CN117503790A - Application of AMPK activator in preparation of antiviral drugs or anti-inflammatory drugs - Google Patents
Application of AMPK activator in preparation of antiviral drugs or anti-inflammatory drugs Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
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- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract
The invention provides an application of an AMPK activator in preparing antiviral drugs or anti-inflammatory drugs. Based on HEV acute and chronic infection and replicon model constructed by HEV strain Kernow-C1 (p 6) of genotype 3, the invention discovers that adding AICAR with effective concentration into the p6 chronic infection model can obviously activate AMPK and strongly inhibit replication of HEV; in the acute infection model of HEV, AICAR is effective in alleviating the viral-induced inflammatory response. The anti-inflammatory and antiviral method provided by the invention has the advantages of safety, high efficiency, simplicity, convenience and the like. The result not only provides a new thought and theoretical basis for developing the medicine for treating HEV, but also lays a solid foundation for exploring the effect of AMPK in HEV replication, clarifying the mechanism of the AMPK affecting HEV replication, searching a new medicine effect target point in cells and developing a new medicine for resisting HEV.
Description
Technical Field
The invention relates to the field of biological medicine and biotechnology, in particular to application of an AMPK activator in preparation of antiviral drugs or anti-inflammatory drugs.
Background
Hepatitis E Virus (HEV) is a non-enveloped single-stranded positive-strand RNA virus belonging to the genus hepatitis virus, family hepatitis virus. The genome sequence is approximately 7.3kb in length, and contains three major Open Reading Frames (ORFs). Mammalian-infected HEVs have mainly 4 genotypes, of which genotypes 1 and 2 are only human-infected, and genotypes 3 and 4 are zoonotic. HEV infection is one of the most common causes of liver inflammation. Approximately 2000 tens of thousands of people worldwide infect HEV each year, and approximately 7 tens of thousands die from diseases associated with HEV infection. In healthy people, most HEV infected people can self-heal or only develop mild digestive tract symptoms; however, in people who already have basic liver diseases or low immunity, chronic or fulminant hepatitis is easily caused, and even cirrhosis is developed; pregnant women are infected with HEV, liver failure is easy to occur, and the death rate of partial genotype HEV infection is up to 30%, or abortion and stillbirth occur. Furthermore, it was found that after infection with HEV, the expression of NLRP3 and IL-1. Beta. Can be up-regulated by NF-kB signaling pathway, causing inflammatory reaction. Therefore, researching the replication mechanism of HEV, searching a new antiviral drug action target point and exploring a new prevention and control strategy has important significance.
Accordingly, the current technology is still further improved and developed.
Disclosure of Invention
In view of the shortcomings of the prior art, the invention aims to provide an application of an AMPK activator in preparing antiviral drugs or anti-inflammatory drugs, and aims to solve the problems that the research on the pathogenic mechanism of hepatitis E virus is insufficient and targeted intervention drugs are lacking at present.
The technical scheme of the invention is as follows:
an application of AMPK activator in preparing antiviral or antiinflammatory medicine is provided.
The use, wherein the AMPK activator comprises AICAR.
The use, wherein the concentration of the AICAR is 0.1-1mM.
The use, wherein the virus is an RNA virus.
The use, wherein the RNA virus is hepatitis E virus.
The use, wherein the AICAR inhibits replication of hepatitis e virus, reduces hepatitis e virus-induced liver inflammation.
Use of an AMPK activator in screening antiviral or anti-inflammatory drugs, wherein the AMPK activator comprises AICAR.
A medicament against hepatitis e virus, wherein the medicament comprises an AMPK activator comprising AICAR.
An anti-liver inflammation medicament, wherein the medicament comprises an AMPK activator comprising AICAR.
The medicament as claimed in any one of the above, wherein the medicament further comprises pharmaceutically acceptable carriers and/or auxiliary materials, and is prepared into any one of pharmaceutically acceptable dosage forms.
The beneficial effects are that: the invention provides an application of an AMPK activator in preparing antiviral drugs or anti-inflammatory drugs. The invention explores the role and potential action mechanism of an AMPK activator AICAR in HEV replication based on HEV acute and chronic infection and a replicator model constructed by a gene 3 type HEV strain Kernow-C1 (p 6). The addition of an effective concentration of AICAR to the p6 chronic infection model can significantly activate AMPK and strongly inhibit HEV replication; in the acute infection model of HEV, AICAR is effective in alleviating the viral-induced inflammatory response. The anti-inflammatory and antiviral method provided by the invention has the advantages of safety, high efficiency, simplicity, convenience and the like. The result not only provides new thought and theoretical basis for developing the medicine for treating HEV, but also lays a solid foundation for exploring the effect of AMPK in HEV replication, clarifying the mechanism of the AMPK affecting HEV replication, searching a new medicine effect target point in cells, developing new medicine for resisting HEV and searching more effective prevention and control means.
