Antiviral compositions containing nucleic acid-derived nucleoside analogs and pharmaceutically acceptable salts thereof

Abstract

The present application relates to antiviral compositions, immune enhancing compositions, feeds or feed additives comprising nucleotide-derived nucleoside analogs.

Description

[Technical Field]

[0001] This application relates to antiviral, immunomodulatory and feed compositions comprising nucleic acid-derived nucleoside analogs and their pharmaceutically acceptable salts. [Background technology]

[0002] Viruses are infectious agents that infect not only animals and plants, but also microorganisms, causing various diseases and disrupting the life cycle of their hosts or even leading to death. Recently, various animal viruses, such as SARS-CoV-2, MERS, and influenza, have infected humans, causing enormous losses of life worldwide, posing a major challenge for humanity today. One solution to this situation could be to control viral diseases in animals, thereby freeing us from the fear of cross-species infectious viruses originating from animals.

[0003] Until recently, scientists have devoted endless passion and effort to various methods of research to control animal viruses, but no reliable method for complete control has yet been found. For example, the use of vaccines as bait for wild animals and commercial vaccinations for domestic and pet animals have been used, but the frequent mutation of viruses and the slow pace of vaccine development make it difficult to expect these methods to be fully effective in reality. Furthermore, as is well known, only by administering vaccines and treatments simultaneously and strictly adhering to quarantine rules can we achieve the level of effectiveness we expect.

[0004] In support of this assertion, we already know from experience that currently ongoing various vaccinations and large-scale national quarantines are not enough to completely control regional or global epidemics of animal viral diseases. Many scientists would agree that effective viral disease control may be possible if viral therapeutic agents are properly utilized as the final puzzle piece to create an effective virus-related solution in the current situation.

[0005] Furthermore, because it is not possible to prevent various viruses that constantly emerge according to the laws of nature, there is an increasing need for therapeutic or inhibitory agents that can control viruses after the fact, rather than preventive-level vaccines that are difficult to respond to quickly. However, humanity currently does not have an effective and efficient therapeutic agent for animal viruses, and as a result, humanity is still suffering enormous economic and human damage from various viruses transmitted from animals.

[0006] In this situation where there is a dire need for virus treatment drugs, priority should be given to viruses of economic animals and pets that are closely related to human life, This patent describes substances for effective viral growth inhibition against African Swine Fever Virus (ASFV), Classical Swine Fever Virus (CSFV), Low pathogenic Avian influenza virus (LPAIV), Canine coronavirus (CCoV), Canine adenovirus (CAV), Canine distemper virus (CDV), Feline parvovirus (FPV), Feline calicivirus (FCV), Feline infectious peritonitis virus (FIPV, also known as Feline Coronavirus (FCoV)), and Foot and Mouth disease virus (FMDV). Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present application is to provide antiviral, immunomodulatory or feed compositions comprising nucleic acid-derived nucleoside analogs and pharmaceutically acceptable salts thereof. [Means for solving the problem]

[0008] One aspect of the present application may be an antiviral composition containing a nucleoside of the dialdehyde form of inosine, the dialdehyde form of xanthosine, the dialdehyde form of guanosine, or the acyclic diol form of inosine, the acyclic diol form of xanthosine, or the acyclic diol form of guanosine.

[0009] One aspect of the present application may be an immunomodulatory composition comprising a nucleoside of the dialdehyde form of inosine, the dialdehyde form of xanthosine, the dialdehyde form of guanosine, or the acyclic diol form of inosine, the acyclic diol form of xanthosine, or the acyclic diol form of guanosine.

[0010] One aspect of the present application may be a pharmaceutical, feed, or feed additive comprising the antiviral composition.

[0011] Specifically, the composition may be a composition that exhibits an antiviral effect against one or more viruses selected from the group consisting of African swine fever virus (ASFV), classical swine fever virus (CSFV), low pathogenic avian influenza virus (LPAIV), canine coronavirus (CCoV), canine adenovirus (CAV), canine distemper virus (CDV), feline parvovirus (FPV), feline calicivirus (FCV), feline infectious peritonitis virus (FIPV, also known as feline coronavirus, FCoV), and foot and mouth disease virus (FMDV).

[0012] One aspect of the present application may be a method for preventing, ameliorating, or treating a virus, comprising administering to an individual a nucleoside that is the dialdehyde form of inosine, the dialdehyde form of xanthosine, the dialdehyde form of guanosine, or the acyclic diol form of inosine, the acyclic diol form of xanthosine, or the acyclic diol form of guanosine.

[0013] One aspect of the present application may be an immunomodulatory method comprising administering to an individual a nucleoside of the dialdehyde form of inosine, the dialdehyde form of xanthosine, the dialdehyde form of guanosine, or the acyclic diol form of inosine, the acyclic diol form of xanthosine, or the acyclic diol form of guanosine.

[0014] One aspect of the present application may be the use of a nucleoside of the dialdehyde form of inosine, the dialdehyde form of xanthosine, the dialdehyde form of guanosine, or the acyclic diol form of inosine, the acyclic diol form of xanthosine, or the acyclic diol form of guanosine for viral prophylaxis or treatment.

[0015] One aspect of the present application may be the immunomodulatory use of nucleosides of the dialdehyde form of inosine, the dialdehyde form of xanthosine, the dialdehyde form of guanosine, or the acyclic diol form of inosine, the acyclic diol form of xanthosine, or the acyclic diol form of guanosine. [Effects of the Invention]

[0016] The nucleic acid-derived nucleoside analogues according to the present application can be useful as antiviral agents. DETAILED DESCRIPTION OF THE INVENTION

[0017] The present application will be described in detail below.

[0018] The antiviral or immunomodulatory composition of the present application is a nucleoside analogue in the form of a dialdehyde or acyclic diol, and in one specific embodiment, it is characterized by containing, as an active ingredient, inosine, xanthosine, guanosine in the form of a dialdehyde or acyclic diol derived from nucleic acids represented by the following chemical formulas 1 to 6, and pharmaceutically acceptable salts thereof.

[0019] [ka] [ka]

[0020] The active ingredients, inosine, xanthosine, or guanosine in the dialdehyde or acyclic diol forms, can be produced through an optimized process, such as, but not limited to, the method described in the examples of the present invention.

