CN114886895B - Application of small molecule inhibitor BAY87-2243 in preparing medicine for treating hepatitis B - Google Patents
Application of small molecule inhibitor BAY87-2243 in preparing medicine for treating hepatitis B Download PDFInfo
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- A—HUMAN NECESSITIES
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- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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Abstract
The invention provides an application of a small molecule inhibitor BAY87-2243 in preparing a medicament for treating hepatitis B virus infection. The invention uses different liver cancer cell lines which can stably produce Hepatitis B Virus (HBV) or HBV-infected human primary liver cells to verify that BAY87-2243 can obviously inhibit HBV transcription and replication and effectively reduce cccDNA expression level through the in vitro treatment of BAY87-2243 with different concentrations.
Description
Technical Field
The invention relates to application of a small molecule inhibitor BAY87-2243 in preparing a medicament for treating hepatitis B
Background
Viral hepatitis B (viral hepatitis type B) is an infectious disease mainly caused by Hepatitis B Virus (HBV) and characterized by liver disease. Clinically, the symptoms of anorexia, nausea, epigastric discomfort, liver pain and hypodynamia are mainly manifested. Some patients may have jaundice fever and hepatomegaly with impaired liver function. Some patients can become chronic, even develop cirrhosis of the liver, and a few can develop liver cancer.
At present, the effect of treating chronic HBV infection by nucleoside (acid) analogues and interferon is very limited, and only a few patients can realize 'functional cure'. The key to cure chronic hepatitis B virus infection is that covalently closed circular DNA (cccDNA) in host hepatocytes must be thoroughly eliminated, and the cccDNA is a template for HBV transcription replication and a viral gene repository and is also a key cause for relapse after drug withdrawal of patients with chronic hepatitis B. At present, the medicine for effectively removing cccDNA is still lacking clinically, so the search and development of the medicine for effectively removing the hepatitis B virus cccDNA have good clinical application prospects.
The small molecule inhibitor BAY87-2243 is a potent selective hypoxia-inhibitor factor-1 (HIF-1) inhibitor. At present, research reports show that the compounds can inhibit tumor cell proliferation by interfering mitochondrial function, can be used for treating cancers such as lung cancer, also report research that the compounds have positive influence on Intestinal Mucosa Barrier (IMB) function, and can be used for treating sepsis. No BAY87-2243 is reported to be used for treating hepatitis B at present.
Disclosure of Invention
In order to solve the problems, the invention provides the application of a small molecule inhibitor BAY87-2243 in preparing a medicament for treating hepatitis B; the BAY87-2243 is a HIF-1 specific inhibitor.
Further, the drug is a drug that reduces the level of hepatitis b surface antigen production.
Further, the drug is a drug that reduces the level of hepatitis b e antigen production.
Further, the drug is a drug that inhibits transcription of hepatitis b virus.
Further, the medicament is a medicament for inhibiting the replication of hepatitis B virus DNA.
Further, the medicament is a medicament that reduces the expression level of hepatitis b virus cccDNA.
Furthermore, the medicine is a preparation prepared by taking a small molecular inhibitor BAY87-2243 as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
Still further, the formulation is an oral formulation; the oral preparation is granule, solution, pill, paste or tablet.
Experiments prove that the small molecular inhibitor BAY87-2243 can obviously inhibit HBV transcription and replication and effectively reduce the cccDNA expression level, so that the complete elimination of the virus carrying state of a hepatitis B patient becomes possible, the aim of antiviral treatment is finally achieved, and the application has practical popularization and application prospects.