Drawings
Fig. 1 is a schematic diagram showing the antiviral effect of the AMPK activator AICAR according to the embodiment of the present invention.
Fig. 2 is a schematic diagram showing the anti-inflammatory effect of AICAR, an AMPK activator, provided in the example of the present invention.
Detailed Description
The invention provides an application of an AMPK activator in preparing antiviral drugs or anti-inflammatory drugs, and the invention is further described in detail below in order to make the purposes, technical schemes and effects of the invention clearer and more definite. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
The embodiment of the invention provides application of an AMPK activator in preparation of antiviral drugs or anti-inflammatory drugs.
AMPK, AMP-dependent protein kinase (AMP-activated protein kinase, AMPK), is a key molecule of the bioenergy metabolic pathway. AMPK can also inhibit or promote different types of viral infections by affecting cellular metabolism, autophagy, apoptosis, inflammation, and immune processes. Activation or inhibition of AMPK has an important effect on viral replication and survival of host cells. AICAR, known as 5-aminoidazole-4-carboxamide 1- β -D-ribofuranoside, also known as aicaroside or academe, chinese name academy, is an adenosine analog, also an activator of AMPK, capable of regulating glucose and lipid metabolism by activating AMPK and inhibiting the production of pro-inflammatory cytokines. The chemical formula of AICAR is shown below:
there is no evidence to date that the AMPK activator AICAR is associated with HEV, nor is it clear whether AICAR can inhibit replication of HEV and its induced inflammatory response. Therefore, the invention explores the role of an AMPK activator AICAR in HEV replication and reveals a potential action mechanism based on an HEV acute and chronic infection and replicator model constructed by a HEV strain Kernow-C1 (p 6) of a gene 3 type. The result shows that the addition of AICAR with effective concentration into the p6 chronic infection model can obviously activate AMPK and strongly inhibit the replication of HEV; in the acute infection model of HEV, AICAR is effective in alleviating the viral-induced inflammatory response. Therefore, the invention provides the application of the AMPK activator in preparing antiviral drugs or anti-inflammatory drugs, and clarifies the effect of the AICAR of the AMPK activator in HEV replication and the potential action mechanism thereof, thereby providing new thought and theoretical basis for developing drugs for treating HEV.
In some embodiments, the AMPK activator comprises AICAR. But is not limited thereto, any AMPK activator similar in function to AICAR may be applied to the present invention.
In some embodiments, the concentration of the AICAR is 0.1-1mM. For example, the concentration may be 0.1mM, 0.2mM, 0.3mM, 0.4mM, 0.5mM, 0.6mM, 0.7mM, 0.8mM, 0.9mM, or 1mM. The AICAR with effective concentration is applied to an acute and chronic infection model and a replicator model of p6, can obviously activate AMPK, and can strongly inhibit replication of HEV and inflammatory reaction caused by viruses. Moreover, the method of the invention is safe and efficient, is simple and easy to use and has wide application range.
In some embodiments, the virus is an RNA virus.
Specifically, the RNA virus is Hepatitis E Virus (HEV).
In some embodiments, the AICAR can inhibit replication of the HEV, reducing HEV-induced inflammatory responses. The invention discovers that the AICAR of the AMPK activator can effectively inhibit the replication of HEV, and the AICAR of the AMPK activator with the concentration of 0.1-1mM has obvious inhibition effect on the replication of HEV and shows dose dependency. HEV infection usually causes inflammatory reaction, and the invention searches whether AICAR which is an activator of AMPK can inhibit inflammatory reaction caused by HEV. As a result, the AICAR is found to remarkably reduce the expression of HEV-induced inflammatory factors IL-1 beta, caspase-1, NLRP3 and regulatory genes p-NF-KB and RIP. Furthermore, we co-cultured THP-1 macrophages with huh7.5-p6 cells at a ratio of 1:4, mimicking the cell population of human liver, and also found that AICAR has anti-inflammatory and antiviral functions after treatment with AICAR. At the same time, AICAR is combined with dexamethasone (dexamethazole) as anti-inflammatory agent, and both have synergistic anti-inflammatory effect. This shows that the AICAR of the AMPK activator can remarkably reduce the inflammation induced by HEV, and lays a foundation for the subsequent research and development of medicines for treating HEV.