[0021] In this case, the compound represented by Chemical Formulas 1 to 6 or a pharmaceutically acceptable salt thereof is used in an amount of 0.0001 to 20 parts by weight, 0.0001 to 15 parts by weight, 0.0001 to 10 parts by weight, 0.0001 to 5 parts by weight, 0.0001 to 1 part by weight, 0.0001 to 0.5 parts by weight, 0.0001 to 0.1 parts by weight, 0.0001 to 0.05 parts by weight, 0.0001 to 0.01 parts ...05 parts by weight, 0.0001 to 0.01 parts by weight, 0.0001 to 0.05 parts by weight, 0.0001 to 0.01 parts by weight, 0.0001 to 0.05 parts by weight, 0.0001 to 0.05 parts by weight, 0.0001 to 0.05 parts by weight, 0.0001 to 0.05 parts by weight, 0.0001 to 001~0.005 parts by weight, 0.0001~0.001 parts by weight, 0.0001~0.0005 parts by weight, 0.001 parts by weight~20 parts by weight, 0.001 parts by weight~15 parts by weight, 0.001 parts by weight~10 parts by weight, 0.00 1~5 parts by weight, 0.001~1 parts by weight, 0.001~0.5 parts by weight, 0.001~0.1 parts by weight, 0.001~0.05 parts by weight, 0.001~0.01 parts by weight, 0.001~0.005 parts by weight, 0.01 parts by weight Parts by weight ~ 20 parts by weight, 0.01 parts by weight ~ 15 parts by weight, 0.01 parts by weight ~ 10 parts by weight, 0.01 ~ 5 parts by weight, 0.01 parts by weight ~ 1 part by weight, 0.01 ~ 0.5 parts by weight, 0.01 ~ 0.1 parts by weight, 0.01 ~ 0.05 parts by weight parts, 0.1 parts to 20 parts by weight, 0.1 parts to 15 parts by weight, 0.1 parts to 10 parts by weight, 0.1 to 5 parts by weight, 0.1 parts to 1 part by weight, 0.1 to 0.5 parts by weight, 1 to 20 parts by weight, 1 to 15 parts by weight, 1 to 10 parts by weight However, if the compound or a pharmaceutically acceptable salt thereof is contained in an amount of less than 0.0001 part by weight, the antiviral effect of the compound will not be exhibited satisfactorily, and if it is contained in an amount exceeding 20 parts by weight, the increase in the antiviral effect will be insignificant compared to the increase in the compound content, which is not preferred.

[0022] The virus is not limited to any particular type, but may be a virus derived from a pet or farm animal, such as a cloven-hoofed animal (e.g., cow, pig, goat, sheep, deer), a fish, an arthropod, a dog, a cat, or a bird.

[0023] Examples of the viruses originating from cloven-hoofed animals such as cattle, pigs, goats, sheep, deer, etc., fish, arthropods, dogs, cats, or birds include, but are not limited to, African swine fever virus (ASFV), classical swine fever virus (CSFV), low pathogenic avian influenza virus (LPAIV), canine coronavirus (CCoV), canine adenovirus (CAV), canine distemper virus (CDV), feline parvovirus (FPV), feline calicivirus (FCV), feline infectious peritonitis virus (FIPV, also known as feline coronavirus, FCoV), and foot and mouth disease virus (FMDV). virus, FMDV).

[0024] Representative viruses among those for which antiviral efficacy has been verified in this application are described below.

[0025] African swine fever, caused by the African swine fever virus (ASFV), is a fatal viral hemorrhagic infectious disease with a 100% mortality rate, causing significant economic damage to the pig farming industry. ASFV has been occurring in Africa since the 1920s and is endemic in most of sub-Saharan Africa. It has also previously appeared in Europe and South America and was eventually eradicated, but it took more than 30 years to completely eradicate the disease in Spain and Portugal. Since African swine fever was introduced into Europe via the Republic of Georgia in 2007, the virus has spread widely among domestic pigs and wild boars in the region, and is now endemic in many Eastern European countries and parts of the Russian Federation.

[0026] ASFV cannot infect humans or other animals, and is only susceptible to animals in the Suidae family. Domestic pigs and wild boars are its natural hosts, and wild pigs in Africa, specifically warthogs and giant forest hogs, act as reservoirs for the virus because they show no clinical symptoms even when infected. The only animals carrying the virus, other than pigs, are soft ticks of the Ornithodoros genus, which act as vectors, spreading the disease by biting pigs and wild boars. Currently, there are no globally available vaccines or treatments, so the best strategy is to prevent the virus from entering each affected country.

[0027] Classical Swine Fever Virus (CSFV) causes an acute, systemic infectious disease, making it a Type 1 livestock infectious disease. When infected, animals develop a severe fever, and external symptoms such as spots on the skin are observed. At autopsy, bleeding spots in the bladder and kidneys, button-shaped ulcers in the ileocecal colon, and hemorrhagic infarction in the spleen are also observed. However, in the case of pigs with partial immunity or on farms where the disease is persistent, these specific symptoms are often absent.

[0028] A preventative measure is the administration of live attenuated vaccines, which can be effectively prevented by administering a vaccine that has been properly stored in a refrigerator according to an appropriate vaccination program. The disease has been eradicated in many countries, including the United States, and Japan has also established an eradication plan and is currently promoting it. In Korea, highly effective vaccines have been developed and are commercially available, making it possible to control disease outbreaks through appropriate vaccination. However, pig farmers avoid vaccination for economic reasons, and outbreaks continue to occur.

[0029] Avian influenza (AI) is a viral infectious disease caused by infection of pathogenic influenza viruses in wild birds and domestic poultry. Clinical symptoms and pathogenicity vary depending on the virulence of the virus, and it is divided into non-pathogenic, low-pathogenic, and highly pathogenic avian influenza. Highly pathogenic avian influenza (HPAI) is classified as a Type 1 livestock infectious disease in Korea and a List A disease by the World Organization for Animal Health (OIE). Most countries conduct thorough surveillance and testing in the event of an outbreak, and in the event of an outbreak, quarantine measures are taken to eradicate the disease, including the establishment of emergency quarantine lines, movement restrictions, and culling. Low-pathogenic avian influenza, on the other hand, is classified as a Type 2 livestock infectious disease in Korea, and quarantine measures are implemented to contain outbreaks, reduce damage, and limit the spread of the disease through vaccination.

[0030] All low-pathogenic avian influenza viruses occurring in Korea are H9N2 strains. First reported in 1996, these viruses have a low mortality rate. However, they have caused serious economic damage to layer farms by causing problems such as reduced egg production, eggshell discoloration, poor egg quality, and reduced feed intake (for meat chickens). The avian influenza virus can be transmitted through droplets, air, and water, primarily through direct contact with feces. In other words, feces can be directly transmitted to other chickens through contact with the boots and clothing of chicken managers, feed trucks, tools, equipment, and the surface of eggs. One gram of feces secreted by an infected chicken contains enough virus to infect approximately one million chickens. Therefore, thorough disinfection is crucial to prevent transmission. A killed H9N2 vaccine is commercially available, which reduces infection symptoms and minimizes economic losses for poultry farms. However, due to the lack of commercially available treatments or preventative medicines, chicken farms rely on simple quarantine measures.

