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Viral infections remain a challenge in human and veterinary medicine due to factors such as viral mutations, new viruses, toxic effects, disease severity, intracellular viability, high costs, and limited availability of antiviral drugs. Despite advancements in immunization and antiviral drugs, there is a need for new and more effective antiviral compounds. Plants produce secondary metabolites that have shown antiviral activity, such as alkaloids, flavonoids, and essential oils. Advanced analytical techniques like HPLC, GC-MS, and NMR spectroscopy are used to identify and characterize these bioactive compounds. Flavonoids, terpenoids, lignans, sulphides, polyphenolics, coumarins, and saponins are among the groups of bioactive compounds found in plants that have demonstrated antiviral activity against viruses like HIV, influenza, herpes simplex, and hepatitis. Screening plant extracts and isolating active compounds allow scientists to identify potential new antiviral drugs. In vitro and in vivo studies have shown significant antiviral activity of plant extracts and their bioactive compounds. However, further research is needed to ensure safety, investigate drug interactions, and explore combination therapies with other natural products. The use of advanced analytical techniques helps identify and characterize bioactive compounds that target different stages of the viral life cycle. Examples of plant extracts and compounds with antiviral activity against specific viruses are mentioned, including SARS-CoV-2 and various veterinary viruses. The abstract emphasizes the ongoing research on natural sources, particularly plants, for the discovery of new and effective antiviral compounds, while highlighting the need for extensive studies on safety, drug interactions, and combination therapies.
*Address all correspondence to: gamilzee@yahoo.com
1. Introduction
Viral diseases continue to cause significant morbidity and mortality globally, posing a persistent threat to public health for both humans and animals [1, 2]. Antivirals are medication drugs used specifically for treating viral diseases or substances that can produce either a protective or therapeutic effect on the virus-infected host [1, 3, 4, 5]. The uses of antiviral drugs in human and veterinary medicine are limited in comparison with the use of antimicrobial agents due to viral mutants resistant to existing antiviral diseases. Furthermore, new viral pathogens have been discovered as having side effects and high costs [6, 7, 8, 9], the severity of viral diseases, and the ability of viruses to survive intracellularly [10].
Approximately 80% of the people as well as domestic animals in developing countries use traditional and medicinal plants for maintaining their health [11, 12]. Medicinal plants became a new source of drug discovery due to advent of today’s advanced analytical chemistry, developed standardized and extraction procedure, as well as standard assays [13, 14]. Twenty-five percent of the drugs in common use are of plant origin, and more than 4,22,000 species of flowering plants have been reported, only 5000 species among them are used for medicinal purposes [14]. Medicinal plants with strong antiviral activity to treat viral infections in humans and animals and those containing novel plant-derived antiviral agents have been identified [15, 16, 17]. Herbal medicines and purified natural products provide a rich resource for novel antiviral drug development [18, 19]. Identification of antiviral mechanism of natural agents has shed light on interaction with the viral life cycle such as viral entry, replication, assembly, and release, as well as targeting of virus–host specific interactions [20].
The antiviral activity of several natural products of the following species Ipomopsis aggregate, Aloe Vera, A L. dissectum, Achillea millefolium, Achillea tenuifolia, Achillea talagonica with Ania somnifera, Ashwagandha, Allium sativum, and Azadirachta indica were examined in vitro and in vivo and found all of these plants’ extracts had antiviral against DNA or RNA viruses [8, 9, 21, 22]. Many phytochemicals showed dose-dependent viral inhibitory effect against common veterinary viral pathogens [23, 24, 25]. This review study aimed to spotlight on antiviral activities of some medicinal plants against viral pathogens including families Herpesviridae, Flaviviridae, Retroviridae, Picornaviridae, Hepadnaviridae, and Paramyxoviridae in vitro and in vivo.
