CN115716831A

CN115716831A - MAT2A inhibitor and application thereof in antivirus

Info

Publication number: CN115716831A
Application number: CN202110982643.0A
Authority: CN
Inventors: 杨巍维; 陈罗泉
Original assignee: Center for Excellence in Molecular Cell Science of CAS
Current assignee: Center for Excellence in Molecular Cell Science of CAS
Priority date: 2021-08-25
Filing date: 2021-08-25
Publication date: 2023-02-28

Abstract

The invention belongs to the field of antivirus, and discloses an MAT2A inhibitor or pharmaceutically acceptable salts, esters, isomers, prodrugs, polymorphs or solvates thereof and application thereof in antivirus. The invention also discloses application of a pharmaceutical composition containing MAT2A inhibitor related compounds in preparing a medicament for preventing and/or treating virus infection diseases. The MAT2A inhibitor is used as an antiviral active ingredient, can effectively inhibit the replication of viruses and prolong the life cycle, thereby having wide clinical application prospect.

Description

MAT2A inhibitor and application thereof in antivirus

Technical Field

The present invention is in the field of antiviral agents, and relates to the use of MAT2A inhibitors in antiviral agents, and to methods of delaying, reducing or inhibiting viral growth and/or functional activity.

Background

Many viruses are important human pathogens, and viral diseases such as SARS (Severe acute respiratory syndrome) and avian influenza etc. raise the global epidemic storm, and the new emergence of influenza virus is also a constant threat to mankind. Currently, antiviral drugs in the market are mainly classified into interferon and nucleoside drugs. Interferon is used as an antiviral drug, although the interferon is widely applied clinically, the toxic and side effects of the interferon are ubiquitous, fever and flu-like syndrome are common, and weight loss, alopecia, emotional activated thrombocytopenia, endocrine system dysfunction and the like of a patient are common; in addition, interferon is too expensive and places a heavy economic burden on most patients. The nucleoside drugs have high drug resistance rate, rebound occurs after most patients stop taking the medicine, the course of treatment is difficult to determine, and some nucleoside drugs have renal toxicity and have toxicity on mitochondria of renal epithelial cells.

To improve the prospects for the treatment and prevention of viral infections, there is a great need to develop new compositions and methods of treatment that are effective against viral infections, e.g., against viral infections associated with high morbidity and mortality, against ongoing or potential viral evolution.

Disclosure of Invention

Methionine adenosyltransferase 2A (MAT 2A) is a key enzyme in the synthesis of S-adenosylmethionine (SAM) in vivo, and MAT2A catalyzes the production of SAM from methionine and Adenosine Triphosphate (ATP). The MAT2A inhibitor (MAT 2A inhibitor) can inhibit the enzyme activity of MAT2A, thereby inhibiting the synthesis of SAM. The MAT2A inhibitor reported at present can be used for resisting tumors, aging and the like, but the application of the MAT2A inhibitor in antivirus is not reported and described.

The invention aims to provide a MAT2A inhibitor and application thereof in preparing antiviral drugs, and provides a novel method and a pharmaceutical composition for preventing and/or treating viruses.

One aspect of the present invention is to provide MAT2A inhibitors or pharmaceutically acceptable salts, esters, isomers, prodrugs, polymorphs, or solvates thereof and their use in the preparation of antiviral medicaments.

Further, the MAT2A inhibitor has a structure shown in a formula I:

wherein R is ¹ 、R ² 、R ³ 、R ⁴ Independently selected from aryl, substituted aryl, heteroaryl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxy-alkoxy or heterocyclyloxy, alkylamino;

wherein the substituent for the substituted aryl group is selected from alkyl (preferably C1-C10 alkyl), cycloalkyl (preferably C1-C6 cycloalkyl), haloalkyl (preferably C1-C10 haloalkyl), haloalkoxy (preferably C1-C10 haloalkoxy), alkoxy (preferably C1-C10 alkoxy), hydroxy, halogen (F, cl, br, I), cyano, alkoxycarbonyl (preferably C1-C10 alkoxycarbonyl), hydroxyalkyl (preferably C1-C10 hydroxyalkyl), alkoxyalkyl (preferably C1-C10 alkoxyalkyl) or aminoalkyl (preferably C1-C10 aminoalkyl);