[0031] Canine coronavirus (CCoV), a member of the Coronaviridae family, is a virus with a single-stranded RNA genome that causes canine coronavirus disease (CCD) in dogs. CCD outbreaks occurred in the United States in 1971, when the causative virus was isolated. Numerous cases of this disease have also been reported in Austria, Japan, and South Korea. CCoV is now recognized as one of the causative agents of canine viral diarrhea, as it can be mixed with canine pavovirus, further exacerbating symptoms. CCoV causes an acute viral gastrointestinal infection characterized by vomiting, diarrhea, and dehydration. While CCoV can infect both puppies and adult dogs, it is particularly prevalent in puppies, where symptoms are more pronounced. Dogs are susceptible regardless of breed or age, and it spreads rapidly and morbidity rates increase, with the disease appearing within a short period of time, particularly in group-housed dogs.

[0032] Commercially available vaccinations are available as a preventative measure against canine coronavirus infection, but caution is required regarding safety. For example, when a live attenuated canine distemper vaccine and a canine pavovirus vaccine were administered together, a side effect of encephalitis was reported. Effective treatments are currently unavailable, and symptomatic treatment through early diagnosis has been the most effective approach. Symptomatic treatments include sap therapy to keep dogs stable, warm, and minimize stress, and antibiotics to prevent secondary bacterial infections.

[0033] Canine adenovirus (CAV) is classified into CAV-1, which causes infectious canine hepatitis, and CAV-2, which causes kennel cough (canine bronchitis or the common cold). The natural hosts of CAV are canines, such as dogs, foxes, and coyotes. CAV is widespread worldwide and can infect animals of any breed, sex, or age. It is typically transmitted orally, and even after recovery, the virus remains partially in the kidneys and is excreted in urine for approximately six to nine months. Therefore, canines infected with this virus act as long-term carriers. After an incubation period of three to eight days after initial infection, the animal becomes weak, develops a runny nose and eye discharge, and exhibits an abnormal fever. These symptoms may also include diarrhea and vomiting. In particular, hepatic edema occurs and abdominal pain becomes severe, and in the final stages of hepatitis, jaundice also appears. In puppies with hepatitis, the eyes turn blue during the recovery period, resulting in "hepatitis blue eye."

[0034] There is no clear cure yet, and the main treatment is symptomatic treatment (antibiotic treatment to prevent secondary infection, sap treatment to balance the body's electrolytes and treat dehydration) to allow infected individuals to develop their own immunity and recover. A commercially available vaccine is available as a preventative measure, and the CAV-2 virus vaccine is used, which has protective capabilities against CAV-1 and CAV-2.

[0035] Canine distemper is caused by the canine distemper virus (CDV) and is a typical acute, febrile viral disease in dogs. After an incubation period of approximately 3-6 days, symptoms include rhinitis, fever, severe respiratory symptoms, impaired digestion, hardened paw pads, and neurological symptoms. It is highly contagious and has a high mortality rate, with nearly 100% mortality in cases where neurological symptoms are present. The disease primarily occurs in puppies under one year of age, although it can occasionally occur in older dogs. Known routes of transmission include feces, urine, and nasal secretions from infected dogs, and the virus can be shed for up to 60-90 days after infection.

[0036] The only countermeasure is preventive vaccination, with the first vaccination administered at two months of age, followed by booster vaccinations every three to four weeks, and additional vaccinations required annually.Current treatments consist only of symptomatic treatments, such as administering sulfa drugs or antibiotics to suppress secondary bacterial infections, and administering glucose or electrolyte supplements in cases of dehydration, as well as administering immune-boosting drugs to speed up recovery.

[0037] Feline panleukopenia (also known as feline infectious enteritis, commonly referred to as feline panleukopenia or feline infectious enteritis) is caused by the feline parvovirus (FPV). It is highly contagious and has a high mortality rate, making it fatal to all cat breeds. The name "panleukopenia" comes from the fact that infected animals exhibit a significant decrease in white blood cells. Infection is primarily caused by contact with the bodily fluids or feces of an infected animal. However, even without contact with these vectors, infection can occur through fleas or bedbugs that have come into contact with the vector. Transmission can also occur through bedding, food, or clothing or shoes worn by an infected animal. Clinical symptoms generally appear within 4 to 6 days of exposure, but can also appear within 2 to 14 days. The disease is not contagious to humans. The causative virus, FPV, is structurally very stable and is known to be able to survive for up to a year in the right environment. Furthermore, animals that have recovered from the disease may retain the virus in their feces for up to six weeks after recovery.

[0038] There are preventive vaccines available, primarily used in combination with vaccines containing many other diseases. Because panleukopenia is a serious disease in cats, preventive vaccinations are recommended for all cats. While no commercially available treatments are available to date, recombinant interferon ω has been shown to inhibit FPV proliferation in in vitro experiments. Symptomatic treatments include whole blood transfusions to increase white blood cell counts, and intravenous injections of sap containing antibiotics and vitamins A, B, and C to prevent sepsis due to dehydration.

[0039] Feline calicivirus (FCV) causes severe acute and chronic respiratory disease in cats. Cats infected with this virus may show clinical signs rapidly or gradually. In rare cases, no clinical signs are present, but symptoms may appear if the cat is stressed or its immune system is weakened. Common clinical signs include rhinitis, conjunctivitis, stomatitis, gingivitis, and glossitis. Pneumonia, fever, abortion, and cystitis are occasionally observed. Even after treatment, cats may shed the virus for months to years.

[0040] To date, there is no specific treatment for FCV infection, and antibiotics and immunomodulators are often prescribed to treat and prevent secondary infections. Treatment of stomatitis is difficult, and the use of steroids can worsen upper respiratory infection symptoms, so close monitoring is necessary. Feline calicivirus vaccines have been widely used for the past 20 years as a preventative measure for this disease, but vaccination does not provide 100% protection, making the development of a treatment urgent. Nevertheless, they are recommended because they can attenuate symptoms of FCV infection.

[0041] Feline infectious peritonitis is caused by a mutation of the feline coronavirus (FCoV). In approximately 10% of cats infected with feline coronavirus, viral mutations occur due to various causes, and they are known to proliferate within macrophages, causing systemic disease accompanied by immune-mediated vasculitis and suppurative granulomatous lesions.

[0042] Clinical symptoms of feline infectious peritonitis include weight loss, loss of appetite, and high fever, and vary depending on the affected organs. It can be divided into two types based on the lesion pattern: effusive (wet) and non-effusive (dry). Exudative feline infectious peritonitis is characterized by fibrinous peritonitis and pleuritis caused by a humoral immune response. Exudative fluid may develop in the peritoneal, pleural, or pericardial cavities, leading to systemic disease. Non-exudative feline infectious peritonitis is primarily mediated by humoral immunity, but cell-mediated immunity is also known to play a role. Granulomatous lesions in affected organs induce clinical symptoms. Neurological symptoms are particularly common in non-exudative forms compared to exudative forms.

