Dermotropic viruses

Favipiravir T , having chemical structure as 6-fluorohydroxypyrazine carboxamide, has been chiefly introduced for therapy of influenza virus infections. Favipiravir was invented and approved in Japan and could be effectively used for the treatment of influenza A, B, and C virus infections. Importantly, favipiravir triphosphate is a broad-spectrum antiviral agent and shows inhibitory activities against the RNA polymerases present in influenza A viruses. Highly pathogenic H5N1 viruses and many other positive- and negative-sense RNA viruses also belong to the group of influenza A virus and hence favipiravir is active against them.

It also inhibits the growth of human norovirus and human arena viruses Machupo, Junin, and Pichinde viruses , but these new applications need further extensive researches and clinical trials.

Plants are the foundational element of many medicinal structures under application today. Antivirals extracted from natural origin have found to possess pharmacological and pharmaceutical properties.

Using different medicinal plants in combination therapy has been proved to be effective against a numerous viruses such as HSV and influenza viruses [2] , [3]. Many plant extracts are observed to have broad spectrum of antiviral activity.

Many phytochemicals may also have dose-dependent viral inhibition [7] , [8]. Moreover, they are resolving an important issue of drug resistance generated because of synthetic drugs [9] , e. Polycitone A is functional against the resistant strains of HIV [10].

Plant-derived products are also inexpensive and could be easily accessible in different parts of the world. Natural products are even found to be less toxic, cheaper, and impart no side effects in comparison with the synthetic drugs. Apart from this, they have proved their wide therapeutic benefits for different types of conditions.

Plant-derived ingredients have shown different kind of mechanisms against the activities of viruses:. The enhancement of defensive immune reaction is one of the most important mechanisms of antiviral treatment.

Many of the recently registered products are working on the immunity boosting procedures toward viral infections. Interleukins, colony-stimulating factors, and interferons are the most well-known immunostimulants. Interferons, which are the derivable polypeptides and glycoproteins, act as catalyst to enhance the growth of certain peculiar enzymes that control viral reconstruction in the cell [11] , [12].

Interleukins are the factors that increase the activation, development, distinction, progression, and guidance of immune cells, which can be able to nullify the virus [13]. Similarly, colony-stimulating factors regulate the proliferation and distinction of progenitor cells in the white blood cells lineage [14]. However, many of the drugs, such as ribavirin, also affect positively the immune responses [15].

Many of natural materials have been researched for their immunomodulatory activities. Carbohydrates, stilbenoids, alkaloids, polyphenols, lectins, and peptides from plant sources are the chief categories of drugs that could be used as immunomodulators. Another most important target for the antiviral therapy is the adjunction of virus to the host cell and its entrance. The entry of the virus occurs into the cell by interacting either by a single cell surface receptor or by certain coreceptors.

After that, the viral envelop gets fused with host cell membrane, and as it intrudes into the cell, the virus is dismantled to release its genome. Many of the approved drugs affect this procedure of viral infection, e. Studies on different plant-derived materials have shown the similar mechanisms for preventing viral growth, e. Other categories of plant materials, which includes, galactose, glucose, and N-acetylgalactosamine, have been found to contain antiviral action against severe acute respiratory syndrome corona virus SARS-coV and the feline infectious peritonitis virus.

These factors also inhibit the viral adhesion to the host cell. Many of natural agents also work against influenza virus receptor attaching and merging protein, i. In many studies, retardation of virus dismantling and emergence of genetic matter into the cell has been done by the extracts derived from various seaweeds.

Heparin sulfate molecules extracted from carrageenans, seaweed, also have shown to employ antiviral activity toward dengue virus by arresting the uncoating of virus in host cells. Viral arrangement and mutation processes are the next important mechanism for an antiviral policy. The genome could be managed earlier, and it can utilize the cellular machinery to its benefit RNA viruses or it could directly integrate to the host genome DNA viruses.

Reverse transcription, integration, replication, transcription, and translation are the potential steps of this procedure. Coumarins also known as the calanolides are extracted chiefly from Calophyllum lanigerum and belong to eminent category of plant-derived antivirals. They have been found to irreversibly bind to the active site of the reverse transcriptase enzyme. Large quantity of calanolides could be extracted from the latex of relevant species of the plant.