wherein heterocyclyl or heteroaryl may be substituted by a group independently selected from alkyl (preferably C1-C10 alkyl), cycloalkyl (preferably C1-C6 cycloalkyl), haloalkyl (preferably C1-C10 haloalkyl), haloalkoxy (preferably C1-C10 haloalkoxy), alkoxy (preferably C1-C10 alkoxy), hydroxy, halogen (F, cl, br, I), cyano, alkoxycarbonyl (preferably C1-C10 alkoxycarbonyl), hydroxyalkyl (preferably C1-C10 hydroxyalkyl), alkoxyalkyl (preferably C1-C10 alkoxyalkyl) or aminoalkyl (preferably C1-C10 aminoalkyl).

Another aspect of the present invention is to provide an antiviral composition comprising a therapeutically effective amount of a MAT2A inhibitor as described in the above-mentioned use, or a pharmaceutically acceptable salt, ester, isomer, prodrug, polymorph or solvate thereof, in admixture with at least one pharmaceutically acceptable excipient.

In another preferred embodiment, the composition comprises a pharmaceutical composition, a food composition or a nutraceutical composition.

In another preferred embodiment, the dosage form of the composition is selected from the group consisting of: injection, injectable sterile powder, tablet, capsule, spirit, powder, granule, syrup, solution, tincture, aerosol, powder spray, or suppository.

In the present invention, the pharmaceutical composition may also be administered in combination with at least one immune system modulator and/or at least one antiviral agent that inhibits replication of HCV.

Another aspect of the present invention provides the use of the pharmaceutical composition for the preparation of a medicament for the prevention and/or treatment of a viral infection.

In the invention, the virus is one or more of single-stranded RNA, double-stranded RNA virus and DNA virus. In a specific embodiment, the virus is vesicular stomatitis virus.

In another aspect the invention provides a method of inhibiting a virus in vitro (preferably non-therapeutically), said method comprising: administering to a subject in need of virus inhibition an effective amount of a MAT2A inhibitor as described above, or a pharmaceutically acceptable salt, ester, isomer, prodrug, polymorph or solvate thereof.

Compared with the prior art, the invention has the beneficial effects that:

the invention creatively uses MAT2A inhibitor for resisting virus infection. In vitro and in vivo virus inhibition tests show that the MAT2A inhibitor provided by the invention has an unexpected good virus inhibition effect, and particularly has a good inhibition function on VSV virus RNA replication and inhibits the functional activity of the VSV virus RNA replication.

The MAT2A inhibitor can effectively resist and inhibit virus infection, prolongs the life cycle, has broad-spectrum antiviral effect and has no toxic or side effect on animals.

The application range of the MAT2A inhibitor is expanded, and the MAT2A inhibitor can be further developed into a novel antiviral drug. The invention expands the source range of antiviral drugs.

Drawings

Figure 1 is a graph of the effect of MAT2A inhibitor on viral infection in mouse primary peritoneal macrophages in vitro.

Figure 2 is a graph of the effect of MAT2A inhibitor on mouse viral infection in vivo. Wherein A is VSV RNA replication in organs (liver, spleen, lung); b is the TCID of half of the organs (liver, spleen and lung) ₅₀ ) (ii) a C is lung section H&E staining for diseaseLung injury in mice after toxic infection.

FIG. 3 is a graph of the effect of MAT2A inhibitors on survival of mice following VSV virus infection.

Detailed Description

Through years of research on the catalytic action of MAT2A, the present inventors have surprisingly found that inhibition of MAT2A prevents viral infection and inhibits viral replication, and that the antiviral effect is excellent. The present invention aims to provide the use of MAT2A inhibitors in antiviral agents for the prevention and/or treatment of viral infections.

The present invention provides the use of a MAT2A inhibitor or a pharmaceutically acceptable salt, ester, isomer, prodrug, polymorph or solvate thereof in a medicament for the prevention and/or treatment of a viral infection.