[0043] Vaccines are available as a preventative measure, but veterinarians have differing opinions on their effectiveness. In other words, peritonitis can occur despite vaccination, and there are safety concerns (vaccines can induce disease), so vaccination is not recommended in most cases. Unfortunately, to date, it is an incurable disease that cannot be completely treated or cured, and symptomatic treatment is the only option. Symptomatic treatment also focuses on alleviating symptoms through immune regulation. In Japan, some veterinarians believe that treatment is possible with omega interferon, but it is not an official treatment, and many animals die despite its use, and it is very expensive, so it is not often used.

[0044] Foot-and-mouth disease virus (FMDV) is a small RNA virus classified into seven serotypes—A, O, C, Asia1, SAT1, SAT2, and SAT3—with these major serotypes further divided into over 80 subtypes. This virus infects animals with two cloven hooves (even-toed ungulates), including cattle, pigs, goats, sheep, and deer. While the mortality rate is relatively low, it causes blisters on the lips, tongue, nose, and between the hooves, leading to loss of appetite, elevated body temperature, stunted growth, impaired mobility, and, in dairy cows, reduced milk production, significantly reducing the commercial value of livestock. Due to its highly contagious nature, FMDV is classified as a List A disease by the World Organization for Animal Health (OIE) (a disease that spreads rapidly and causes significant economic damage to international trade). It is also designated as a Type 1 livestock infectious disease in Korea.

[0045] Currently, the only preventative measure is vaccination, but the level of cross-protection between viruses is very weak, so different vaccines must be applied depending on the serotype and subtype, and the preventive effect of vaccines does not last very long, about six months, so they must be administered at regular intervals, which is inconvenient.In addition, because vaccines produce the same antibodies as those produced by the actual disease, it is difficult to distinguish infected livestock from vaccinated livestock through blood tests.If vaccination is carried out, a country will not be certified as FMD-free, which will cause problems with the export of related livestock products, and this could cause major economic problems.

[0046] The pharmaceutically acceptable salts include acid addition salts formed with pharmaceutically acceptable free acids. Examples of the free acids include inorganic and organic acids. Examples of inorganic acids include hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, and phosphoric acid. Examples of organic acids include citric acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, and aspartic acid. Pharmaceutical compositions containing the nucleoside analogs represented by Chemical Formulas 1 to 6 of the present application may include not only pharmaceutically acceptable salts, but also all salts, hydrates, and solvates that can be prepared by conventional methods.

[0047] The addition salts of the present application can be prepared by a conventional method, for example, by dissolving a compound selected from the group consisting of the compounds represented by Chemical Formulas 1 to 6 in a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile, adding an excess amount of an organic acid or an aqueous solution of an inorganic acid, and then precipitating or crystallizing the resulting salt. The solvent or excess acid is then evaporated from the mixture, and the resulting mixture is dried to obtain the addition salt, or the precipitated salt can be filtered off with suction.

[0048] In addition, the composition may be selected from a pharmaceutical composition or a health food composition. In a specific embodiment, when the antiviral composition is a pharmaceutical composition, it may further comprise one or more additives selected from the group consisting of suitable carriers, excipients, disintegrants, sweeteners, coating agents, leavening agents, lubricants, flavoring agents, antioxidants, buffers, bacteriostats, diluents, dispersants, surfactants, binders, and lubricants commonly used in the preparation of pharmaceutical compositions. Specifically, carriers, excipients, and diluents that can be used include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, etc., which can be prepared by mixing the composition with at least one or more excipients, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc can also be used. Oral liquid preparations include suspensions, oral solutions, emulsions, syrups, etc., which may contain various excipients such as wetting agents, sweeteners, flavorings, preservatives, etc. in addition to commonly used simple diluents such as water and liquid paraffin. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, etc. Non-aqueous solvents and suspensions that can be used include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

[0049] In another embodiment of the present application, the pharmaceutical composition can be formulated and used as granules, powders, coated tablets, tablets, pills, capsules, suppositories, gels, syrups, suspensions, emulsions, infusions, or liquids by conventional methods. According to one embodiment of the present application, the pharmaceutical composition can be administered to a subject by conventional methods known in the art, for example, but not limited to, oral, intravenous, intraarterial, intramuscular, subcutaneous, intraarterial, intraperitoneal, intrasternal, transdermal, intranasal, inhalation, topical, rectal, intraocular, or intradermal routes.

[0050] The specific dosage of the compounds represented by Chemical Formulas 1 to 6 or pharmaceutically acceptable salts thereof may vary depending on the condition and weight of the subject, the type and severity of the disease, the drug form, the administration route and period, and can be appropriately selected by those skilled in the art.

[0051] In yet another specific example of the present application, the pharmaceutical composition may contain, relative to 100 parts by weight of the total pharmaceutical composition, 0.01 to 90 parts by weight, 0.01 to 50 parts by weight, 0.01 to 10 parts by weight, 0.01 to 5 parts by weight, 0.01 to 1 part by weight, 0.01 to 5 parts by weight, 0.01 to 1 part by weight, 0.01 to 0.1 parts by weight, 0.1 to 90 parts by weight, 0.1 to 50 parts by weight, 0.1 to 10 parts by weight, 0.1 to 5 parts by weight, 0.1 to 1 part by weight, 1 to 90 parts by weight, 1 to 50 parts by weight, 1 to 10 parts by weight, 1 to 5 parts by weight, 10 to 90 parts by weight, 10 to 70 parts by weight, 10 to 50 parts by weight, 10 to 30 parts by weight, or 10 to 20 parts by weight of a compound selected from the group consisting of compounds of Chemical Formulas 1 to 6 and pharmaceutically acceptable salts thereof, but the amount is not limited thereto.

[0052] According to one embodiment of the present application, when an appropriate amount for each livestock species is orally administered to animals as described below, but is not limited thereto, it is absorbed through intestinal epithelial cells, flows into the bloodstream, and diffuses to various organ tissues. In particular, it is delivered / absorbed by cells present in tissues where viruses grow, and inhibits viral growth in infected cells upon viral challenge, and as a result, it can be used as a therapeutic agent for virus-infected animals.

[0053] In the present application, the subject may be, but is not limited to, a mammal, a bird, a fish, or an arthropod. The mammal subject may be a pig, a cow, a dog, a cat, or a chicken. The fish subject may be a flounder, a salmon, a sea bream, an eel, a black rockfish, or a trout. The arthropod subject may be a shrimp or a lobster.

