transmission or block infection are also being developing [8]. Plant production technology is being adopted to create vaccines and inexpensive antiviral proteins [9]. Different kinds of plants such as turnip, potato, tobacco, and others have been used for vaccine production [10].
At the same time, it is important to educate people in the use of plants that help to support the immune system, and to establish research programs to develop functional foods such as probiotics that can suppress viral infection. Naja and Hamdeh (2020) described a multi-level action plan to support optimal nutrition at the individual, societal, and national levels during the pandemic [11]. The main goal was to maintain a healthy diet, but this must be supported by creating a comprehensive scientific database on herbal products and plant derivatives, which can be used to prevent or treat illness in many different countries. The types of bioactive compounds from crops and herbs and the mechanism of their support of the human immune system against infections have been thoroughly discussed, along with the absence of evidence for SARS-CoV-2 transmission through the food chain [12,13].
Plants represent a major source of chemo-diversity on the planet, and it is likely that some safe and effective plant compounds can be found that could help to protect human lives from the devastation of COVID-19. In the scientific databases, there are huge numbers of research articles about the antiviral, antifungal, antibacterial, antiviral, and anthelmintic activities of medicinal herbs and crops with different ethnobotanical background [14,15,16,17]. Connections between the health effects of medicinal plants and presence of specific secondary metabolites which can be responsible for some effects are also described. It was suggested that terpenoids, alkaloids, stilbenes, and flavonoids are the main biological active compounds for the development of antiviral plant-based drugs [18]. To search antiviral plant-based drugs among such a large quantity of scientific data, however, caution must be used to guard against misinformation and bogus recommendations.
As a complement to the recommended COVID-19 prophylaxis, the evaluation of the effectiveness of plant extracts of different medicinal herbs and crops and natural antiviral compounds could be included in randomized controlled testing of large populations. Therefore, the present review presents detailed characteristics of medicinal plants and crops based on their ethnobotanical background, the plant part used, their antiviral potential, and already known plant-based antiviral compounds. To develop further scientific trends for the prophylaxis of COVID-19, VOSviewer visualization was used.

2. Results and Discussion

2.1. Ethnobotanical Background of Plants with Antiviral Potential

During the pandemic, many scientists have concentrated on how best to take care of the population before a vaccine becomes available. One of their goals is to develop an efficient viral inactivation system by exploiting naturally occurring antiviral compounds from medicinal plants. One example of this strategy would be to incorporate such a compound into nanofiber respiratory masks [5]. The contemporary clinical efficacy and safety profile of medications such as hydroxychloroquine and half synthetic antibiotic azithromycin against COVID-19 have been described as well [19]. Another strategy is to enhance people’s antiviral immune response through a nutritious diet including plant-derived supplements characterized by high antiviral potential to minimize the risk of SARS-CoV-2 and similar infections. At the same time, natural antiviral plant compounds can be used to develop antiviral plant drugs. Several studies on the antiviral potential of plant extracts have been conducted using in vitro model systems of cultured Vero cells or human cell lines as a pre-clinical stage of research. During the SARS-CoV-2 pandemic, researchers have been taking advantage of molecular docking models for testing chemical libraries for bioactive compounds [20]. These new techniques have been utilized together with pharmacological network analysis to characterize biologically active compounds from fruits of Juniperus communis and herbs such as Thymus vulgaris, Curcuma longa, Rosmarinus officinalis, Ocimum basilicum, Melissa officinalis, and Mentha piperita [21]. It has been shown that quercetin from onions (Allium cepa), apples (Malus domestica), green tea (Camellia sinensis) and buckwheat (Fagopyrum esculentum) can inhibit the 6LU7 and 6Y2E proteases of SARS-CoV-2 by binding to them [20,22]. The latest information from the literature on plants with antivirus potential is presented in Table 1. This table lists the medicinal plants as therapeutic tools to suppress various viral agents such as Herpes simplex virus type 1 and 2 (HSV-1, HSV-2), human immunodeficiency virus (HIV), SARS-CoV-2, HCoV-NL63, influenza A, and others causing diseases such as oral and genital herpes, AIDS, SARS, or flu.
Viruses can develop resistance through mutation to current antimicrobial agents, and this increases the need for the discovery and development of new effective compounds against old and new viral infections, especially against SARS-CoV-2. The source of such drugs is often a library of plant-derived compounds with antiviral properties and various mechanisms of action. Secondary metabolites such as terpenes, flavonoids, alkaloids, saponins, and stilbenes have been characterized through antiviral activity assays [23]. Some plants containing compounds that inhibited viruses were identified from Gillan’s plants by Iranian scientists, and specific alkaloids were extracted from them such as trshvash, chuchaq, cote d’couto and khlvash in Iran. The names of the plants were those used in particular regions of Iran and the Latin names were not given [24]; however, it seems that they correspond with Oxalis corniculata, Eryngium planum, and Ziziphora persica. Some people in Iran drink a tea made from a mixture of Stachys schtschegleevi and Origanum vulgare to prevent infection, while those infected with coronavirus are told to drink Echium amoenum tea daily. Local healers encourage people to gargle with an extract of Rhus coriaria or Myrtus communis along with other practices such as hand washing and wearing masks to block the virus from entering the nose and respiratory system. Currently in China, almost 85% of patients treated for COVID-19 are receiving treatment with traditional Chinese medicine based on the observed antiviral effects of plant-derived compounds [25,26].
The literature review, performed to create a scientific database of plants with antiviral potential, obtained results from a search of PubMed and Google Scholar combined with some of the primary traditional Persian manuscripts on medicine, including the book of AlHavi, the Canon of Medicine, Zakhireh-iKharazmshahi, Qarabadine-kabir, Tohfat ol Moemenin, and Makhzan-ol-advieh. The search was performed with terms for medicinal plants used in treating respiratory system disorders [27,28]. Nearly twenty medicinal plants containing mucilage were found [27]. The descriptions of plants with antiviral activity that could be useful for future studies against COVID-19 and other diseases are presented in Table 1. The literature analysis, which was performed to create a scientific database of plants with antiviral potential (Table 1), obtained results from a search of PubMed, Scopus and Web of Knowledge databases combined with some of the primary traditional Azerbaijani manuscripts on herbal medicine.