Further, the MAT2A inhibitor has the following structure:

in the formula I, R ¹ 、R ² 、R ³ 、R ⁴ Independently selected from aryl, substituted aryl, heteroaryl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxy alkoxy or heterocyclyloxy, alkylamino;

wherein heterocyclyl or heteroaryl may be substituted by groups independently selected from alkyl (preferably C1-C10 alkyl), cycloalkyl (preferably C1-C6 cycloalkyl), haloalkyl (preferably C1-C10 haloalkyl), haloalkoxy (preferably C1-C10 haloalkoxy), alkoxy (preferably C1-C10 alkoxy), hydroxy, halogen (F, cl, br, I), cyano, alkoxycarbonyl (preferably C1-C10 alkoxycarbonyl), hydroxyalkyl (preferably C1-C10 hydroxyalkyl), alkoxyalkyl (preferably C1-C10 alkoxyalkyl) or aminoalkyl (preferably C1-C10 aminoalkyl);

preferably, R ¹ Is a benzene ring.

Preferably, R ² Is a benzene ring.

Preferably, R ³ Is composed of

Preferably, R ⁴ Is composed of

Further preferably, the MAT2A inhibitor has the formula C31H22N6OS, and the structure is a compound represented by formula I below:

in the compound and the application thereof, the active compound, namely MAT2A inhibitor or pharmaceutically acceptable salt, ester, isomer, prodrug, polymorph or solvate has antiviral activity, can reduce, delay or inhibit the growth and/or replication of viruses, has a prevention and/or treatment effect on viral infection, and is an antiviral agent effective on the viruses.

In the compound and the application thereof, the salt and ester of the MAT2A inhibitor can be used in the form of pharmaceutically or physiologically acceptable salt or ester. By "pharmaceutically acceptable salt" is meant generally any salt which is physiologically tolerable (meaning generally non-toxic, in particular as a result of counterions) when used in an appropriate manner in therapy, in particular when applied or used in humans and/or mammals. These physiologically acceptable salts may be formed with cations or bases and in the context of the present invention, especially when administered in humans and/or mammals, they are to be understood as being salts formed from at least one compound provided according to the invention, usually an acid (deprotonated), such as an anion, and at least one physiologically tolerated cation, preferably an inorganic cation. In the context of the present invention, salts with alkali metals and alkaline earth metals, and salts with ammonium cations (NH 4 +) may be specifically included, and specifically may include, but are not limited to, salts with (mono) or (di) sodium, (mono) or (di) potassium, magnesium or calcium. These physiologically acceptable salts may also be formed with anions or acids, and in the context of the present invention, in particular when administered in humans and/or mammals, they are to be understood as being salts formed by at least one compound, usually protonated, such as a cation and at least one physiologically tolerable anion, provided according to the present invention. Salts and esters of the MAT2A inhibitor include, but are not limited to, salts and esters with: hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, succinic acid, oxalic acid, fumaric acid, maleic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or isethionic acid. Salts of halides are also suitable. Other salts include: salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium.

In the compounds and their use of the present invention, the term "prodrug" refers to a compound that undergoes a metabolic or chemical reaction in the human body to convert it into the active MAT2A inhibitor or a pharmaceutically acceptable salt, ester, isomer, prodrug, polymorph or solvate thereof, when administered by an appropriate method.

The compounds of the invention and their use are useful in the prevention or treatment of dominant or latent infections caused by single or double stranded RNA or DNA viruses, including without limitation adenoviruses, herpesviruses, papovaviruses (including simian virus 40, papilloma and polyoma viruses), poxviruses such as smallpox and vaccinia, arboviruses, arenavirus, coronaviruses, myxoviruses ((New castle disease), mumps, measles), rhinoviruses, paramyxoviruses such as influenza a, b or c, parvovirus picornaviruses, togaviruses, reductases, reoviruses and rotaviruses, rubella, herpes simplex, varicella-zoster, chicken pox, cytomegalovirus, unclassified RNA viruses, rabies and hepatitis b. In some embodiments, in the present invention, the virus is selected from the group consisting of: influenza virus, parainfluenza virus, measles virus, mumps virus, herpes virus, adenovirus, respiratory syncytial virus, poliovirus, coxsackie virus, or echovirus. In a more preferred embodiment, the Virus is Vesicular Stomatitis Virus (VSV).