It will be apparent that various other modifications, substitutions and alterations can be made in the present invention without departing from the basic technical concept of the invention as described above, according to the common technical knowledge and common practice in the field.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
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FIG. 1 statistical data of the study on HBsAg/HBeAg secretion by BAY87-2243 treatment (A: effect of different concentrations of BAY87-2243 treatment on HepAD38 cytotoxicity and HBsAg secretion, B: effect of different concentrations of BAY87-2243 treatment on HepG2.2.15 cytotoxicity and HBsAg secretion, C: effect of different concentrations of BAY87-2243 treatment on HepAD38 cytotoxicity and HBeAg secretion, D: effect of different concentrations of BAY87-2243 treatment on HepG2.2.15 cytotoxicity and HBeAg secretion)
FIG. 2 statistical data of the effects of BAY87-2243 treatment on HBV transcription and replication levels and HBV cccDNA expression levels (A: the effect of BAY87-2243 treatment on HBV total RNA expression level in HepAD38 cells, B: the effect of BAY87-2243 treatment on HBVpgRNA expression level in HepAD38 cells, C: the effect of BAY87-2243 treatment on HBVDNA replication level in HepAD38 cells, D: the effect of BAY87-2243 treatment on HBVccc DNA expression level in HepAD38 cells) FIG. 3 in HBV-infected human primary hepatocytes, statistical data of the effects of BAY87-2243 treatment on HBV transcription and HBV replication levels and HBV cccDNA expression level (A: the effect of BAY87-2243 treatment on HBsAg secretion level, B: the effect of BAY87-2243 treatment on HBeAg secretion level, C: the effect of BAY87-2243 treatment on HBV total RNA expression level, B: the effect of BAY87-2243 treatment on HBgRNA expression level in HBeAg, and VpeAg expression level of HBgRNA in HBeAg
Detailed Description
Example 1 Effect of BAY87-2243 on secretion of HBsAg/HBeAg in hepatoma cells stably producing HBV
First, 8 × 10 4 One/well hepg2.215 and HepAD38 cells were seeded in 48-well plates, respectively. The next day after cell plating, cells were treated with different concentration gradients (0.01-100 nM) of BAY87-2243, respectively. After BAY87 treated the cells for 72h, cell Counting Kit-8 reagent (MedChemexpress, HY-K0301) was added to the 48-well plate, and the change in absorbance of the cells was detected by a multifunctional microplate reader at a wavelength of 450 nm. In addition, the cell supernatant was collected and the levels of HBsAg and HBeAg secreted in the cell supernatant were detected using a hepatitis B virus surface antigen diagnostic kit (enzyme-linked immunosorbent assay; shanghai Kehua, SI 0910113) and a hepatitis B virus E antigen detection kit (enzyme-linked immunosorbent assay; shanghai Kehua, 20163400144), respectively. The specific results of the microplate reader and the ELISA kit are shown in FIGS. 1A-D. From the results of the figures, it can be seen that: BAY87-2243 concentrations have a lesser effect on cytotoxicity at 100nM, and lower concentrations (<0.1 nM) of BAY87-2243 is effective in inhibiting secretion of HBsAg and HBeAg.
Example 2 Effect of BAY87-2243 on HBV transcription and replication levels and HBV cccDNA expression levels in HepAD38 cells
Will be 3X 10 5 One/well HepAD38 cells were seeded in 12-well plates, treated the next day with BAY87 at different concentration gradients (1, 2 or 4 nM) for 72h, then total intracellular RNA was extracted using Trizol reagent (Invitrogen, 15596026), and One-Step real RT-qPCR kit [ One Step TB
PrimeScript TM RT-PCR Kit II(Perfect Real Time)，TaKaRa，RR086]Expression levels of HBV total RNA (FIG. 2A) and pgRNA (FIG. 2B) were measured in cells. From the results of the figures, it can be seen that: BAY87-2243 treatment with different concentrations can obviously reduce the expression level of HBV total RNA and pgRNA in cells, which indicates that BAY87-2243 can effectively inhibit HBV transcription in cells.
Will be 6X 10 5 The HepAD38 cells per well are inoculated in a 6-well plate, the next day, the cells are treated for 72h by BAY87-2243 with different concentration gradients (1, 2 or 4 nM), the cells are lysed, HBV DNA wrapped by nucleocapsid in the cells is extracted, and the influence of BAY87-2243 on the replication level of the HBV DNA in the cells is detected by a Southern blot method. The specific results are shown in FIG. 2C. From the graph results, it can be seen that: treatment with BAY87-2243 with different concentrations can obviously reduce the replication level of HBV DNA in cells, and the suggestion that BAY87-2243 can effectively inhibit the replication of HBV DNA in cells.
Will be 6X 10 5 HepAD38 cells were seeded in 6-well plates and treated the following day with varying concentration gradients (1, 2 or 4 nM) of BAY87-2243 for 96h. Then washing the cells with PBS 2 times, lysing the cells overnight, extracting DNA with phenol chloroform, subjecting the cccDNA obtained to an enzymatic cleavage reaction with T5 exonuclease, and performing Realtime qPCR (polymerase chain reaction)
Probe qPCR Master Mix, promega, a 6101) to detect HBV cccDNA expression levels in cells. The specific results are shown in FIG. 2D. From the graph results, it can be seen that: treatment of BAY87-2243 with different concentrations can obviously reduce the expression level of HBV cccDNA in cells, and the fact that BAY87-2243 can effectively reduce the expression level of HBVcccDNA in cells is suggested.