2.2. Plant-Derived Antiviral Compounds Against Coronavirus

The novel coronavirus is a respiratory virus that spreads through droplets of saliva or discharge from the nose. The main knowledge, with the parallel development of vaccines, is to avoid any contact with an infected person’s breath or sneezes [127]. At the same time, identifying novel antiviral drugs is of critical importance and natural products are an excellent source for such discoveries [128].
The plant metabolites with antiviral activity can kill viruses and prevent the infection of the respiratory system [129,130]. The coronavirus genome is a single-stranded RNA, comprising about 30,000 nucleotides encoding four structural proteins—a membrane protein, a spike protein, an envelope protein, and a nucleocapsid protein—and some nonstructural proteins. The nucleocapsid is a shell made of protein that surrounds the single-stranded, positive-strand RNA genome [131]. The N protein coats the RNA and allows the virus to enter and hijack human cells, turning them into virus factories. The mechanism of formation of the virus structure is one of the important research areas for the development of drugs to prevent virus particles from binding to human cells and infecting them. Plant metabolites are highly antioxidant and can be used for the development of plant-based drugs or to support the immune system [14,19].
The source of such plant-based drugs is often a chemical library of plant-derived compounds with antiviral properties and a variety of mechanisms of action. Plant natural products or extracts have been used in folk medicine for hundreds of years to treat viral diseases [132]. The market for herbal supplements with specific nutraceutical properties is huge [133,134,135], and with the pandemic threatening people’s lives and livelihoods, it is logical select natural products with antiviral potential. Some natural compounds such as lycorine, homoharringtonine, silvestrol, ouabain, tylophorine, and 7-methoxycryptopleurine have been reported to have antiviral activity at nanomolar concentrations and may lead to future antiviral drug development [132]. Many natural products possess anti-coronavirus potential, and these should be studied as potential dietary supplements for reducing infectivity and modulating the immune response.

2.2.1. Zoonotic Interventions

Regarding the zoonotic origins of some viruses, including SARS-CoV-2, plants and their products should also be tested for animal treatment and promising compounds could be further investigated for human application. Lelešius et al. (2019) examined extracts of different medicinal herbs and found that Mentha piperita, Thymus vulgaris and Desmodium canadense extracts were the most effective against avian infectious bronchitis virus prior to and during infection [53]. Kaempferol and its glucoside derivatives (rhamnose), the kaempferol glycosides afzelin, juglanine and tiliroside from the holly oak, Quercus ilex L., were also effective against the 3a channel protein of a coronavirus [136]. Holm oaks (Quercus Ilex L.), oleanders (Nerium Oleander L.), and wild olive trees (Olea europaea L.) are typical Mediterranean plants presented in Italian forested areas, which are suggested to have immunoprotecting potential and have shown lower COVID-19 mortality rates for the population [137].

2.2.2. Antiviral Flavonoids

Naturally occurring flavonoid compounds have high antiviral potential. For example, the flavonoid scutellarein, from the root of Scutellaria baicalensis (Lamiacaea), has been shown to inhibit the nsP13 helicase of SARS-CoV-2 by altering its ATPase activity [110]. The pharmacology research has shown the potential therapeutic effects of baicalin and baicalein, which are other specific flavone glycosides of Scutellaria baicalensis, in response to COVID-19. The exact therapeutic effects of Scutellaria baicalensis extract still needs to be determined in clinical trials [138]. It is important to remember that the use of extracts is complicated by the presence of multiple compounds. The antiviral and antimicrobial capacities of separate biologically active compounds may be different from their effects in extracts, which can be additive or synergistic, or even antagonistic [139,140]. For example, after removal of the tannins from the aqueous extract of Euphorbia hirta L., the inhibition of viral replication was markedly decreased. It was concluded that the tannins were likely responsible for the high antiretroviral activity [141]. Studies using protein-molecular docking with network pharmacology analysis were able to identify and characterize other bioactive compounds from the fruits of Juniperus communis and the brown alga, Ecklonia cava [76,79]. Here, quercetin isolated from E. cava was effective in treating respiratory diseases and could be used to mitigate the airway damage from SARS-CoV-2 infection directly in the respiratory system.