Calanolide are also chosen for phase II clinical studies for antiretroviral treatment and has shown a synergistic effect with currently approved drugs. These medicines hinder the transcription of newly amalgamated viral proteins into virions and their liberation out of the cell.

Neuraminidase inhibitors work by hampering the influenza virus liberation out of the infected cells, hence resulting in safeguarding cell-to-cell transmission.

Zanamivir and oseltamivir are the two most important parts of the approved drugs of this group. Up till now, more than 30 various types of protease inhibitors are extracted from plants possessing potential antiviral activities. Compounds of different botanical and chemical sources have been studied for this purpose. Extracts from Zingiber zerumbet, Orostachys japonicus, Boesenbergia pandurata, Alpinia galanga, Coccinia grandis, Cassia garretiana , and Eclipta prostrata have proved their antiviral potential exploiting their protease inhibiting property.

Same as the protease inhibitors, this compound possesses the ability of suppressing the cleavage of Gag polyprotein of HIV. Hence, both the structural and enzymatic proteins are not formed. Another Chinese preparation, Ching-fang-pai-tu-san consumed as a traditional herbal decoction, contains quercetin, isoquercetin, and chaihu. These compounds stop influenza virus replication by interrupting the intracellular protein processing, transportation, and budding properties [17].

Shikimic acid having a chemical formula 3,4,5-trihydroxycyclohexenecarboxylic acid is an organic compound found naturally and is an important link in the pathway for the development of aromatic amino acids, lignin, and various alkaloids present in plants and microorganisms. Shikimic acid is a primary progenitor of the pharmaceutical manufacturing as antiinfluenza drug oseltamivir. Oseltamivir is marketed under the brand name Tamiflu.

It is a potential antiviral medicine used to cure and prevent influenza A and influenza B infections. The mode of application is by mouth, either in the form of pill or liquid. Oseltamivir was the first neuraminidase inhibitor available orally. It was approved for medical use and now found in the complementary list of World Health Organization's List of Essential Medicines, indicating a lower cost—benefit ratio. Its generic version was approved in the United States in Oseltamivir is a compound acting as neuraminidase inhibitor, which is a potential inhibitor of influenza's neuraminidase enzyme.

Neuraminidase inhibitors NAIs define a class of drugs that stop and block the activity of neuraminidase enzyme and hence they are generally utilized as antiviral medicines.

They inhibit the action of viral neuraminidases present in influenza viruses and prevent their reproduction through budding in the host cells. This enzyme is responsible for cleaving the sialic acid, which is present in glycoproteins on the surface of human cells, which in turn helps new virions to come out from the cell. Oseltamivir inhibits the function of neuraminidase protein and prevents new viral particles from being released, so that the virus cannot leave the cell to infect other cells.

Eventually, the virus dies. The isolation of shikimic acid from the fruit of Illicium religiosum was primarily reported by Ekmann in [18]. The name shikimic acid was derived after the oriental plant shikimi-no-ki in Japanese. Shikimic acid is now available in more quantities through the extraction from the fruit Illicium verum Chinese star anise.

It was recently reported that Liquidambar styraciflua , more commonly known as the sweetgum tree, could be a renewable source of shikimic acid. In fact, it was shown that the sweetgum tree can yield shikimic acid in amounts comparable with that of I.

Other plants to which shikimic acid have been isolated from were presented in Table Shikimic acid, obtained from star anise present in its anionic form shikimate, is a cyclohexanecarboxylic acid, a cyclohexene, and a cyclitol.

The shikimic acid is formed through the following biosynthesis pathway as described in Fig. Phosphoenolpyruvate reacts with erythrose 4-phosphate to yield 3-deoxy- d -arabino-heptulosonatephosphate DAHP , in the presence of catalyst, i. DHQ is dehydrated to 3-dehydroshikimic acid by the enzyme 3-dehydroquinate dehydratase in the next biosynthetic step, which transformed into shikimic acid in the reduction reaction catalyzed by the shikimate dehydrogenase.

Nicotinamide adenine dinucleotide phosphate NADPH contributes as a cofactor in this reduction reaction. Shikimic acid, a natural compound, has key role as an intermediary substance in the manufacturing of amino acids. Therefore, this derivative is wide spread in various plants and has potential biological properties. Apart from this, shikimic acid has pharmacological relevance because it also acts as an intermediate in the manufacturing of many drugs and the mostly related to antiviral agent called oseltamivir Tamiflu.