Example 3 investigation of the Effect of BAY87-2243 on HBV transcription and replication levels and HBV cccDNA expression levels in HBV-infected human primary hepatocytes
Commercial human primary cells were expanded at 5X 10 5 One/well was seeded in 12-well plates, and the next day after cell plating, cells were incubated with William's E complete medium containing HBV viral particles (MOI: 1000); 24h after HBV infection, cells were washed 3 times with PBS and then treated with BAY87-2243 at different concentration gradients (2 nM and 4 nM) for 6 consecutive days. Collecting cell supernatant, using (hepatitis B virus surface antigen diagnostic kit (enzyme linked immunosorbent assay) and hepatitis B virus E antigen detection kit (enzyme linked immunosorbent assay) to respectively collect cell supernatant and then detect the level of HBsAg and HBeAg secreted in the cell supernatant, and the specific results are shown in figures 3A-B, and the results of the figures show that BAY87-2243 can effectively inhibit the secretion of HBsAg and HBeAg.
Cells treated as in FIGS. 3A-B were washed 2 times with PBS, total RNA in the cells was extracted using Trizol reagent, and expression levels of HBV total RNA (FIG. 3C) and pgRNA (FIG. 3D) in the cells were measured using One-step simple RT-qPCR kit. From the results of the figures, it can be seen that: BAY87-2243 with different concentrations can obviously reduce the expression level of HBV total RNA and pgRNA in hepatocytes, which indicates that BAY87-2243 can effectively inhibit HBV transcription in primary human hepatocytes.
Cells treated as in FIGS. 3A-B were washed 2 times with PBS, lysed and nucleocapsid-encapsulated HBV DNA extracted from cells with phenol-chloroform and subjected to Realtime qPCR (TB)
Premix Ex Taq TM II (Tli RNaseH Plus), taKaRa, RR 820) test the effect of BAY87-2243 on the expression level of HBV DNA in cells. The specific results are shown in FIG. 3E. From the graph results, it can be seen that: BAY87-2243 treatment can obviously reduce the expression level of HBV DNA in cells, and the suggestion that BAY87-2243 can effectively inhibit the replication of HBVDNA in primary human hepatocytes.
The cells treated as in FIGS. 3A-B were washed 2 times with PBS, lysed and then the DNA was extracted with phenol chloroform, and finally the cccDNA obtained was cleaved with T5 exonuclease and processed with Realtime qPCR (R) (C)
Probe qPCR Master Mix, promega, a 6101) to detect HBV cccDNA expression levels in cells. The specific results are shown in FIG. 3F. From the graph results, it can be seen that: BAY87-2243 treatment can obviously reduce the expression level of HBV cccDNA in cells, and suggests that BAY87-2243 can effectively reduce the expression level of HBV cccDNA in human primary hepatocytes.
In conclusion, a series of experiments prove that the small molecular inhibitor BAY87-2243 can obviously inhibit HBV transcription and replication, effectively reduce cccDNA expression level, enable complete elimination of the virus carrying state of a hepatitis B patient to be possible, finally realize the aim of antiviral therapy, and has practical popularization and application prospects.
Claims (9)
1. The use of small molecule inhibitor BAY87-2243 in the preparation of medicine for treating hepatitis B; the BAY87-2243 is a HIF-1 specific inhibitor.
2. The use according to claim 1, wherein the medicament is a medicament for reducing the level of hepatitis b surface antigen production.
3. The use of claim 1, wherein the medicament is a medicament that reduces the level of hepatitis b e antigen production.
4. The use according to claim 1, wherein the medicament is a medicament for inhibiting transcription of hepatitis b virus.
5. The use according to claim 1, wherein the medicament is a medicament for inhibiting replication of hepatitis b virus DNA.
6. The use of claim 1, wherein the medicament is a medicament that reduces the expression level of hepatitis b virus cccDNA.
7. The use according to any one of claims 1 to 6, characterized in that the medicament is a preparation prepared by taking a small molecule inhibitor BAY87-2243 as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
8. Use according to claim 7, wherein the formulation is an oral formulation.
9. Use according to claim 8, characterized in that the oral formulation is a granule, solution, pill, paste or tablet.
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