2.2.3. Antiviral Terpenoids

Terpenoids constitute a large group of secondary metabolites with a wide spectrum of structures and effects, including antiviral properties. Some of these compounds are relatively simple, such as monoterpenes from Lamiaceae plants in Table 1 [142]. More complex molecules were isolated and identified from species of the genus Bupleurum, which is widespread in the old world and an important herb in Chinese traditional medicine. Antiviral effects of its triterpenoid saikosaponins were studied on a human fetal lung fibroblast model. It was found that saikosaponins were active in the early stage of HCoV-22E9 infection, preventing viral attachment and penetration [143]. Other identified active compounds from this plant included the above-mentioned antioxidant flavonoids such as quercetin, isorhamnetin, narcissin, rutin, eugenin, and saikochrome A, which may have anti-inflammatory effects [45]. The oleanane triterpenes in ethanolic extracts of Camellia japonica flowers were shown to possess significant antiviral activity against the PEDV coronavirus in research with a Vero cell model. Inhibitory effects on key gene and protein synthesis during PEDV replication have been shown as well [46]. Camellia japonica does not produce purine alkaloids, but it does contain the flavonoids quercetin, kaempferol and apigenin [144,145,146]. A screening study of antiviral action of herbal extracts in 1979 found that a triterpenoid saponin from licorice (Glycyrrhyza glabra) roots, glycyrrhyzic acid, was active against viruses [147]. This plant is native to the Mediterranean region, Iran-Turan, and Azerbaijan, where it has been used in folk medicine for many years. The latest studies confirmed the antiviral activity towards HSV-1, Epstein–Barr virus, human cytomegalovirus, and RNA viruses such as influenza A virus (IAV), H5N1, and H1N1, and the immunomodulation capacity of its extract [64,148,149] inhibits the PLpro and 3CLpro targets, which are known to be essential for viral replication [16,18,150]. The rational supporting combinations of glycyrrhizin with tenofovir and (hydroxy)chloroquine (two drugs active against SARS-CoV-2) are discussed but need more clinical studies [151].
In another study using molecular docking, researchers examined 171 essential oils (see Table 1) in connection with specific enzymes of SARS-CoV-2, such as the main protease, endoribonuclease, and RNA-dependent RNA polymerase. However, the most promising compounds such as isomers of farnesene and (E,E)-farnesol did not display strong docking activity. Despite this, the authors suggested that they possessed a hypothetical synergistic effect in the whole extract [152].
Cannabis sativa originated in central Asia and has been used for treating illness for more than 5000 years [152]. The phytocannabinoid, cannabidiol (CBD), was discovered in C. sativa in 1940 and makes up about 40% of the extract [153]. CBD has been shown to be a modulator of angiotensin-converting enzyme II (ACE2) expression in COVID-19 target tissues [154]. Down-regulation of ACE2, which is associated with receptor-mediated entry into human lung epithelial cells, may provide a reasonable strategy for reducing COVID-19 severity. Researchers in Canada have developed over 800 new C. sativa lines and extracts with high-CBD content for antiviral testing. It was also confirmed that some C. sativa extracts down-regulated another protein required for SARS-CoV-2 entry into host cells, the serine protease, TMPRSS2 [154]. While preclinical studies encourage the potential effectiveness of CBD in viral diseases such as Kaposi sarcoma, hepatitis C and SARS-CoV-2, clinical evidence is still lacking [155].
South America and Africa have a very long history of utilizing native plants in traditional medicine, which has played an important role in the health of the population. There may be some evidence for this assertion; an extract from the bark of Ampelozizyphus amazonicus Ducke was tested and found to have immunomodulatory and anti-inflammatory activities [36]. In Brazil, this plant is widely used to prevent malaria and it is known to contain triterpenic saponins, averaging about 48% of the dry weight [156]. Artemisia species native to Madagascar have been discovered to possess antimalarial effect as well, probably thanks to sesquiterpenic lacton artemisinin [157], and they have antiviral and immunomodulatory potential [41,98]. Beside Artemisia, other plants from Madagascar were previously tested for activity against viruses, and extracts of Cynometra cloiselii, Cynometra madagascariensis, Evonymopsis longipes, Ravensara retusa, and Terminalia seyrigii were able to completely inactivate an HSV test inoculum at low concentrations [158]. During the COVID-19 pandemic, Madagascar has been developing COVID-Organics clinical trials with a herbal background [159].