[0054] In yet another specific example of the present application, the health food may contain, relative to 100 parts by weight of the total health food, 0.01 to 90 parts by weight, 0.01 to 50 parts by weight, 0.01 to 10 parts by weight, 0.01 to 5 parts by weight, 0.01 to 1 part by weight, 0.01 to 5 parts by weight, 0.01 to 1 part by weight, 0.01 to 0.1 parts by weight, 0.1 to 90 parts by weight, 0.1 to 50 parts by weight, 0.1 to 10 parts by weight, 0.1 to 5 parts by weight, 0.1 to 10 parts by weight, 0.1 to 5 parts by weight, 0.1 to 1 part by weight, 1 to 90 parts by weight, 10 to 70 parts by weight, 10 to 50 parts by weight, 10 to 30 parts by weight, or 10 to 20 parts by weight of a compound selected from the group consisting of compounds of Chemical Formulas 1 to 6 and pharmaceutically acceptable salts thereof, but the amount is not limited thereto. In another specific example of the present application, the health food may further include one or more additives selected from the group consisting of organic acids, phosphates, antioxidants, lactose casein, dextrin, glucose, sugar, and sorbitol. The organic acids may be, but are not limited to, citric acid, malic acid, adipic acid, or lactic acid. The phosphates may be, but are not limited to, sodium phosphate, potassium phosphate, acid pyrophosphate, or polyphosphate (polymerized phosphate). The antioxidants may be, but are not limited to, natural antioxidants such as polyphenols, catechins, α-tocopherol, rosemary extract, licorice extract, chitosan, tannic acid, or phytic acid. In another specific example of the present application, the health food may contain, in addition to the active ingredients, various nutritional supplements, probiotics, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and enhancers (cheese, chocolate, etc.), pectinic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonation agents used in carbonated drinks, etc. According to one embodiment of the present application, the dosage form of the health food may be, but is not limited to, solid, powder, granule, tablet, capsule, liquid, or beverage form.Furthermore, the health food may be used to produce foods such as, but not limited to, confectioneries, sugars, ice cream products, dairy products, meat products, fish products, tofu or soybeans, edible oils and fats, noodles, tea, beverages, special nutritional foods, health supplements, seasonings, ice, ginseng products, kimchi pickles, dried foods, fruits, vegetables, dried fruit or vegetable products, cut products, fruit juice, vegetable juice, mixed juices thereof, chips, noodles, processed livestock foods, processed seafood foods, processed dairy foods, fermented milk foods, bean foods, grain foods, microbial fermented foods, confectioneries and breads, seasonings, processed meat products, acidic drinks, licorice, and snake plants.

[0055] The present application also provides a feed additive containing, as an active ingredient, a compound selected from the group consisting of compounds of Chemical Formulas 1 to 6 and pharmaceutically acceptable salts thereof.

[0056] In one embodiment, the feed additive of the present application may be applied in various forms, similar to the antiviral composition. Examples of formulation forms include, but are not limited to, liquids, suspensions, powders, granules, tablets, capsules, and pills. To formulate the feed additive in these forms, in addition to the active ingredient, one or more additives and excipients typically found in feed additives, such as diluents, lubricants, binders, disintegrants, sweeteners, stabilizers, and preservatives, may be selected and used. Flavorings, immune enhancers, and the like may also be mixed to provide additional functions. Specifically, the diluent may be lactose, corn starch, soybean oil, microcrystalline cellulose, or mannitol; the lubricant may be magnesium stearate or talc; and the binder may be polyvinylpyrrolidone or hydroxypropyl cellulose. The disintegrant may be calcium carboxymethylcellulose, sodium starch glycolate, polacrilin potassium, or crospovidone; the sweetener may be sucrose, fructose, sorbitol, aspartame, or nucleic acid (IMP, GMP); the stabilizer may be sodium carboxymethylcellulose, β-cyclodextrin, white beeswax, or xanthan gum; and the preservative may be methyl parahydroxybenzoate, propyl parahydroxybenzoate, or potassium sorbate.

[0057] The feed additive may be selected from the group consisting of mammals, fish, birds or arthropods, specifically pigs, cows, chickens, goats, sheep, horses, fish, shrimp, insects, dogs and cats, specifically but not limited to pigs, cows, chickens, dogs and cats. The feed additive is capable of suppressing the activity of a virus selected from the group consisting of African swine fever virus (ASFV), classical swine fever virus (CSFV), low pathogenic avian influenza virus (LPAIV), canine coronavirus (CCoV), canine adenovirus (CAV), canine distemper virus (CDV), feline parvovirus (FPV), feline calicivirus (FCV), feline infectious peritonitis virus (FIPV, also known as feline coronavirus (FCoV)), and foot and mouth disease virus (FMDV).

[0058] The feed additive may be fed to mammals, fish, birds, or arthropods, specifically pigs, cows, chickens, goats, sheep, horses, fish, shrimp, insects, dogs, or cats, in the same dosage and administration as the antiviral composition of the present application, and may be fed orally using a feeding method well known in the art, for example, by mixing with feed, but is not limited thereto.

[0059] In one embodiment, the feed additive of the present application may be added in various proportions such as 0.01 to 300 g, 1 g to 200 g, or 10 g to 100 g per 1 kg of feed on a dry weight basis (i.e., 0.001 wt % to 30 wt %, 0.1 wt % to 20 wt %, or 1 wt % to 10 wt % based on the total dry weight of the feed) to meet the above-mentioned dosage and administration, but is not limited thereto.

[0060] The antiviral material selected from the compounds of Formulas 1 to 6 and pharmaceutically acceptable salts thereof contained in the antiviral composition, pharmaceutical composition, or feed additive according to the present application effectively suppresses viral infection and proliferation by inhibiting the function of inosine monophosphate dehydrogenase (IMP Dehydrogenase, IMPDH), which produces GMP necessary for viruses to invade cells and replicate their genes, thereby starving the source of viral gene replication and thereby inhibiting smooth viral gene replication, or by causing abnormalities in the functional proteins of viruses that are generated as final products by insertion of guanosine analogs during the viral gene replication process, thereby reducing infectivity.

[0061] The well-known mechanisms of efficacy of some nucleoside analogues, such as immunomodulatory effects, increased expression of interferon stimulating factors, and inhibition of viral RNA polymerase, may also be the mechanisms of efficacy selected from the compounds of Chemical Formulas 1 to 6 and their pharmaceutically acceptable salts contained in the antiviral composition, pharmaceutical composition, or feed additive of the present application.

[0062] The present application will be described in detail below with reference to examples to facilitate understanding of the present application. However, the following examples are merely illustrative of the contents of the present application, and the scope of the present application is not limited to the following examples. The examples of the present application are provided to more completely explain the present application to those with average knowledge in the art.

[0063] [Example] Production Example 1: Production of nucleoside analogues using inosine monophosphate (IMP), xanthosine monophosphate (XMP), and guanosine monophosphate (GMP) 1-1. Method for producing dialdehyde nucleosides For oxidative cleavage, IMP, XMP, or GMP (manufactured and supplied by CJ CheilJedang) dissolved in water is prepared using periodate (NaIO4) as a catalyst and an organic solvent, then filtered using filter paper. The permeate is purified using an anion exchange resin (WA30) and freeze-dried to obtain the final product (Maria Meurillon et al., 2014 Eur. J. Med. Chem. 77:18-37).

[0064] 1-2. Method for producing acyclic diol nucleosides For oxidative cleavage, IMP, XMP, or GMP (manufactured and supplied by CJ CheilJedang) is dissolved in water and treated with periodate (NaIO4) as a catalyst in an organic solvent. The mixture is then filtered through filter paper, and the permeate is reduced by adding sodium borohydride (NaBH4), followed by freeze-drying to obtain the final product (Maria Meurillon et al., 2014 Eur. J. Med. Chem. 77:18-37).