The invention also provides application of the AMPK activator in screening antiviral drugs or anti-inflammatory drugs, the AMPK activator can be AICAR, but the invention is not limited to the AICAR, and any AMPK activator with functions similar to AICAR can be applied to the invention. The invention researches the function and mechanism of an AMPK activator AICAR in HEV replication based on an HEV acute and chronic infection and replicator model constructed by a gene 3 HEV strain Kernow-C1 (p 6), and provides a new thought and theoretical basis for searching a new medicine action target point in cells and developing medicines for treating HEV.
The present invention also provides an anti-HEV drug comprising an AMPK activator, which may be an AICAR, but is not limited thereto, and any AMPK activator having a function similar to that of AICAR may be applied to the present invention. The medicine also comprises pharmaceutically acceptable carriers and/or auxiliary materials, and is prepared into any pharmaceutically acceptable dosage form.
The present invention also provides an anti-liver inflammation drug including an AMPK activator, which may be AICAR, but is not limited thereto, and any AMPK activator having a function similar to AICAR may be applied to the present invention. The medicine also comprises pharmaceutically acceptable carriers and/or auxiliary materials, and is prepared into any pharmaceutically acceptable dosage form.
In some embodiments, the drug may be in the form of a salt, composition, dosage form, or the like.
Specifically, the carrier such as excipient, additive and flavoring agent can be made into various dosage forms, including powder, tablet, micropill, capsule, microcapsule, granule or liquid.
The application of the AMPK activator in preparing antiviral drugs or anti-inflammatory drugs is further explained by the following specific examples:
generally, the nomenclature used for cell and tissue culture, molecular biology, immunology, microbiology, genetics, protein and nucleic acid chemistry, and the like, and the techniques thereof, described herein are well known and commonly employed in the art. Unless otherwise indicated, the methods and techniques of the present invention are generally performed according to conventional methods well known in the art and as described in various general and more specific references.
Example 1 Effect of the AMPK activator AICAR on HEV replication
In order to explore the influence of AICAR (AICAR) as an AMPK activator on HEV replication, the invention firstly spreads a chronic infection cell line containing P6 virus in a 12-well plate, and after the cells are attached, AICAR (0, 0.1, 0.5 and 1 mM) with different concentrations is respectively added, the cell culture plate was placed in a carbon dioxide incubator at 37 ℃ for 48 hours, then the cells were collected, and the effect of the AMPK activator AICAR on HEV virus replication was detected by fluorescence quantitative PCR, luciferase reporting experiments and western blot methods, and the results are shown in fig. 1. Whether using fluorescent quantitative PCR (fig. 1A), luciferase reporter assay (fig. 1B) or western blot (fig. 1E) detection methods, the results showed that 0.1, 0.5 and 1mM AMPK activator AICAR significantly inhibited HEV replication and exhibited dose dependence.
Next, the present invention selects 1mM of AMPK activator AICAR to treat p6 chronic cell line, places the culture plate in a carbon dioxide cell incubator at 37℃and cultures for 24 hours, 48 hours, 72 hours and 96 hours, collects cells, and detects the effect of AMPK activator AICAR on HEV replication by fluorescence quantitative PCR and western-blot methods, and the results are shown in FIGS. 1C and 1F. The fluorescence quantification results (fig. 1C) show: the 1mM AMPK activator AICAR significantly inhibited HEV replication after treatment of chronic cell lines for 48, 72 and 96 hours. The Western blot results (FIG. 1F) show: the 1mM AMPK activator AICAR significantly inhibited HEV replication when treated with chronic cell lines for 48 and 72 hours.
The invention also collects p6 cell lines treated for 48h with 1mM AMPK activator AICAR for secondary sequencing and immunofluorescence detection, respectively, and as a result, the AMPK activator AICAR can reduce the FPKM value (figure 1D) and the expression level (figure 1G) of HEV.