In the compounds of the invention and their uses, the active compounds may also be used in combination with other therapeutic agents. For example in combination with one or more antiviral useful ingredients selected from the group consisting of: amantadine, vidarabine, moroxydine, vidarabine monophosphate, acyclovir, penciclovir, zidovudine, didanosine, the thymosin acyclovir, ganciclovir, valacyclovir, cidofovir, famciclovir, ribavirin, rimantadine, interferons, oseltamivir, palivizumab, rimantadine, zanamivir, nucleoside analog reverse transcriptase inhibitors (NRTI), such as zidovudine, didanosine, zalcitabine, stavudine, lamivudine, and abacavir, and non-nucleoside reverse transcriptase inhibitors (NKRTIs), such as Neviraprae, delavirdine, and efaviren, protease inhibitors, such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and other known antiviral compounds and formulations.

The compounds of the invention and their use, when the active compound is used in combination with other therapeutic agents, the active compound is co-administered with the other therapeutic agent. "coadministration" means simultaneous administration via the same or different routes, or sequential administration via the same or different routes, in the same formulation or in two different formulations. By "sequential" administration is meant having a time difference in seconds, minutes, hours, or days between administration of two or more different compounds.

The present invention also provides a composition comprising a MAT2A inhibitor as described above, or a pharmaceutically acceptable salt, ester, isomer, prodrug, polymorph or solvate thereof, optionally together with one or more pharmaceutically acceptable carriers, vehicles. Such acceptable carriers, media such as sterile water or physiological saline, stabilizers, excipients, antioxidants (ascorbic acid, etc.), buffers (phosphoric acid, citric acid, other organic acids, etc.), preservatives, surfactants (PEG, tween, etc.), chelating agents (EDTA, etc.), binders, and the like. Moreover, other low molecular weight polypeptides may also be present; proteins such as serum albumin, gelatin, and immunoglobulin; amino acids such as glycine, glutamine, asparagine, arginine, and lysine; saccharides or carbohydrates such as polysaccharides and monosaccharides; sugar alcohols such as mannitol and sorbitol. When an aqueous solution for injection is prepared, for example, physiological saline, an isotonic solution containing glucose or other auxiliary drugs, such as D-sorbitol, D-mannose, D-mannitol, sodium chloride, may be used in combination with an appropriate solubilizing agent such as alcohol (ethanol, etc.), polyhydric alcohol (propylene glycol, PEG, etc.), nonionic surfactant (Tween 80, HCO-50), etc.

In the composition of the present invention, the composition includes, but is not limited to, a pharmaceutical composition, a food composition, and a nutraceutical composition.

In the pharmaceutical composition of the present invention, the MAT2A inhibitor or a pharmaceutically acceptable salt, ester, isomer, prodrug, polymorph or solvate thereof may be a single active ingredient, or may be combined with other active ingredients to form a combined preparation. Preferably, the composition further comprises one or more ingredients useful for antiviral activity selected from the group consisting of: amantadine, vidarabine, moroxydine, vidarabine monophosphate, acyclovir, penciclovir, zidovudine, didanosine, the thymosin acyclovir, ganciclovir, valacyclovir, cidofovir, famciclovir, ribavirin, rimantadine, interferons, oseltamivir, palivizumab, rimantadine, zanamivir, nucleoside analog reverse transcriptase inhibitors (NRTI), such as zidovudine, didanosine, zalcitabine, stavudine, lamivudine, and abacavir, and non-nucleoside reverse transcriptase inhibitors (NKRTIs), such as Neviraprae, delavirdine, and efaviren, protease inhibitors, such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and other known antiviral compounds and formulations.

The amount of active ingredient (MAT 2A inhibitor or a pharmaceutically acceptable salt, ester, isomer, prodrug, polymorph or solvate thereof) in the pharmaceutical composition of the present invention is generally a safe and effective amount which should be adjusted by those skilled in the art, for example, the amount of active ingredient administered will generally depend on the body weight of the patient, the type of application, the condition and severity of the disease, for example, the amount of active ingredient administered will generally be 1 to 1000mg/kg/day, 20 to 200mg/kg/day, 1 to 3mg/kg/day, 3 to 5mg/kg/day, 5 to 10mg/kg/day, 10 to 20mg/kg/day, 20 to 30mg/kg/day, 30 to 40mg/kg/day, 40 to 60mg/kg/day, 60 to 80mg/kg/day, 80 to 100mg/kg/day, 100 to 150mg/kg/day, 150 to 200mg/kg/day, 200 to 200mg/kg/day, 300mg/kg/day, 500mg/kg/day, or 500 mg/kg/day.