1.1 Viral infection control
Viruses differ from bacterial and fungal infections in that they require living cells to replicate, and this makes controlling them a difficult task. Viruses integrate into host cells both functionally and physically, making it extremely challenging to distinguish them. Some viruses can persist as latent infections, which is a concerning problem. Moreover, many viral infections lack effective treatments, and antiviral drugs can have potential toxic effects, along with the emergence of cross-resistant mutants. As a result, plant extracts and phytochemicals are receiving increasing attention as alternative approaches for controlling contagious diseases in livestock, with scientists continuing to study their potential as antivirals [26, 27].
1.2 Antiviral drugs limitations
The limited efficacy of antiviral drugs compared to antimicrobial agents is due to the difficulty of identifying specific viral targets with high selectivity and low side effects. However, in recent years, a more rational approach has been taken to the development of new antiviral drugs. Currently, only one antiviral compound, feline interferon-omega (IFN-), has been licensed for use in veterinary medicine due to its undefined mechanism. Although several antiviral drugs are licensed for use in cats with feline herpes virus-1 (FeHV-1), such as idoxuridine, trifluridine, and acyclovir, or against feline immunodeficiency virus (FIV), there are many reasons why antiviral agents are not widely used in veterinary medicine. These include their high cost, especially for use in food species, their lower cytotoxicity in animals, and the lack of rapid diagnostic techniques. Despite these factors, animal viruses have been used as models for developing antiviral drugs for humans, with bovine viral diarrhea (BVD) considered a valuable surrogate for the hepatitis C virus.
1.3 Plants are a source of antiviral agents
Plants possess a natural ability to synthesize medicinal compounds, leading to the discovery of new drugs with potent therapeutic effects. Traditional medicine still serves as a primary source of healthcare for almost 80% of the world’s population, with plants and plant products being utilized for centuries to treat diseases even before the active constituents were identified. It is noteworthy that approximately 50% of all prescribed medications are derived from plants or their derivatives [28]. Medicinal plants in combination therapy have been shown to be effective against various viruses, including herpes and influenza viruses. Additionally, many plant extracts, such as those obtained from Agrimonia apilosa and Ocimumba silica, have demonstrated antiviral activity against a broad range of DNA and RNA viruses [29]. In addition to their traditional use in medicine, plants have also been a source of new drugs with potent therapeutic effects. In fact, about half of the drugs that are prescribed today are either derived from plants or are plant-produced. Combining different medicinal plants has also proven effective against various viruses, including herpes and influenza viruses. Many plant extracts, such as A. apilosa and O. silica, have demonstrated antiviral effects against a broad spectrum of DNA and RNA viruses. This highlights the potential of plant-based therapies as an alternative approach to treating viral infections.
1.4 Coronavirus and medicinal plants
The coronavirus (CoV) is a type of single-stranded, positive-sense RNA (ssRNA) virus that belongs to the family Coronaviridae. This family of viruses is responsible for causing respiratory and gastrointestinal infections in both mammals and birds. Although in humans, it usually causes mild symptoms such as a cold or flu, it can lead to more severe complications such as pneumonia and severe acute respiratory syndrome (SARS). There are several documented types of human coronavirus (HCoV), including HCoV-229E, -OC43, -NL63, and -HKU1. The most widely known member of the family is the severe acute respiratory coronavirus syndrome (SARS-CoV), which caused a high mortality rate in 2003. In 2012, the World Health Organization (WHO) reported a sixth highly lethal form of HCoV infection known as the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) [30, 31]. The severe acute coronavirus 2 respiratory syndromes (SARS-CoV-2) were first reported in December 2019 in Wuhan, Hubei, China, and declared a pandemic by the World Health Organization (WHO) on March 11, 2020.
The World Health Organization proposed the name 2019-nCoV; later, the International Committee on Taxonomy of Viruses renamed it SARS-CoV-2 (coronavirus disease 2019). The Wuhan strain was identified as a new Group 2B Betacorona virus strain with nearly 70% genetic similarity to SARS-CoV. The virus seems to have a 96% resemblance to the coronavirus bat, and therefore it is generally believed to emanate from bats. There seem to be no precise medications or treatment options for COVID-19 [32]. Coronaviruses are large, pleomorphic, spherical particles with a bulbous surface projection. The diameter of the virus particles is approximately 120 nm.