[0065] Example 1: African Swine Fever Virus (ASFV) To evaluate the viral infection and inhibitory efficacy of the dialdehyde and acyclic diol forms of inosine, xanthosine, and guanosine against African swine fever virus (ASFV, China / 2018 / AnhuiXCGQ), porcine alveolar macrophages (PAM cell line) were cultured in 48-well plates at 0.5 x 10 5After seeding cells per well, the cells were cultured for one day. The following day, the cells were co-treated with ASFV at 1 MOI and the dialdehyde and acyclic diol forms of inosine, xanthosine, and guanosine. Two days later, DNA was extracted from infected cells using a Viral Gene (DNA / RNA) Extraction Kit (iNtRON, 101410754). The extracted DNA was subjected to real-time RT-qPCR analysis using ASFV-specific primers (F-AGTTCGGATGTCACAACGCT, R-ACTGGTTCCCTCCACCGATA) and a 95°C, 5-minute cycle, followed by 40 cycles of 95°C, 10 seconds, 65°C, 30 seconds, and 56°C, 60 seconds.

[0066] As can be seen from Table 1, when cells were treated with the dialdehyde and acyclic diol forms of inosine, xanthosine, and guanosine, ASFV infection and proliferation were inhibited. The dialdehyde form of guanosine showed the highest efficacy (IC 50 :79.0μM), and showed antiviral effects in the order of inosine, xanthosine. Furthermore, acyclic diol materials also showed antiviral efficacy against ASFV in the order of guanosine, inosine, and xanthosine.

[0067] [Table 1]

[0068] Example 2: Classical Swine Fever Virus (CSFV) To evaluate the viral infection and inhibitory efficacy of dialdehyde and acyclic diol forms of inosine, xanthosine, and guanosine against classical swine fever virus (CSFV), pig kidney cells (PK15 cell line) were plated at 1x10 in a 96-well plate. 4 After seeding at cells / well, 100 TCID 50 Cells were co-treated with 1 / well of CSFV and the dialdehyde and acyclic diol forms of inosine, xanthosine, and guanosine. After two days, RNA was isolated from infected cells using a commercially available Viral RNA extraction kit (Ribospin™ vRD II). The isolated RNA was subjected to real-time RT-qPCR testing (95°C, 15 minutes, 1 cycle, 95°C, 20 seconds, 58°C, 40 seconds, 40 cycles) using CSFV-specific primers (F-CTCTGGTCAGGGTGCTCAAG, R-GAGGGACTGTGCAACCATCA) to test the antiviral efficacy of the materials.

[0069] As can be seen from Table 2, the dialdehyde and acyclic diol forms of inosine, xanthosine, and guanosine were confirmed to be effective in inhibiting CSFV infection and proliferation. The dialdehyde form of xanthosine showed the highest efficacy (IC 50 The IC50 values ​​were 156.7 μM, with guanosine showing the highest antiviral effect, followed by inosine and then by inosine. In addition, the IC50 values ​​for the acyclic diol forms were 156.7 μM, followed by inosine, xanthosine, and then guanosine. 50 values, and have a relatively higher IC than the dialdehyde form of the material. 50 The values ​​were shown.

[0070] [Table 2]

[0071] Example 3: Low pathogenic Avian influenza virus (LPAIV) To evaluate the efficacy of dialdehyde and acyclic diol forms of inosine, xanthosine, and guanosine in inhibiting viral infection and proliferation against low pathogenic avian influenza (LPAIV, H9N2), canine kidney (MDCK) cell line cells were cultured in a 96-well plate at 1.4 × 10 4 After seeding cells / well, the cells were cultured for one day. The next day, 20 TCID 50 Cells were co-treated with 1 / well of LPAIV and the dialdehyde and acyclic diol forms of inosine, xanthosine, and guanosine. Two days later, RNA was isolated from infected cells using a commercially available viral RNA extraction kit (Ribospin™ vRD II). The extracted RNA was subjected to real-time RT-qPCR testing (95°C, 15 minutes, 1 cycle, 95°C, 20 seconds, 58°C, 40 seconds, 40 cycles) using LPAIV-specific primers (F-GCTAGGCAGATGGTACAGGC, R-TGCACTCCCATCCGTTTCTG) to test the antiviral efficacy of the material.

[0072] As can be seen from Table 3, the dialdehyde form of guanosine had the best efficacy (IC 50 The results showed that xanthosine, inosine, and xanthosine were effective in inhibiting viral infection and proliferation, respectively. In addition, the acyclic diol materials showed antiviral efficacy against LPAIV in the order of guanosine, inosine, and xanthosine.

[0073] [Table 3]

[0074] Example 4: Canine coronavirus (CCoV) To evaluate the viral infection and inhibitory efficacy of dialdehyde and acyclic diol forms of inosine, xanthosine, and guanosine against canine coronavirus (CCoV), canine fibroblasts (A-72 cell line) were cultured in 96-well plates at 1.4 x 10 4 After seeding cells / well, the cells were cultured for one day. The next day, 50 TCID 50 Cells were co-treated with 1000p / well of CCoV and the dialdehyde and acyclic diol forms of inosine, xanthosine, and guanosine. Two days later, RNA was extracted from infected cells using a commercially available Viral RNA extraction kit (Ribospin™ vRD II). The extracted RNA was subjected to real-time RT-qPCR testing (one cycle of 95°C for 15 minutes, followed by 40 cycles of 95°C for 20 seconds and 58°C for 40 seconds) using CCoV-specific primers (F-TGAAGGTGTGCCAACTGGTGT, R-GCCCATCCTGTCGCACTACT) to test the antiviral efficacy of the material.

[0075] As can be seen from Table 4, dialdehyde forms of inosine and xanthosine have excellent efficacy (IC 50 45.1 μM and 43.0 μM), and guanosine had an IC of 109.7 μM. 50 Furthermore, the antiviral efficacy of acyclic diol materials against CCoV was observed in the order of inosine, guanosine, and xanthosine.

[0076] [Table 4]

[0077] Example 5: Canine adenovirus (CAV) To evaluate the viral infection and inhibitory efficacy of dialdehyde and acyclic diol forms of inosine, xanthosine, and guanosine against canine coronavirus (CAV), monkey kidney cells (Vero cell line) were cultured in 96-well plates at 2 x 10 4 After seeding cells / well, the cells were cultured for one day. The next day, 100 TCID 50 Cells were co-treated with 1 / well of CAV and the dialdehyde and acyclic diol forms of inosine, xanthosine, and guanosine. Two days later, DNA was extracted from infected cells using a commercially available Viral Gene (DNA / RNA) Extraction Kit (iNtRON, 101410754). The extracted DNA was subjected to real-time RT-qPCR testing (95°C, 5 minutes, 1 cycle, 95°C, 15 seconds, 60°C, 30 seconds) using CAV-specific primers (F-CGCTGAACATTACTACCTTGTC, R-GCAGAGTCTAGAACAAATGGC) to verify the antiviral efficacy of the material.