Those skilled in the art will recognize that the effective amount may be administered depending on the severity of the condition and the health and age of the recipient. An effective amount will typically vary from 0.01ng/kg body weight to about 100mg/kg body weight.

The active ingredient or pharmaceutical composition containing the active ingredient provided by the present invention may be adapted to any form of administration, and may be administered orally or parenterally, for example, by intrapulmonary, nasal, rectal and/or intravenous injection, more specifically, intradermal, subcutaneous, intramuscular, intraarticular, intraperitoneal, pulmonary, buccal, sublingual, buccal, nasal, transdermal, vaginal, oral or parenteral administration; the injection administration includes intravenous injection, intramuscular injection, subcutaneous injection and the like, transdermal administration and the like.

As used herein, the dosage form of the pharmaceutical composition is selected from: injection, injectable sterile powder, tablet, pill, capsule, lozenge, spirit, powder, granule, syrup, solution, tincture, aerosol, powder spray, or suppository. Those skilled in the art can select a suitable formulation according to the administration mode, for example, a formulation suitable for oral administration may be, but is not limited to, a pill, a tablet, a chewable agent, a capsule, a granule, a solution, a drop, a syrup, an aerosol, a powder spray, etc., and a formulation suitable for parenteral administration may be, for example, a solution, a suspension, a reconstitutable dry preparation, a spray, etc., and for rectal administration, a suppository may be, for example, a sterile powder for injection, etc.

Wherein the tablet, lozenge, pill, capsule, etc. may also contain the following components: binders, such as gums, acacia, corn starch or gelatin; excipients, such as dicalcium phosphate; disintegrating agents such as corn starch, potato starch, alginic acid and the like; lubricants, such as magnesium stearate; sweetening agents such as sucrose, lactose or saccharin may be added, or flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring. When the unit dosage form is a capsule, it may contain, in addition to the materials described above, a liquid carrier. Various other materials may be present in a coated form or used to modify the physical form of the unit dosage form. For example, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a color and flavoring such as cherry or orange flavor. Any material used in preparing any unit dosage form should be pharmaceutically pure and substantially non-toxic in amounts used. In addition, the active compounds may be incorporated into sustained release preparations or formulations.

The present invention further provides a method of preventing infection of a cell in contact with a virus comprising contacting the MAT2A inhibitor or a pharmaceutically acceptable salt, ester, isomer, prodrug, polymorph or solvate or pharmaceutical composition thereof with the virus-contacted cell.

The present invention further provides a method of reducing, delaying or inhibiting viral growth and/or replication comprising contacting a cell infected with or contacted with a virus with said MAT2A inhibitor, or a pharmaceutically acceptable salt, ester, isomer, prodrug, polymorph or solvate thereof.

The present invention further provides a method of therapeutically or prophylactically treating a subject in contact with or infected with a virus, comprising administering to a subject (such as a mammal) in need of inhibition of the virus an effective amount of a MAT2A inhibitor or a pharmaceutically acceptable salt, ester, isomer, prodrug, polymorph, solvate or pharmaceutical composition. The method may also be in vitro or non-therapeutic.

In accordance with the methods of the present invention, the MAT2A inhibitor is co-administered with other therapeutic agents. "coadministration" means simultaneous administration via the same or different routes, or sequential administration via the same or different routes, in the same formulation or in two different formulations. By "sequential" administration is meant having a time difference in seconds, minutes, hours, or days between the administration of two or more different compounds.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are exemplary only.

References herein to "comprising," "including," and the like are to be understood to be inclusive, rather than exclusive or exhaustive; i.e., meaning "including but not limited to".

Reference herein to a "therapeutically effective amount" generally refers to an amount which, after an appropriate period of administration, is effective to treat the disease conditions as set forth above.

References herein to "therapeutic" and "prophylactic" are to be understood in their broadest sense. The term "therapeutic" does not necessarily imply that the mammal is receiving treatment until complete recovery. Similarly, "prophylactic" does not necessarily mean that the subject will not ultimately be infected with the disease condition. Thus, treatment and prevention includes alleviation of the symptoms of a particular disorder or prevention or reduction of the risk of development of a particular disorder. The term "prevention" is to be understood as reducing the severity of the onset of a particular condition. Treatment may also reduce the severity of existing conditions or the frequency of acute episodes.