The SA first isolated of microbial source was from Escherichia coli by Millcan [32]. It was also reported that bacillus species increases the yield of SA by initiating the activity of shikimate dehydrogenase and shikimate kinase enzyme. Other strains of E. Adachi et al. The enzymes obtained quinate dehydrogenase and 3-dehydroquinate dehydratase and were utilized to transform quinic acid into 3-dehydroshikimate.

Dehydroshikimate was then treated with NADPH-dependent d -glucose dehydrogenase and shikimate dehydrogenase for obtaining shikimic acid. This technique is suitable for laboratory recovery of shikimic acid only but not from the perspective of industrial production.

The shikimic acid pathway is a biosynthetic pathway which is absent in mammals. It involves the metabolism of carbohydrates and allows the biosynthesis of aromatic amino acids and aromatic compounds such as naphthoquinones, ubiquinones, and folates. The shikimate pathway is a part of the metabolism occurred only in plants and microorganisms such as microbial eukaryotes, bacteria, and parasites. The sequence of seven-step shikimate pathway consists of transforming phosphoenolpyruvate and erythrosephosphate starting with the condensation of them.

Their condensation and cyclization lead to the synthesis of chorismic acid. Gallic acid in combination with simple sugars transforms to the tannin compounds such as gallic and ellagic tannins and, after the addition of a molecule of phosphoenolpyruvate and additional intermediate stages, leads to the formation of aromatic amino acids tyrosine and phenylalanine amino acids. The pathway includes various enzymes such as 2-keto3-deoxy- d -arabinoheptulosonatephosphate synthase, 3-enoylpyruvylshikimatephosphate synthase, shikimate dehydrogenase, shikimate kinase, 5-dehydroquinate dehydratase, and chorismate synthase.

Shikimic acid is the intermediate product of this biological pathway by shikimate dehydrogenase, which facilitates the reversible transformation by reduction of 3-dehydroshikimate into shikimate.

The shikimic acid pathway provides a new methodology for developing new herbicides and herbicide-resistant crops. It also provides the opportunity for engineering new antibiotic and antiparasitic drugs by interrupting the action of its enzymes.

Hence, various important researches are being carried out to explore this pathway. The Illicium genus is the basic source of shikimic acid, and the acid was discovered in from its fruits. The techniques are constantly improving for isolation of shikimic acid from these plants' fruits.

Adams et al. In their method, about 25 g of I. The extract was then treated with water and few drops of formaldehyde solution to obtain an orange clear solution which was passed through an anion exchange column Amberlite IRA, acetate form, dry weight 25 g.

Shikimic acid was than eluted with acetic acid and the yellow eluent was collected, which was again heated with methanol, activated carbon and recrystallized with toluene to yield a brilliant white, crystalline substance.

The modified Adams's and Payne's methods are being exploited in China for the industrial production of shikimic acid from Illicium genus plants. Weinstein et al. For this purpose, the plant was kept for metabolism in an atmosphere of radioactive carbon dioxide for several days. The column of Dowex 1-X8 acetate form was used to pass the eluate. The excellent separation of shikimic and quinic acids was achieved by gradual elution with an aqueous acetic acid, and sufficiently pure compounds were found after the final passage through the Dowex 1-X8 column.

A modified technique was employed by Underhill et al. These techniques are important from the perspective of research but could not be used to the industrial-level production of shikimic acid as they are multistage process and results in high product loss. An efficient method for isolating shikimic acid from leaves of plants of the Liquidambar genus was developed by Li et al.

The above-described method is being actively exploited in the Chinese industry for the production of shikimic acid from the Liquidambar genus plants. As discussed above, oseltamivir commercialized under the trade name Tamiflu is an antiviral drug, which is being synthesized from shikimic acid. The oseltamivir help to lower down the rate of spread of influenza flu virus among cells in the body by interrupting the removal of the virus from its host cell.