2.2.4. Antiviral Alkaloids

Another group of secondary metabolites with high antiviral potential against coronaviruses are the alkaloids. The bisbenzylisoquinoline alkaloids, tetrandrine, fangchinoline, and cepharanthine from roots of Stephania tetrandra inhibit expression of the human coronavirus, HCoV-OC43, spike and nucleocapsid proteins. These alkaloids were also able to provide beneficial immunomodulation [114,115] and were active against laboratory HIV-1 strains [160]. The isolated alkaloid lycorine from Lycoris radiata exhibited significantly greater inhibition of SARS-CoV (BJ-001) compared to the total alkaloid extract. However, lycorine extracted from plants showed lower inhibition of SARS-CoV (BJ-001) than synthetic lycorine [161]. Extracts of Houttuynia cordata L. contained the alkaloids arisolactam, piperolactam A, and caldensin, the terpene cycloart-25-ene-3b,24-diol, and several flavonoids [162]. A water extract of Houttuynia cordata significantly stimulated the proliferation of mouse splenic lymphocytes in a dose-dependent manner. Houttuynia cordata extracts have been shown to halt viral tRNA polymerase activity (RdRp) and increase secretion of the interleukins IL-2 and IL-10 [69]. These effects may be attributed to a synergistic interaction of specific compounds from the terpenoid, alkaloid, and flavonoid groups or the effect of their interaction in the plant water extract. The beneficial presence of natural compounds in the lungs after oral administration was further shown in the case of isoquinoline alkaloid emetin, which antagonizes viral replication, including that of coronaviruses. This secondary metabolite is found in the roots of the Brazilian shrub Carapichea ipecacuanha (Rubiaceae), and is processed into ipecac syrup [162,163]. As in the case of Artemisia, some antimalarial medicines have also been recommended for the treatment of COVID-19, namely chloroquine and hydroxychloroquine, which were synthesized as substitutes for quinoline alkaloid quinine that is extracted from the bark of the Peruvian tree, Cinchona officinalis [163,164]. The anecdotal and unproven use of Artemisia for COVID-19 following claims from politicians and others in low-income countries highlights the need for hard data to establish the active ingredients, especially to develop formulations and dosing, and to evaluate efficacy through controlled trials [164]. Another Brazilian herb, Aspidosperma tomentosum, inhibited replication of the avian metapneumovirus by 99% after the virus entered cells [42]. Plants belonging to the genus Aspidosperma, a member of the family Apocynaceae, are rich sources of β-carboline alkaloids, which make them potentially poisonous. Some of the identified alkaloids possess antitumor, antiplasmodial, antimicrobial, and antiviral activity [42,43,164]. The population of Valle of Juruena (Brazil) makes use of a wide array of medicinal plants, including Aspidosperma tomentosum extracts, in the treatments of respiratory ailments [165].

2.3. VOSviewer Visualization of Scientific Data Analysis of Antiviral Potential of Natural Compounds from Various Medicinal Herbs and Crops