In the present invention, the subject or individual to be treated therapeutically or prophylactically is preferably a mammal, such as, but not limited to, a human, a primate, a livestock (e.g., sheep, cattle, horse, donkey, pig), a pet (e.g., dog, cat), a laboratory test animal (e.g., mouse, rabbit, rat, guinea pig, hamster) or a captured wild animal (e.g., fox, deer). The subject is preferably a primate. The subject is most preferably a human.

Reference herein to "functional activity" of a virus is to be understood as reference to any one or more of the functions performed or involved by the virus.

Reference herein to "viral replication" is to be understood to include one or more stages or aspects of the viral life cycle, such as inhibiting assembly or release of virions. Thus, the active compounds of the present invention include those that mediate viral replication by inducing a cascade of steps that may mediate any one or more aspects or stages of the viral life cycle.

Reference herein to a "cell" infected with a virus is to be understood as a reference to any cell which has been infected with a virus, including eukaryotic or prokaryotic cells.

The compounds of the invention and methods thereof are useful for preventing and/or treating viral infections, not only in the early stages of viral infection to prevent the establishment of viral pools in infected individuals or cells, but also as a prophylactic treatment administered prior to or after exposure to the virus for a period of time. For example, antiviral activity can be achieved in a subject known to be infected with a virus to prevent viral replication, thereby preventing the onset of disease. Alternatively, the active compounds, pharmaceutical compositions, methods of the invention can be used to reduce serum viral load or alleviate symptoms of viral infection.

The invention is further illustrated by the following examples. These examples are intended to illustrate the invention and are not intended to limit the scope of the invention. The procedures, conditions, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.

Test object

All mice were housed in a pathogen-free facility at the central innovation of molecular cell science of the academy of sciences of china. Animals were randomly assigned to experimental groups. All animal experiments were approved by the Institute of Animal Care and Use (IACUC) of the central agency of molecular and cellular sciences of the academy of sciences of China, and met all relevant ethical norms.

Example 1 Effect of MAT2A inhibitors of formula II on Primary peritoneal macrophages in mice

1.1 isolation and culture of mouse peritoneal macrophages

2ml of 3% thioglycollate medium was injected into the abdominal cavity of the mouse, and abdominal cells were collected 3 days later. The cervical vertebra of a mouse is killed by dislocation, the mouse is soaked in 75% alcohol for 3 minutes, the mouse is taken out, the abdomen of the mouse faces upwards, the skin of the lower abdomen of the mouse is lifted by a pair of tweezers, a small opening is cut, the skin is torn, and the peritoneum is completely exposed. The peritoneal cavity was then flushed repeatedly in different directions with 10ml serum free medium with the tip facing up, avoiding the intestine and fat, back-pumping, aspirating the peritoneal cavity, repeating this procedure three times, centrifuging the collected peritoneal cavity for 5 minutes at 1000rpm, and resuspending in RPMI1640 containing 10% fcs. If red blood cells are present, tris-NH is used ₄ Cl lyses the red blood cells. And (3) placing the cell suspension into a culture plate, culturing for 2 hours at 37 ℃, removing the supernatant, washing once by using a preheating culture medium, and leaving adherent cells, namely the freshly separated mouse abdominal cavity macrophages.

1.2 Effect of MAT2A inhibitors of formula II on Virus infection in vitro in mouse Primary peritoneal macrophages

Wherein the MAT2A inhibitor of formula II has the formula C31H22N6OS, available from MedChemexpress under the trade designation HY-112569.

DMSO or the MAT2A inhibitor of formula II (10 μ M each) was added to the mouse primary peritoneal macrophages, VSV virus (MOI, 1) was added 2 hours later, and VSV viral RNA replication was measured 12 hours later.

As shown in fig. 1, it can be seen that the MAT2A inhibitor of the present invention significantly inhibited the infection of cells by VSV virus (fig. 1).

Example 2 MAT2A inhibitors of formula II inhibit VSV infection

The inhibition of VSV virus infection by MAT2A inhibitors was determined by a VSV virus infection animal model.