In electron micrographs, the virus membrane was observed as a distinct double-layered structure. This viral envelope is composed of a lipid bilayer, which houses the membrane, envelope, and spike structural proteins. A specific subtype of beta coronaviruses known as subgroup A features a truncated spike protein, known as hemagglutinin esterase (HE). Moreover, nucleocapsids develop copies of the nucleocapsid protein attached to the positive-sense single-stranded RNA genome. The genome size for coronaviruses ranges from 27 to 34 kilobases, the largest among documented RNA viruses [33].
The lipid bilayer envelope, membrane protein, and nucleocapsid safeguard the virus outside the host cell. A specific genome sequence analysis of viruses found in pangolins and humans has revealed only one amino acid variation. Currently, only about 92% of the genetic material between pangolin coronavirus and SARS-CoV-2 has been compared as a complete genome, which is not enough evidence to establish pangolins as intermediate hosts. The virus is assumed to have originated in bats as it is 96% identical to the bat coronavirus. The name coronavirus originates from the Latin word “corona, meaning” “crown” or “halo,” as the virus particles exhibit a crown-like appearance due to the presence of club-shaped protein spikes on their surface, as observed under two-dimensional electron microscopy. Currently, there are no specific treatments or preventive vaccines for CoV infection, and there is a need for the development of new antivirals to prevent and treat CoV infection, as highlighted by Agarwal et al. [34]. The complete list of potent plant extracts and their bioactive compounds that inhibit coronaviruses Ginsenoside Rb1 (Gynosaponin C), one of the bioactive ginsenosides extrapolated from Panax ginseng, displayed antiviral activity. Tetra-O-galloyl-beta-d-glucose, luteolin, and tetra-O-galloyl-beta-d-glucose blocked the SARS-CoV host cell entry. Herbal extracts have been studied for their potential antiviral properties. Among the 200 extracts analyzed, Lycoris radiata, Artemisia annua, Pyrrosia lingua, and Lindera aggregate were found to have anti-SARS-CoV effects with an EC50 range of 2.4–88.2 g/ml. Black tea phenolics such as tannic acid, 3-isotheaflavin-3-gallate, and theaflavin-3,3′-digallate have also exhibited inhibitory effects. These compounds have IC50 values of 3, 7, and 9.5 M, respectively, against SARS-CoV 3CLpro. On the other hand, phenolic compounds from Isatis indigotica have been shown to inhibit SARS-CoV 3CLpro with IC50 values of 217, 752, 8.3, 365, and 1210 M for sinigrine, indigo, aloe emodin, hesperetine, and sitosterol, respectively [35, 36].
1.5 Antiviral activity targeting plant extracts
Antiviral compounds found in medicinal plants have the potential to inhibit various stages of virus replication, including viral attachment to cells, virus-specific enzymes, and egress of viruses from infected cells. Such compounds may also target the virus itself. However, specific information about the viruses causing respiratory infections is often limited. One potential drawback of targeting specific antivirals directed at viral genes or products is the emergence of virus-resistant mutations [37]. People have used combinations of two or more antiviral drugs to solve the problem. However, there is an alternative approach that has the capacity to inhibit many different respiratory viruses [38, 39]. These targets include virus attachment, entry inhibitors, modifiers of the viral genome, protein processing, virus assembly, release inhibitors, and immunomedulators, as shown in Figure 1.
Figure 1.
Virus life cycle and possible antivirus targets.