With the rapid development and expansion of the field of plant-derived natural products and its global importance, it was worthwhile to conduct a timely assessment of the most influential articles (as measured by citations) and to identify seminal papers and scientific trends. To do this, we prepared a bibliometric network of publications dealing with antiviral compounds of plant origin using the software VOSviewer version 1.6.15 [166], a tool for the bibliometric analysis and visualization of scientific literature data [167]; the software is especially valuable for displaying large bibliometric maps in an easy-to-interpret way, and has been previously used to identify and analyze antimicrobial resistance [168], global research on leishmaniasis [169], and the 100 most-cited papers on the topic of nutraceuticals and functional foods [170], among others. The produced bibliometric network consists of nodes and edges that are weighted based on the frequency of the terms and the strength of the relationships between them; such analysis can provide critical insights into the mechanisms, hazards, and potential antiviral efficacy of plant extracts and isolated compounds as well as changes in research topics with respect to time. For our visualization, we used data from 173 papers published between 1967 and 2020, extracted from the Web of Science database. We selected all publications dealing with plant-based antiviral products present in any of the species presented in Table 1. For the complete list of papers, as well as the complete set of queries needed for data extraction, data used for all publications included the title, year of publication, authors’ names, nationalities, affiliations, name of publishing journal, keywords, abstract, times of citation, country, and H-index. In the following map, nodes correspond to paper keywords, and the edges indicate not only the relationship between two nodes, but also the strength of this relationship. Additionally, Figure 1 uses a color code for displaying the time of publication.
The visualization corresponds to a distance-based map, in which the space between items reflects the strength of the relationship between them. A smaller distance indicates a stronger relationship, making it easier to identify clusters of related elements. Likewise, the relative importance is indicated by the size of each circle. The output includes all the results obtained from all species mentioned in Table 1. In total, 11 clusters and 223 links were identified.
Our analysis shows that, as expected, the interest in the study of natural compounds for the treatment of diseases or developing plant-based drugs seems to increase when there are widespread health crises; in the graph, nodes for Chikungunya (the middle left) and H1N1 (bottom) are visible in connection with the main node of “antiviral activity”, and the graph also shows that the publications dealing with Chikungunya appear to be more common after 2014—similarly, most papers using the keyword H1N1 were published around 2010. The increase in scientific output in these topics appears to be related to both the Chikungunya outbreak from 2013 to 2017 and the H1N1 epidemic in 2009. According to the World Health Organization [171], the first documented outbreak of Chikungunya occurred in 2013, with autochthonous transmission in the Americas; in 2014, Europe faced its highest Chikungunya burden, and more than 1 million suspected cases were reported to the Pan American Health Organization (PAHO) regional office. In 2017, as in previous years, Asia and the Americas were the regions most affected by the Chikungunya virus, and the efforts to find a specific antiviral drug treatment redoubled. There is no specific antiviral drug treatment for Chikungunya, and the clinical management targets primarily the relieving of the symptoms; therefore, promising approaches such as the green synthesis or photosynthesis of AgNPs from medicinal plants [172] could allow a broader understanding of all the alternatives for treatment against viral diseases which have no specific antiviral or vaccines available. Additionally, the visual output shows a strong cooccurrence of the topics “antiviral” activity and “ethnopharmacobotany”, meaning that a good portion of the articles published on these topics are based on the traditional knowledge and the use of plants for medicine, namely, antivirals, antifungal or antibacterial, with most papers focusing on Chinese ethnopharmacobotany, as well as Australian aboriginal medicine and Indian and Korean traditional treatments, amongst others. This also reflects the importance of traditional knowledge in the pharmaceutical and medical research, as highlighted by refs [172,173]. Finally, the map also shows a wide variety of topics, with the most researched topics of the use of the selected medicinal plants and crops, including investigations on herpes simplex virus (type 1 and type 2), respiratory syncytial virus, flavonoids, influenza virus, and hepatitis virus (types a, b, and c). Curiously, the research interest regarding potential use of plants also includes the analysis of viruses exclusively infecting livestock, such as the porcine reproductive and respiratory syndrome virus (PRRS) or Aujeszky’s disease (pseudorabies) virus that also primarily infects pigs. Some of the investigations on animal infections could have applications for human health. This is the case for the Newcastle’s disease virus (NDV) (upper right in bright green), which causes a deadly infection in many kinds of birds and some mild flu-like symptoms in humans. It is important to mention that some of the compounds and plants identified by the queries also showed activities against nonviral diseases, such as the anticancer applications of plants of the Plantago genus (Plantaginaceae). The analysis showed that the dynamics of the research of the plant-based antiviral products are probably heavily influenced by current events of public health at the local and global scale, additionally suggesting a close relationship between ethnobotanical research and antiviral properties in plants; we suggest that these trends might be investigated further to deepen our understanding of the dynamics of available products.

3. Methodology

The available information on the medicinal herbs and crops which characterized antiviral potential was collected from scientific databases and covered from 1967 up to 2021. The following electronic databases were used: PubMed, Science Direct, Scopus, Web of Science, and Google Scholar. The search terms used for this review included coronaviruses group; SARS-CoV; biological active compounds; plant chemo diversity; antiviral potential; natural antiviral plant extracts; and plant-based antiviral drugs. No limitations were set for languages. Knowledge databases were combined with some of the primary traditional Azerbaijani manuscripts on herbal medicine. A total of 173 articles were included in the present review. A VOSviewer visualization of scientific data analysis of antiviral potential of natural compounds from various medicinal herbs and crops has been used. The tool for bibliometric analysis and visualization of scientific literature data was the software VOSviewer version 1.6.15.

4. Conclusions

The literature analysis of plants with significant antiviral potential was performed through a thorough literature search and VOSviewer visualization. A total of 66 medicinal herbs and crops with different origin native areas which characterized antiviral potentials were described. The most promising compounds to develop plant-based drugs can be reccomended the kaempferol glycosides, the scutellarein, baicalin and quercetin flavonoids; the saikosaponins triterpenoids; the lycorine, tetrandrine, fangchinoline, and cepharanthine alkaloids; the triterpene oleanane; and the terpene cycloart-25-ene-3b,24-diol. Even though preclinical studies suggest the potential effectiveness of described compounds to mitigate the current COVID-19 pandemic, clinical evidence is still missing. The dynamics of the worldwide research of the plant-based antiviral products are probably heavily influenced by current events of public health at the local and global scale, also suggesting a close relationship between ethnobotanical research and antiviral properties in plants which may be used for further studies to develop plant-based drugs against coronavirus, or to support backgrounds for healthy food recommendations during a pandemic.