The drug is ingested orally in capsules or in the form of suspension. Both influenza A virus and influenza B virus may be treated by it. After ingestion of oseltamivir, firstly it acts like an inactive chemical or prodrug which changes into its active state by metabolic process inside the liver, where because of hydroxylation, it changes to active metabolite—the free carboxylate of oseltamivir GS It was the firstly used orally active neuraminidase inhibitor, which serves as a competitive inhibitor for the action of the viral neuraminidase NA enzyme on sialic acid, present on glycoproteins found on the surface of normal host cells.

By hindering the activity of the enzyme, oseltamivir stops new viral particles from being formed by infected cells. Oseltamivir is indicated for the treatment and prevention of infections due to influenza A and B viruses. Consequently, the oseltamivir is well distributed after ingestion as pill to the nasal mucosa, the tracheal lining, and the tissues of the middle ear.

The elimination of oseltamivir carboxylate from the body follows the route for its elimination by glomerular filtration and then renal tubular excretion without undergoing further metabolism process. The estimated average half-life of elimination in adults ranges from 6 to 10 h. Influenza A and B are the two most important viruses responsible for the yearly flu seasons in human beings.

They are named on the basis of major types of antigenic proteins present on the viral coating. These antigenic proteins are hemagglutinin HA and neuraminidase NA , out of which the NA is a primary target of oseltamivir and zanamivir. Despite the rapid growth of pharmaceutical and biotechnological approaches, the development of effective antiviral therapy is still a challenge. Influenza has created a global menace for the society as it has yet not developed the appropriate technology to manage the epidemic from resistant strains.

Apart from the emergence of drug resistance, development of mutant strains of the virus, introduction of a more virulent strain, expensive available drugs, time lapse in vaccine manufacture, and mass mortality cause difficult problems.

In this scenario, counterpart and alternate medicine offers huge possibilities to help patients. Herbs possess a wide array of biological actions and could be efficiently exploited for managing pandemic flu. Nutritional and botanical properties together are responsible for providing potent tools for controlling different types of viral infections. The accessibility of a wide array of herbs and constituents with potentially active phytochemicals, to increase the effect as antiinfluenza agents, could have an important role in the ongoing research toward the novel H1N1 infection.

Shikimic acid is also found as potential antiviral source as it could be used as a precursor for industrial production of the antiviral oseltamivir or Tamiflu, a potent viral neuraminidase inhibitor. Rigorous researches for optimization of shikimic acid production and its utilization can bring a revolutionary change in antiviral therapy.

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Abstract This chapter explains the application of shikimic acid as preventive medicine for the outbreak of swine or Avian flu due to H1N1 virus. Introduction Viruses are small infectious organism or obligate intracellular parasite found in virtually all ecosystem, numbering in millions. Description of the various classes of viruses Viruses that are pathogenic to human are broadly classified according to the different regions of the body mostly affected and clinical nature of the infection or disease produced Table Table Open in a separate window.

Influenza and its various forms Influenza is a contagious respiratory infection caused by an influenza virus, commonly known as the flu. Types of influenza viruses On the basis of surface antigens, there are four genera of this family: types A, B, C, and thogotovirus. Type A influenza Type A influenza is the most dangerous and known to cause outbreaks and diseases. Influenza B Influenza B infections occur only in humans and are not divided into subtypes, but can be further broken down into lineages and strains.

Influenza type C Influenza type C infections cause a mild respiratory illness comparable to other common respiratory viruses and nearly all adults have been infected with influenza C virus. FDA-approved drugs for influenza Influenza is a serious infectious disease, which is very dangerous and deadly specifically in young one, elderly, and weak immunity patients. Influenza virus inhibitors Eight drugs have been accepted to cure influenza virus infections on April Rimantadine and amantadine Amantadine 1-adamantanamine approved in was the first antiviral compound for the treatment of widely distributed influenza A virus infections.

Zanamivir, oseltamivir, peramivir, and laninamivir octanoate Zanamivir is a distinct and potent inhibitor of neuraminidases protein of influenza A and B virus. Ribavirin Ribavirin also known as Virazole 1- d -ribofuranosyl-1,2,4-triazolecarboxamide has been reported as the first synthetic nucleoside analogue, which is active toward a broad spectrum of RNA viruses RSV, HCV, and influenza virus.

Favipiravir Favipiravir T , having chemical structure as 6-fluorohydroxypyrazine carboxamide, has been chiefly introduced for therapy of influenza virus infections.