6 to 8-week-old wild-type C57BL/6 mice (5 mice per group) were injected intraperitoneally with DMSO or MAT2A inhibitor of formula II (80 mg/kg, respectively), and 4 hours later with VSV (1X 10 VSV) ⁷ pfu/g), mice were sacrificed 18 hours after virus injection and organs were isolated.

The inventors examined RNA replication of VSV virus in organs (liver, spleen, and lung) (FIG. 2A), and found that the MAT2A inhibitor of the present invention significantly inhibited RNA replication of VSV virus and inhibited its functional activity.

Detection of infection amount (TCID) in half of organs (liver, spleen, lung) by tissue culture ₅₀ ) As shown in fig. 2B, the MAT2A inhibitor of the present invention significantly inhibited infection of tissues by VSV virus and inhibited functional activity thereof.

The lung injury condition of the mice after virus infection is detected by lung section H & E staining (figure 2C), and the result shows that the MAT2A inhibitor provided by the invention obviously inhibits VSV virus infection of the lungs of the mice.

In parallel experiments, 6 to 8 week old wild type C57BL/6 mice (8 mice per group) were injected intraperitoneally with DMSO or MAT2A inhibitor (80 mg/kg) 4 hours later with VSV (1X 10 VSV) in the tail vein ⁸ pfu/g) and monitoring the survival rate of mice after VSV virus infection, survival assays were performed and the results are shown in figure 3, where MAT2A inhibitor significantly extended the survival time of mice.

The above examples are only intended to illustrate the technical solution of the present invention and not to limit it; although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that: modifications to the specific embodiments of the invention or equivalent substitutions for parts of the technical features may be made; variations and advantages that may occur to those skilled in the art may be made without departing from the spirit and scope of the inventive concept, which is intended to be covered by the claims.

Claims

Use of a MAT2A inhibitor or a pharmaceutically acceptable salt, ester, isomer, prodrug, polymorph or solvate thereof for the manufacture of a medicament for the prevention and/or treatment of a disease caused by a viral infection.
2. The use of claim 1, wherein the MAT2A inhibitor has the structure of formula I:

in the formula I, R ¹ 、R ² 、R ³ 、R ⁴ Independently selected from aryl, substituted aryl, heteroaryl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxy-alkoxy or heterocyclyloxy, alkylamino;

wherein the substituent of the substituted aryl is selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl or aminoalkyl;

wherein heterocyclyl or heteroaryl is substituted with a substituent independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl or aminoalkyl.
3. The use of claim 2, wherein the alkyl is C1-C10 alkyl, the cycloalkyl is C1-C6 cycloalkyl, the haloalkyl is C1-C10 haloalkyl, the haloalkoxy is C1-C10 haloalkoxy, the alkoxy is C1-C10 alkoxy, the halogen is F, cl, br or I, the alkoxycarbonyl is C1-C10 alkoxycarbonyl, the hydroxyalkyl is C1-C10 hydroxyalkyl, the alkoxyalkyl is C1-C10 alkoxyalkyl, and the aminoalkyl is C1-C10 aminoalkyl.
4. The method of claim 2Characterized in that R is ¹ Is a benzene ring, and/or R ² Is a benzene ring and/or R ³ Is composed of
And/or, R ⁴ Is composed of
5. The use of claim 2 wherein said MAT2A inhibitor is of formula C ₃₁ H ₂₂ N ₆ OS, the structure is shown in formula II below:
6. the use of claim 1, wherein the virus is one or more of a single-stranded RNA virus, a double-stranded RNA virus or a DNA virus.
7. The use of claim 1, wherein the virus is vesicular stomatitis virus.
8. An antiviral pharmaceutical composition comprising the MAT2A inhibitor or a pharmaceutically acceptable salt, ester, isomer, prodrug, polymorph or solvate thereof, as claimed in any one of claims 1 to 6, and a pharmaceutically acceptable carrier, vehicle.
9. The antiviral pharmaceutical composition of claim 8, wherein said pharmaceutical composition is administered in combination with at least one of an immune system modulator, an antiviral agent that inhibits viral replication.
10. A method of inhibiting a virus in vitro, comprising: administering to a subject in need of virus inhibition an effective amount of a MAT2A inhibitor as described in any one of claims 1 to 6, or a pharmaceutically acceptable salt, ester, isomer, prodrug, polymorph or solvate thereof.