[0078] As can be seen from Table 5, the dialdehyde and acyclic diol forms of inosine, xanthosine, and guanosine were confirmed to be effective in inhibiting CAV infection and proliferation. The dialdehyde form of guanosine showed the best efficacy (IC 50:85.9μM), and the order of antiviral effects was xanthosine, inosine, and guanosine. In addition, the acyclic diol forms showed antiviral effects in the order of xanthosine, inosine, and guanosine, and had relatively higher IC than the dialdehyde form. 50 The values ​​were shown.

[0079] [Table 5]

[0080] Example 6: Canine distemper virus (CDV) To evaluate the viral infection and inhibitory efficacy of dialdehyde and acyclic diol forms of inosine, xanthosine, and guanosine against canine coronavirus (CDV), monkey kidney cells (Vero cell line) were cultured in 96-well plates at 2 x 10 4 After seeding cells / well, the cells were cultured for one day. The next day, 100 TCID 50 Cells were co-treated with 1000p / well of CAV and the dialdehyde and acyclic diol forms of inosine, xanthosine, and guanosine. After three days, RNA was extracted from infected cells using a commercially available Viral RNA extraction kit (Ribospin™ vRD II). The extracted RNA was subjected to real-time RT-qPCR testing using CDV-specific primers (F-GCTTACTTCAGACTCGGGCAAGAAATGGTTA, R-CAGTAGCTCGAATTGTCCGGTCCTCTGTTGT) and a 10-minute cycle of 95°C, followed by 40 cycles of 95°C for 15 seconds, 60°C for 30 seconds, and 72°C for 30 seconds.

[0081] As can be seen from Table 6, the dialdehyde form of xanthosine showed the best efficacy (IC 50 The IC50 concentration was 79.9 μM, and the inhibitory effects on viral infection and proliferation were confirmed in the order of inosine and guanosine. The acyclic diol material showed a slightly higher IC50 concentration than the dialdehyde material. 50 The antiviral efficacy was indicated by the values, and the order of efficacy was confirmed to be xanthosine, guanosine, and inosine.

[0082] [Table 6]

[0083] Example 7: Feline parvovirus (FPV) To evaluate the viral infection and inhibitory efficacy of the dialdehyde and acyclic diol forms of inosine, xanthosine, and guanosine against feline pavovirus (FPV), feline kidney (CRFK) cell line cells were cultured in 48-well plates at 3 x 10 4 After seeding cells at 100 TCID per well, the cells were cultured for one day. 50 Cells were co-treated with 1000µg / well of FPV and the dialdehyde and acyclic diol forms of inosine, xanthosine, and guanosine. After two days, DNA was extracted from infected cells using a commercially available Viral Gene (DNA / RNA) Extraction Kit (iNtRON, 101410754). The extracted DNA was subjected to real-time RT-qPCR testing using FPV-specific primers (F-AGAGCATTGGGCTTACCACC, R-CCCCATTTGAGTTACACCACG) and a 95°C, 15-minute cycle, followed by 40 cycles of 95°C, 20 seconds, 58°C, 30 seconds, and 72°C, 30 seconds.

[0084] As can be seen from Table 7, treatment of cells with dialdehyde and acyclic diol forms of inosine, xanthosine, and guanosine inhibited FPV infection and proliferation. Dialdehyde form of xanthosine showed the highest efficacy (IC 50 The IC50 values ​​were 31.0 μM, with guanosine being the most effective, followed by inosine. In addition, the IC50 values ​​for acyclic diols were 31.0 μM, followed by guanosine, inosine, and xanthosine. 50 I was able to check the value.

[0085] [Table 7]

[0086] Example 8: Verification of the efficacy of suppressing infection with feline calicivirus (FCV) To evaluate the viral infection and inhibitory efficacy of the dialdehyde and acyclic diol forms of inosine, xanthosine, and guanosine against feline calicivirus (FCV), feline kidney (CRFK) cell line cells were cultured in 48-well plates at 3 x 10 4 After seeding cells at 100 TCID per well, the cells were cultured for one day. 50Cells were co-treated with 1 / well of FCV and the dialdehyde and acyclic diol forms of inosine, xanthosine, and guanosine, respectively. After 24 hours, RNA was extracted from infected cells using a commercially available Viral RNA extraction kit (Ribospin™ vRD II). The extracted RNA was subjected to real-time RT-qPCR testing using FCV-specific primers (F-GCAAAGATCCGGCTTGCCTC, R-CGCTGTTGACCAAGTGCAGC) and a 15-minute cycle of 95°C, followed by 40 cycles of 95°C for 20 seconds, 58°C for 30 seconds, and 72°C for 30 seconds.

[0087] As can be seen from Table 8, treatment of cells with dialdehyde and acyclic diol forms of inosine, xanthosine, and guanosine inhibited FCV infection and proliferation. Dialdehyde form of guanosine showed the highest efficacy (IC 50 The results showed that xanthosine, inosine, and guanosine were most effective in the acyclic diol form.

[0088] [Table 8]

[0089] Example 9: Feline infectious peritonitis virus (FIPV) To evaluate the viral infection and inhibitory efficacy of the dialdehyde and acyclic diol forms of inosine, xanthosine, and guanosine against feline peritonitis virus (FIPV), fetal feline (FCWF-4) cells were cultured in a 96-well plate at 2 x 10 4 After seeding cells / well, the cells were cultured for one day. The next day, 100 TCID 50 Cells were co-treated with 1 / well of FIPV and the dialdehyde and acyclic diol forms of inosine, xanthosine, and guanosine. Two days later, RNA was extracted from infected cells using a commercially available viral RNA extraction kit (Ribospin™ vRD II). The extracted RNA was subjected to real-time RT-qPCR testing (one cycle of 95°C for 15 minutes, followed by 40 cycles of 95°C for 30 seconds and 58°C for 40 seconds) using FIPV-specific primers (F-TGGCATCTTGCTAACTGGAACT, R-TGCCATAAACGAGCCAGCTA) to test the antiviral efficacy of the material.

[0090] As can be seen from Table 9, dialdehyde inosine has excellent inhibitory effect on FIPV infection and proliferation (IC 50 : 45.5μM), and the order of superior effects was confirmed for guanosine and xanthosine. Nevertheless, the IC 50 The difference in values ​​was not large. Furthermore, the acyclic diol forms showed antiviral efficacy against FIPV in the order of inosine, xanthosine, and guanosine.