Plant-derived phytochemicals with antiviral effects Plants are the foundational element of many medicinal structures under application today. Plant-derived ingredients have shown different kind of mechanisms against the activities of viruses: Immunomodulators The enhancement of defensive immune reaction is one of the most important mechanisms of antiviral treatment.

Virus attachment and entry inhibitors Another most important target for the antiviral therapy is the adjunction of virus to the host cell and its entrance. Modifiers of viral genome and protein processing Viral arrangement and mutation processes are the next important mechanism for an antiviral policy.

Virus assembly and release inhibitors These medicines hinder the transcription of newly amalgamated viral proteins into virions and their liberation out of the cell. Shikimic acid and its mode of action on influenza virus Shikimic acid having a chemical formula 3,4,5-trihydroxycyclohexenecarboxylic acid is an organic compound found naturally and is an important link in the pathway for the development of aromatic amino acids, lignin, and various alkaloids present in plants and microorganisms.

Plant sources of shikimic acid The isolation of shikimic acid from the fruit of Illicium religiosum was primarily reported by Ekmann in [18]. Whole plant Bharathi et al.

Biosynthesis of shikimic acid in plants Shikimic acid, obtained from star anise present in its anionic form shikimate, is a cyclohexanecarboxylic acid, a cyclohexene, and a cyclitol. Figure Other methods for the synthesis of shikimic acid Microbial synthesis The SA first isolated of microbial source was from Escherichia coli by Millcan [32].

Enzymatic approach Adachi et al. Usefulness of shikimic acid pathway The shikimic acid pathway is a biosynthetic pathway which is absent in mammals.

Shikimic acid isolation from plant raw materials The Illicium genus is the basic source of shikimic acid, and the acid was discovered in from its fruits.

Mechanism of action of oseltamivir As discussed above, oseltamivir commercialized under the trade name Tamiflu is an antiviral drug, which is being synthesized from shikimic acid. Conclusion Despite the rapid growth of pharmaceutical and biotechnological approaches, the development of effective antiviral therapy is still a challenge. We have studied certain properties, additional to those previously described 3 , of the virus of vesicular stomatitis of horses, and of the characteristic biological reactions of the virus of equine encephalomyelitis.

It has been found that the virus of stomatitis, ordinarily dermotropic, can acquire neurotropism and the neurotropic encephalomyelitis virus can, in turn, be rendered dermotropic in its action. The neurotropism in both instances is associated with definite, although not pronounced, viscerotropism. Both viruses can bring about a similar infection in the white mouse, rat, guinea pig, rabbit, and rhesus or cynomolgus monkeys.

Of these animals, rabbits show the lowest degree of susceptibility and mice the highest, especially after intracerebral inoculation. The mouse is the best animal for work with these viruses because of the uniform and rapidly lethal encephalitis which can be induced in it. Moreover, the mouse is highly sensitive to the instillation of the viruses in the nasal passages: 1 to 10 million dilution sufficing to induce a fatal encephalitis.

The uninjured nasal mucosa of mice appears, therefore, to be as susceptible to experimental infection as the traumatized brain or pads of animals. The microscopic changes accompanying the reactions to both viruses reveal, in rapidly lethal infections, pronounced destructive lesions in the cells of the central nervous system.

When the experimental disease is more protracted in its course, however, these lesions are associated with beginning productive, inflammatory reactions, consisting chiefly of mononuclear infiltrations. In the latter instances, characteristic, intranuclear inclusion bodies can be more readily observed. Both viruses can be cultivated with facility in the medium of minced chicken embryonic tissue suspended in Tyrode's solution, although 24 to 48 hour old chicks are refractory to artificial infection.

No cross-immunity reactions occur between the two strains of stomatitis virus or between them and the encephalomyelitis strain. The viruses are evidently similar in many biological properties. In view of the fact that the horse is the natural host for both, it is suggested that they may be generically related. They are not, of course, identical since cross-immunity between them does not exist. The absence of cross-immunity does not, however, exclude the possibility of a generic relationship, for there are at least three immunologically distinct types of foot-and-mouth disease, two of vesicular stomatitis, and two of equine encephalomyelitis 14 virus.