Autor Contributions

O.S. and M.B., conceptualization; O.S., M.B., S.H., M.S., J.K., U.I., S.I., L.L.-T. and M.L., investigation; O.S., M.B., S.H., U.I. and M.S., table contribution; L.L.-T., M.S., J.K., VOSviewer schematic visualization; O.S., S.H., L.L.-T., writing; M.B., M.S. and M.L., funding acquisition. All authors have read and agreed to the published version of the manuscript.

Funding

This work was financially supported by project VEGA 1/0589/19 “Phenotyping of crop genetic resources for conditions of climatic extremes”.

Data Availability Statement

The data presented in this study are available in this article.

Acknowledgments

This research was performed within the Centre for Infectious Animal Deseases initiative (Faculty of Agrobiology, Food and Natural Resources, Czech University of Life Sciences Prague).

Conflicts of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Molecules 26 00727 g001 550
Figure 1. Schematic visualization of analyzed scientific data regarding the antiviral potential of natural plant resources.
Figure 1. Schematic visualization of analyzed scientific data regarding the antiviral potential of natural plant resources.
Molecules 26 00727 g001
Table
Table 1. Description of medicinal plants and crops and their antiviral activity. The abbreviations of the authors of the scientific names have been omitted for the sake of clarity (see http://www.theplantlist.org).
Table 1. Description of medicinal plants and crops and their antiviral activity. The abbreviations of the authors of the scientific names have been omitted for the sake of clarity (see http://www.theplantlist.org).
Plant SpeciesFamilyPlant PartOrigin
Native Area		Mode of Action
Pharmaceutical Activity		Reference
Acacia niloticaFabaceaeWhole plantAfrica and Middle East, Indian subcontinentInhibits human immunodeficiency virus (HIV) protease; antiviral and cytotoxic[6,29]
Alhagi maurorumFabaceaeGum tragacanthSouth-east Europe, south-west AsiaInhibits influenza and cold viruses; relieves cough, pectoral aches, fever, vomiting and thirst[30]
Allium sativumAlliaceaeBulbCentral Asia, IranInhibits avian coronavirus; antiviral, fungistatic[31,32]
Althaea officinalisMalvaceaeWhole plantWestern palearctic, boreal area, Europe, Asia and AfricaAnti-inflammatory in diseases of the upper respiratory tract; antitussive, chest emollient, immuno-modulator, antiviral[33,34,35]
Ampelozizyphus amazonicusRhamnaceaeWhole plantSouth AmericaImmunomodulation, anti-inflammatory[36]
Andrographis paniculataAcanthaceaeLeavesIndia, Sri LankaAntiviral[6,37]
Anthemis hyalinaAsteraceaeWhole plantMediterranean region, south-west Asia to IranInhibits coronavirus replication and expression of transient receptor potential gene family[38]
Arrabidaea samydoidesBignoniaceaeWhole plantSouth AmericaAntiviral activity against human herpes simplex virus-1 (HSV-1), vaccinia virus and murine encephalomyocarditis virus[39]
Artemisia sp. (Artemisia absinthium)AsteraceaeWhole plantEurasia, north Africa, North AmericaReduces coronavirus replication; antibacterial, anti-inflammatory[40,41]
Aspidosperma sp.ApocynaceaeWhole plantSouth AmericaAntiviral activity against avian metapneumovirus and other groups[42,43]
Bryophyllum pinnatumCrassulaceaeWhole plantMadagascarAnti-inflammatory immunomodulator; induces production of host antiviral agents; prescribed for polio and enteroviruses[33,44]
Camellia japonicaTheaceaeWhole plant, FlowersEast AsiaHigh antiviral activity on porcine epidemic diarrhea virus (PEDV) of coronavirus family; inhibitory effects on key gene and protein syntheses during PEDV replication[45,46]
Cichorium intybusAsteraceaeWhole plant, RootsEurasia, Mediterranean regionImmunomodulation; antiviral activity against HSV-1 and adenovirus type 5[37,47]
Cinnamomum cassiaLauraceaeBarkVietnam and eastern Himalayas, ChinaAntiviral, anti-inflammatory; inhibits attachment of human respiratory syncytial virus[48,49,50]
Citrus trifoliataRutaceaeSeedsNorthern China and KoreaAntiviral against oseltamivir-resistant influenza virus[51]
Clitoria ternateaFabaceaeWhole plantIndian sub-continent, Southeast AsiaAntiviral[6]
Cynara scolymusAsteraceaeFlower headsMediterranean regionACE inhibitor, antiviral[6,52]
Desmodium canadenseFabaceaeWhole plantNorth AmericaHigh antiviral activity towards coronaviruses[53]
Echinacea angustifoliaAsteraceaeFlowersNorth AmericaAntiviral activity against cold and flu viruses; inhibits viral growth and secretion of pro-inflammatory cytokines.[54]
Echinops sp.AsteraceaeTrehala mannaIranAntiviral, cough suppressant[55]
Echium amoenumBoraginaceaeFlowersIran, Caucasus, RussiaAntiviral[56,57]
Euphorbia sp.EuphorbiaceaeRootsSouthern Africa and Madagascar, North and South America, Mediterranean regionAntiviral activity against HIV-1, HIV-2, HSV-2 and SIVmac251[35,58,59]
Ferula assa-foetidaApiaceaeOleo-Gum-resinIran, AfghanistanAntiviral activity; great potency against H1N1;
anti-inflammatory		[60,61]
Firmiana simplexMalvaceaeLeavesSouth Japan, China and IndonesiaImmunomodulation; general tonic and adaptogenic drug[33]
Glycyrrhiza glabraFabaceaeRootsMediterranean area, Iran-Turan, AzerbaijanImmunomodulation; antiviral activity against HSV-1, Epstein–Barr virus, human cytomegalo-virus, and RNA viruses such as influenza A, H5N1, and H1N1[35,62,63,64]
Gymnema sylvestreApocynaceaeLeaves, Whole plantAsia, Africa, AustraliaInhibition of viral DNA synthesis; immunomodulation[6,65]
Hippophae rhamnoidesElaeagnaceaeFruitsCold-temperate regions of Europe and AsiaAnti-influenza activities against influenza A/Victoria virus and B | Immunomodulation[66,67,68]
Houttuynia cordataSaururaceaeWhole plantSouthern AsiaInhibits viral SARS-3CLpro and tRNA polymerase activity (RdRp); stimulates secretion of IL-2 and IL-10[69]