[0091] [Table 9]

[0092] Example 10: Foot and Mouth disease virus (FMDV) To evaluate the efficacy of dialdehyde forms of inosine and guanosine and acyclic diol forms of inosine, xanthosine, and guanosine in suppressing infection with foot-and-mouth disease virus (FMDV), hamster kidney cells (BHK-21 cell line) were cultured in 48-well plates at 5 x 10 4 After seeding cells per well, the cells were cultured for one day. The next day, the cells were co-treated with FMDV at an MOI of 0.01 and the dialdehyde forms of inosine and guanosine, and the acyclic diol forms of inosine, xanthosine, and guanosine. 36 hours later, RNA was extracted from the infected cells using a commercially available Viral RNA extraction kit (Ribospin™ vRD II). The extracted RNA was subjected to real-time RT-qPCR using FMDV-specific primers (F-CCGACCCCTCATTCAGCAGACCTC, R-GAGGGTTCTTTTCCGCGTCGCC) and a melting curve consisting of one cycle of 95°C for 5 minutes, 95°C for 10 seconds, 60°C for 30 seconds, and 40 cycles, followed by one cycle of 95°C for 15 seconds, 60°C for 60 seconds, and 95°C for 15 seconds. The antiviral efficacy of the material was verified.

[0093] As can be seen from Table 10, the dialdehyde form of guanosine has excellent inhibitory efficacy (IC) against infection and proliferation of FMDV. 50 The acyclic diol forms of the materials showed antiviral efficacy against FMDV in the order of inosine, xanthosine, and guanosine, but had slightly higher IC than the dialdehyde forms. 50 The values ​​were shown.

[0094] [Table 10]

[0095] Example 11: Evaluation of the immune-enhancing efficacy of nucleic acid-derived nucleoside analogs One of the major antiviral mechanisms of nucleoside analogues is the enhancement of interferon-stimulating gene expression (Johnson YN Lau, et al. 2002. Mechanism of action of ribavirin in the combination treatment of chronic HCV infection. Hepatology. 35(5):1002-9. Doi: 10.1053 / jhep.2002.32672, Paeshuyse J., et al., 2011. Ribavirin for the treatment of chronic hepatitis C virus infection: a review of the proposed mechanism of action. Curr. Opin. Virol. 1: 590-598. Doi: To confirm this, we used the dialdehyde forms of inosine, xanthosine, and guanosine, as well as the acyclic diol forms of inosine, xanthosine, and guanosine, to evaluate their effect on increasing the expression of ISG15, Mx1, and RNaseL, which are representative interferon-stimulating genes that are crucial for inducing an antiviral immune state. Porcine alveolar macrophages (PAM cell line) were plated at 1x10 in a 48-well plate. 5After seeding cells per well, the cells were cultured for one day. The next day, the cells were treated with the dialdehyde forms of inosine, xanthosine, and guanosine, or the acyclic diol forms of inosine, xanthosine, and guanosine. After 12 hours, RNA was extracted from the infected cells using a commercially available easy-spin [DNA-free] total RNA extraction kit (iNtRON). The extracted RNA was subjected to gene quantification using porcine beta-actin (F-GACCACCTTCAACTCGATCA, R-GTGTTGGCGTAGAGGTCCTT) to ensure uniformity. The expression of immunomodulatory factors in the samples was then assessed using real-time RT-qPCR with ISG15, Mx1, and RNaseL-specific primers (ISG15: F-GGTGCAAAGCTTCAGAGACC, R-GTCAGCCAGACCTCATAGGC; Mx1: F-AGCGCAGTGACACCAGCGAC, R-GCCCGGTTCAGCCTGGGAAC; RNaseL: F-GCCAGACCTAGTGGCTTCTG, R-AGAGGCCCAGAGAGTTGTGA). One cycle of 95°C for 5 minutes was followed by 40 cycles of 95°C for 10 seconds, 65°C for 30 seconds, and 56°C for 60 seconds.

[0096] As can be seen from Table 11, the dialdehyde and acyclic diol forms of inosine, xanthosine, and guanosine were confirmed to increase the expression of interferon-stimulating genes (ISG15, Mx1, and RNaseL). The dialdehyde forms of inosine, xanthosine, and guanosine increased ISG15 gene expression by 4-4.7-fold, Mx1 gene expression by 3.5-fold, and RNaseL gene expression by 2.5-3.4-fold. The acyclic diol forms of inosine, xanthosine, and guanosine increased ISG15 gene expression by 4.2-6.3 fold, Mx1 gene expression by 2.8-4.0 fold, and RNaseL expression by 1.7-3.0 fold. This increase in interferon-stimulating genes indicates that dialdehyde- and acyclic diol-form materials have an immune-enhancing effect by inducing antiviral efficacy.

[0097] [Table 11]

Claims

1. An antiviral composition comprising one or more nucleoside analogs selected from the group consisting of nucleoside analogs of the following chemical formulas 1 to 6 and pharmaceutically acceptable salts thereof: 【Chemistry 1】 【Chemistry 2】

2. The viruses include African Swine Fever Virus (ASFV), Classical Swine Fever Virus (CSFV), Low Pathogenic Avian Influenza Virus (LPAIV), Canine Coronavirus (CCoV), Canine Adenovirus (CAV), Canine Distemper Virus (CDV), Feline Parvovirus (FPV), and Feline Calicivirus (FPV).

2. The composition of claim 1, wherein the virus is one or more viruses selected from the group consisting of feline infectious peritonitis virus (FIPV, also known as feline coronavirus (FCoV)), feline infectious peritonitis virus (FIPV, also known as feline coronavirus (FCoV)), and foot and mouth disease virus (FMDV).

3. An immunomodulatory composition comprising one or more nucleoside analogs selected from the group consisting of nucleoside analogs of the following formulas 1 to 6 and pharmaceutically acceptable salts thereof: 【Transformation 3】 【Chemistry 4】

4. 3. The composition according to claim 1 or 2, characterized in that it is a pharmaceutical composition or a food composition.

5. A feed additive comprising one or more nucleoside analogs selected from the group consisting of nucleoside analogs of the following chemical formulas 1 to 6 and pharmaceutically acceptable salts thereof: 【Transformation 5】 【Transformation 6】

6. The feed additive according to claim 5, which is for mammals, birds, fish or arthropods.

7. A feed comprising one or more nucleoside analogs selected from the group consisting of nucleoside analogs of the following chemical formulas 1 to 6 and pharmaceutically acceptable salts thereof: 【Transformation 7】 【Transformation 8】

8. 8. The feed of claim 7, which is for mammals, birds, fish or arthropods.

9. A method for preventing, ameliorating, or treating a virus, comprising administering to an individual one or more nucleoside analogs selected from the group consisting of nucleoside analogs of the following formulas 1 to 6 and pharmaceutically acceptable salts thereof: 【Chemistry 9】 【Chemistry 10】

10. An immunomodulatory method comprising the step of administering to an individual one or more nucleoside analogs selected from the group consisting of nucleoside analogs of the following formulas 1 to 6 and pharmaceutically acceptable salts thereof: 【Chemistry 11】 【Chemistry 12】

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