The life cycle of a virus can be summarized as follows:
I. Attachment: The virus attaches to a host cell using its spike protein, which binds to specific receptors on the cell surface. II. Entry: The virus enters the host cell either by fusing with the host cell membrane or by endocytosis. III. Uncoating: Once inside the host cell, the viral genome (usually RNA) is released from the capsid. IV. Replication: The viral genome is copied by viral RNA-dependent RNA polymerase (RdRp), which produces new viral RNA strands. V. Translation: The viral RNA is translated into viral proteins, including the structural proteins and enzymes required for viral replication. VI. Assembly: The new viral RNA and proteins assemble into new virus particles. Release: The newly assembled virus particles are released from the host cell, usually by budding through the host cell membrane. To develop antiviral drugs, scientists often target specific steps in the viral life cycle. For example: Attachment: Drugs can be developed to block the binding of the viral spike protein to host cell receptors, preventing the virus from entering the cell. Replication: Drugs can be developed to inhibit RdRp activity, preventing the virus from replicating its genome. Assembly: Drugs can be developed to disrupt the formation of new virus particles, preventing their release from the host cell. Release: Drugs can be developed to inhibit the budding or release of new virus particles, preventing their spread to other cells. Overall, understanding the life cycle of a virus and its interactions with the host cell is essential for developing effective antiviral drugs.
Antiviral therapy targets the attachment and entry of viruses into host cells. The virus enters the host cell by interacting with surface receptors or co-receptors, leading to fusion of the viral envelope to the host cell membrane and release of the viral genome. Various antiviral plant products have shown similar mechanisms in inhibiting viral replication by targeting virus attachment and entry. For instance, plant-derived mannose-specific lectins from the Galanthus and Hippeastrum genera can inhibit viral envelope glycoproteins, thereby preventing viral entry into the cell. These agents may also interfere with viral attachment to the host cell, as shown in Figure 2. Also, extracts from seaweeds, carrageenans, and sea-weed-derived heparin sulphate molecules have an antiviral inhibitory effect against the dengue virus by preventing the uncoating of the virus. The viral envelope is a good target for antiviral drugs on enveloped and nonenveloped viruses, including herpes viruses, orthomyxoviruses, paramyxoviruses, rhabdoviruses, coronaviruses, retroviruses, arenaviruses, togaviruses, flaviviruses, and bunyaviruses [40, 41].
Figure 2.
Targets of antiviral agents’ therapy.
2.1 Modifiers of viral genome and protein processing
The next target for an antiviral strategy that targets viral transcription and translation processes. DNA viruses are getting directly integrated into the host genome or may be processed cellular machinery in RNA viruses. The antiviral agents can inhibit reverse transcription, integration, replication, transcription and translation that providing potential targets [42, 43]. The viral nucleic acid targets for chemotherapy and medicinal plant overlap and inhibit the viral protein synthesis. The binding of Calophyllum lanigerum to the active site of reverse transcriptase enzyme is irreversible, thereby inhibiting the activity of the enzyme [44, 45].
2.2 Virus assembly and release inhibitors
Antiviral drugs are known to prevent the assembly of newly synthesized viral proteins and inhibit their release from host cells. Protease inhibitors are a class of antiviral drugs that prevent the cleavage of polypeptides, thereby disrupting viral assembly. Neuraminidase inhibitors, on the other hand, block the release of influenza virus from infected cells, and antiviral drugs that prevent virus transmission from cell-to-cell, such as oseltamivir and zanamivir. There are currently more than 30 different protease inhibitors derived from plant sources, such as Eclipta prostrata, Alpinia galanga, Zingiber zerumbet, Coccinia grandis, Boesenbergia [46, 47], and Pandurata, Cassia garretiana, and Orostachys japonicus, which have antiretroviral efficacy [46, 48, 49].
2.3 Other targets as immune-modulators
The increased attempt to synthesize antiviral agents that will stimulate the defense mechanism of the host is exemplified by the variety of biological response modifiers and interferon inducers. The induction of a protective immune response is one of the primary targets of antiviral therapy. Many of the currently registered products adapt this mechanism against viral infections. Interferons, interleukins, and colony-stimulating factors are the most prominent immunostimulants. Interferon-induced polypeptides and glycoproteins that serve as mediators to induce the production of certain enzymes that inhibit viral replication in the cell [8, 9].