Humulus lupulusCannabaceaeInflorescencesEurope, western Asia, North AmericaImmunomodulation; antiviral activity against influenza and cold viruses, hepatitis C, and herpesvirus; inhibits viral replication[70,71,72]
Hyoscyamus nigerSolanaceaeWhole plantContinental Europe, Asia, Middle EastViral inhibition; bronchodilator; antiviral effect against human influenza virus A/WSN/33[6,73,74]
Hypericum connatumHypericaceaeWhole plantNorth America, eastern AsiaHigh antiviral activity[75]
Inula heleniumAsteraceaeRhizomes, RootsEastern Europe, Caucasus, western Siberia, Far East and Central AsiaAnti-inflammatory[71]
Isatis tinctoriaBrassicaceaeRoots extractsCaucasus, Central Asia, eastern Siberia, western AsiaInhibits cleavage activity of SARS-3CLpro enzyme; high antioxidant potential and anti-inflammatory effects[76,77]
Juniperus communisCupressaceaeFruitsNorth America, Europe, AsiaInhibits replication, 3CLpro; anti-inflammatory, antiseptic[78,79]
Litchi chinensisSapindaceaeSeedsSoutheastern ChinaInhibit SARS-3CLpro; terpenoids inhibit HIV-1 protease[17,53,80,81,82]
Mentha piperitaLamiaceaeWhole plantEurope, Middle EastHigh antiviral activity against coronavirus group[17]
Mosla sp.LamiaceaeWhole plantEastern and south-eastern Asia, HimalayasAnti-influenza activity[83,84]
Nigella sativaRanunculaceaeWhole plantEastern Mediterranean, northern Africa, Indian Subcontinent, western AsiaImmunomodulator, anti-inflammatory agent, and broncho-dilator; antiviral activity against avian influenza virus (H9N2)[85,86,87,88]
Ocimum kilimandscharicumLamiaceaeWhole plantCentral Africa, Southeast AsiaAntiviral activity against HIV-1, SARS-CoV-2[6,21]
Oplopanax elatusAraliaceaeWhole plantNorth America, north-eastern AsiaImmunomodulation and anti-inflammatory activities[33,89,90]
Origanum vulgareLamiaceaeLeaves, StemsWestern and south-western Eurasia, Mediterranean regionRespiratory and antiviral activity[91,92,93]
Pelargonium sidoidesGeraniaceaeLeaves, Whole plantSouth AfricaDecreases rhinovirus infection via modulation of viral binding proteins on human bronchial epithelial cells[87,94]
Plantago majorPlantaginaceaeLeaves, Whole plantEurope, Northern and central AsiaAnti-inflammatory; antiviral activity against herpesviruses and adenoviruses[35,95,96]
Punica granatumLythraceaeFruits, Peel, SeedsIran to northern India, Mediterranean regionInhibits viral glycoproteins; antiviral activity against HSV-1 and influenza virus[6,97]
Rhaponticum carthamoidesAsteraceaeRootsSouthern Siberia, Kazakhstan, Altay regionImmunomodulation[33]
Rosmarinus officinalisLamiaceaeWhole plantMediterranean regionAntiviral activity against human respiratory syncytial virus; immunomodu-lator; anti-inflammatory[33,98]
Rubus sp.RosaceaeFruits, FlowersForest-steppe zones of EurasiaAntiviral effect against human influenza virus[33,71,99,100]
Rhus coriariaAnacardiaceaeFruitMild Mediterranean climates of southern Europe and western AsiaAntiviral potential[101,102]
Rosa sp.RosaceaeCompletely matured fruitsEurope, North America, Northwestern AfricaImmunomodulatory effects; antiviral activity against HIV and HSV[103,104,105,106]
Salvia officinalisLamiaceaeWhole plantMediterranean basinHigh binding to COVID-19 proteases; Inhibits SARS-CoV and HSV-1 replication[21,107]
Sambucus nigraAdoxaceaeWhole plantEurope and North AmericaAntiviral activity against HIV, HSV, influenza, hepatitis, and coxsackievirus[75,108]
Saposhnikovia divaricataApiaceaeWhole plantChinaHigh antiviral activity against PEDV corona-virus[45,109]
Scutellaria baicalensisLamiaceaeRootsChina, Korea, Mongolia, Russian far east, SiberiaInhibit nsP13 by affecting the ATPase activity[110,111]
Sphaeranthus indicusAsteraceaeWhole plantNorthern Australia, Indomalayan realmAntiviral activity against mouse coronavirus; bronchodilation and anti-inflammatory activities[6,112]
Stachys schtschegleeviiLamiaceaeLeavesIranAntiviral activity against SARS-CoV-2; anti-inflammatory potential[113]
Stephania tetrandraMenispermaceaeRootsChina, TaiwanInhibits expression of HCoV-OC43 spike and nucleocapsid proteins; immunomodulation and anticancer potential[114,115]
Strobilanthes cusiaAcanthaceaeLeaves,
Whole plant		Tropical Asia, MadagascarInhibits HCoV-NL63 via tryptanthrin; anti-influenza virus activity; anti-inflammatory potential[6,116,117]
Tabebuia sp.BignoniaceaeWhole plantSouth AmericaAntiviral potential[118,119]
Thymus vulgarisLamiaceaeWhole plantSouthern EuropeHigh antiviral activity towards coronaviruses; antioxidant effects[21,53]
Thuja occidentalisCupressaceaeLeaves
Whole plant		Eastern Canada, north, central and upper north-eastern United StatesImmunostimulation; antiviral activity against acute common cold[120]
Urtica dioicaUrticaceaeLeavesEurope, temperate Asia, and western North AfricaInhibition of SARS coronavirus replication[121]
Viburnum opulusAdoxaceaeFruitsEastern Europe, Caucasus, western and eastern Siberia and Central AsiaImmunomodulation; anti-inflammatory effects[33,122]
Vitex trifoliaVerbenaceaeWhole plantTropical East Africa, French PolynesiaAnti-inflammatory effects on lungs; immunomodulation; strong antiviral activity against HSV and mouse coronavirus (surrogate for human SARS virus)[6,123]
Zingiber officinaleZingiberaceaeRhizomeMaritime Southeast AsiaAntiviral activity against human respiratory syncytial virus[124]
Ziziphus jujubaRhamnaceaeFruitSoutheastern Europe to ChinaAntiviral activity; potential therapeutic agent for treating influenza[125]
Zostera marinaZosteraceaeWhole plantNorth America, Europe, AsiaAntiviral activity against influenza A virus[126]
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Sytar, O.; Brestic, M.; Hajihashemi, S.; Skalicky, M.; Kubeš, J.; Lamilla-Tamayo, L.; Ibrahimova, U.; Ibadullayeva, S.; Landi, M. COVID-19 Prophylaxis Efforts Based on Natural Antiviral Plant Extracts and Their Compounds. Molecules 2021, 26, 727. https://doi.org/10.3390/molecules26030727