Example 2 Effect of the AICAR activator of AMPK on HEV-induced inflammation
Natural immunity is the first line of defense of the body against infection by pathogenic microorganisms and plays a vital role in clearing pathogenic immune responses. When a pathogen invades the body, the natural immune cells initiate a series of immune cascades through their pattern recognition receptors, producing type I Interferons (IFNs) and other downstream effector proteins to help the body clear the pathogen infection. Thus, the present invention next explores whether the antiviral effect of AICAR is to modulate innate immune function by activating AMPK. I amIt was found that after treatment of huh7.5 cells for 48h with 1mM AMPK activator AICAR, AICAR was able to induce expression of IFN (IFNa, IFNb, IFN. Lambda.1 and IFNlambda.2) and interferon-stimulated genes (ISGs) (e.g. ISG15, IRF9, stat1, IRF7, etc.) (FIG. 2A). HEV infection usually causes inflammation in the liver, and the present invention will explore whether AICAR-activated AMPK can inhibit HEV-induced inflammatory response. We follow 5 x 10 5 Cell amount per well THP1 cells were inoculated into 12-well plates, each well was differentiated by adding 20ng/ml PMA for 48 hours, then, the culture was carried out in 1640 medium containing 10% FBS for 24 hours, and simultaneously, HEV virus particles and 1Mm AMPK activator were added to co-treat the differentiated THP1 cells for 48 hours, and the cells were collected. Fluorescent quantitation showed that the activator AICAR of AMPK significantly inhibited gene expression of IL-1 β induced by HEV virus particles (fig. 2B). Meanwhile, the results of WB showed that AICAR inhibited protein expression of IL-1βp17, pro IL-1β and caspase-1 induced by HEV virus particles (FIG. 2C). After 48h co-treatment of huh7.5 cell line with HEV virus particles and AICAR, WB results showed that AICAR inhibited HEV virus particle-induced expression of RIP protein (fig. 2D), immunofluorescence results showed that AICAR inhibited NF-kB p-p65 and protein expression of NLRP3 (fig. 2E and 2F). Co-culture (1:4) with THP1 and p6 cells to simulate liver cell populations, mixed cells were seeded into 12-well plates, treated with AICAR (0, 0.1, 0.5, 1 mM) at various concentrations for 48H, and fluorescent quantitation was found to significantly reduce HEV viral replication (FIG. 2G), and gene expression of inflammatory factor IL-1β (FIG. 2H). In contrast, AICAR was used in combination with the anti-inflammatory agent dexamethasone, both of which were found to have synergistic anti-inflammatory effects (FIG. 2I).
The result shows that the AICAR activator of the AMPK can effectively inhibit the replication of HEV virus, can obviously relieve inflammatory response induced by HEV, and lays a foundation for the subsequent research and development of medicaments for treating HEV.
In summary, the invention provides an application of an AMPK activator in preparing antiviral drugs or anti-inflammatory drugs. The invention is based on HEV acute and chronic infection and replicative models constructed by HEV strain Kernow-C1 (p 6) of genotype 3, explores the role of AICAR of an AMPK activator in HEV replication, reveals a potential action mechanism, and discovers that the AICAR with effective concentration can effectively activate AMPK when applied to a cell model of p6 acute and chronic infection, and strongly inhibit the replication of HEV and inflammatory reaction caused by the same. In addition, the anti-inflammatory and antiviral method provided by the invention is safe, efficient, simple and easy to use and wide in application range. The results provide new thought and theoretical basis for developing medicaments for treating HEV, and lay a foundation for researching the effect of AMPK in HEV replication, clarifying the mechanism of the AMPK for influencing HEV replication, discovering new intracellular medicament targets, developing new medicaments for resisting HEV and searching more effective prevention and control strategies.
It is to be understood that the invention is not limited in its application to the examples described above, but is capable of modification and variation in light of the above teachings by those skilled in the art, and that all such modifications and variations are intended to be included within the scope of the appended claims.
Claims (10)
1. An application of AMPK activator in preparing antiviral or antiinflammatory medicine is provided.
2. The use of claim 1, wherein the AMPK activator comprises AICAR.
3. The use according to claim 2, wherein the concentration of AICAR is 0.1-1mM.
4. The use according to claim 2, wherein the virus is an RNA virus.
5. The use according to claim 4, wherein the RNA virus is hepatitis e virus.
6. The use of claim 5, wherein the AICAR inhibits replication of hepatitis e virus and reduces hepatitis e virus-induced inflammation.
7. Use of an AMPK activator in screening antiviral or anti-inflammatory agents, wherein the AMPK activator comprises AICAR.
8. A medicament against hepatitis e virus, comprising an AMPK activator comprising AICAR.
9. An anti-liver inflammation medicament comprising an AMPK activator comprising AICAR.
10. The medicament according to any of claims 8 to 9, further comprising pharmaceutically acceptable carriers and/or excipients, formulated into any pharmaceutically acceptable dosage form.
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