Interleukin are involved in the stimulation, growth, differentiation, maturation, and regulation of immune cells that can help in the neutralization of the virus [50]. The β-sitosterol obtained principally from the plants of genus Nigella, enhance the cellular immune response by enhancing the activity of natural killer (NK) cells, CTLs, and by the increased secretion of cytokines. Tinosp sitosterolia plant extracts have the ability to cause lymphocytic activation [8, 9, 38, 39]. The flowering plant Echinacea purpurea has been used for its immune-stimulating properties, and it is believed that the Asteraceae family of plants possess the largest number of plants with immunomodulatory activity. Proteins derived from Allium sativum, also known as garlic, have been found to exhibit mitogenic activity toward human lymphocytes, splenocytes, and thymocytes (Figure 3) [51].
Figure 3.
Various receptors through which the subtypes of virus enter the target cells. The presence of medicinal plant.
3. Mechanism of active antiviral compound from medicinal plants extracts
3.1 Antiviral plant extracts and their impact on selected veterinary viruses
3.1.1 Antiviral effects of herbal plants against a range of DNA and RNA veterinary viruses
These include herpesviruses such as bovine herpesvirus type-1 (BHV-1), pseudorabies virus, and equine herpesvirus-1 (EHV-1), as well as poxviruses such as poxvirus, parapoxvirus (PPV), and lumpy skin disease virus (LSDV). Canine parvovirus type 2 (CPV-2) from the Parvoviridae family and RNA viruses such as FMD from the Picornaviridae family, bovine viral diarrhea virus (BVDV), and classical swine fever virus (CSFV) from the Flaviviridae family, rotaviruses from the Reoviridae family, and Influenza A from the Orthomyxoviridae family. Additionally, antiviral compounds derived from natural sources have demonstrated broad-spectrum activity against a variety of DNA and RNA viruses as shown in Tables 1–3 [72].
Antiviral activity of plant extracts against RNA viruses.
Plant extracts such as black tea, Citrus aurantium, marine sponges, Stevia rebaudiana, Alpinia katsumadai (AK), and Zingiberaceae contain saikosaponin B2, which inhibits viral attachment and penetration stages of Reoviridae, rotaviruses, and bluetongue virus.
Orthomyxoviridae: Plant extracts from H. erectum, Terminalia chebula, and Momordica cochinchinensis exhibit antiviral effects against influenza A virus. They inhibit viral entry and release, reduce viral hem-agglutination and neuraminidase (NA) activity, and decrease viral nucleoprotein (NP) RNA levels and polymerase activity.
Viral infections remain a significant challenge in human and animal health, as many viruses still lack protective vaccines and efficient antiviral therapies. However, natural products have shown promising antiviral effects against various viruses, including Herpesviridae, Flaviviridae, Retroviridae, and Picornaviridae. Further research into the bioactive compounds and mechanisms of action of these natural products can help to develop effective antiviral drugs. Combination therapy with natural plants also holds potential for reducing the risk of viral drug resistance. However, extensive safety and drug interaction studies are needed to ensure the effectiveness of these natural remedies. Overall, the exploration of natural products and their bioactivity can aid in supporting global health systems and improving viral treatment.
Recommendation
Medicinal plants could be serving as essential sources of antiviral agents for humans and animals diseases but still need further extensive studies for exploration of plants bioactive ingredients consider top global priorities.
Indeed, different research studies have been done to increase the antiviral activity of plant extracts and increase its water solubility.
Studies of the efficacy of plant extracts in vivo is encouraged to help developing effective antiviral drugs as well as studies of natural agent’s combination with chemical antiviral therapeutics as multitarget therapy for reducing viral escape mutant.
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Written By
Gamil S.G. Zeedan and Abeer M. Abdalhamed
Submitted: 18 February 2023Reviewed: 02 May 2023Published: 20 December 2023
Open access peer-reviewed chapter