AMA Style

Sytar O, Brestic M, Hajihashemi S, Skalicky M, Kubeš J, Lamilla-Tamayo L, Ibrahimova U, Ibadullayeva S, Landi M. COVID-19 Prophylaxis Efforts Based on Natural Antiviral Plant Extracts and Their Compounds. Molecules. 2021; 26(3):727. https://doi.org/10.3390/molecules26030727

Chicago/Turabian Style

Sytar, Oksana, Marian Brestic, Shokoofeh Hajihashemi, Milan Skalicky, Jan Kubeš, Laura Lamilla-Tamayo, Ulkar Ibrahimova, Sayyara Ibadullayeva, and Marco Landi. 2021. "COVID-19 Prophylaxis Efforts Based on Natural Antiviral Plant Extracts and Their Compounds" Molecules 26, no. 3: 727. https://doi.org/10.3390/molecules26030727

APA Style

Sytar, O., Brestic, M., Hajihashemi, S., Skalicky, M., Kubeš, J., Lamilla-Tamayo, L., Ibrahimova, U., Ibadullayeva, S., & Landi, M. (2021). COVID-19 Prophylaxis Efforts Based on Natural Antiviral Plant Extracts and Their Compounds. Molecules, 26(3), 727. https://doi.org/10.3390/molecules26030727

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