Application of polyguluronic acid sulfate in the preparation of anti-hepatitis B virus medicine

A technology of guluronic acid sulfate and hepatitis B virus, which is applied in the field of marine drugs, can solve the problems of many adverse reactions, easy relapse after drug withdrawal, virus mutation and drug resistance, etc., and achieve enhanced production and secretion, enhanced Innate immunity, effects of suppressed expression

Active Publication Date: 2018-07-06
MARINE BIOMEDICAL RES INST OF QINGDAO CO LTD +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Aiming at the current clinical treatment of hepatitis B virus, there are many adverse drug reactions, drug withdrawal is easy to relapse, and long-term administration leads to virus mutation and drug resistance. The invention provides polyguluronic acid sulfate in the preparation of anti-hepatitis B virus Application in the medicine of hepatitis virus, polyguluronic acid sulfate provided by the invention can effectively inhibit the expression of hepatitis B virus surface antigen (HBsAg) and hepatitis B virus e antigen (HBeAg) in HepG2.2.15 cells, and its in vitro anti The main mechanism of HBV is to activate NF-κB and MAPK cell signaling pathways, enhance innate immune response, and then inhibit HBV replication

Method used

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  • Application of polyguluronic acid sulfate in the preparation of anti-hepatitis B virus medicine
  • Application of polyguluronic acid sulfate in the preparation of anti-hepatitis B virus medicine
  • Application of polyguluronic acid sulfate in the preparation of anti-hepatitis B virus medicine

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Experimental program
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Effect test

Embodiment 1

[0030] Embodiment 1, structure and physicochemical property analysis of polyguluronic acid sulfate

[0031] The acid degradation method adopted in the present invention prepares and separates polyguluronic acid from seaweed polysaccharide alginate, and then obtains polyguluronic acid sulfate after sulfation reaction (recorded in the patent ZL 200310105718.9 that polyguluronic acid The preparation method of glucuronic acid sulfate PGS).

[0032] The molecular skeleton of the polyguluronic acid sulfate ester of the present invention is composed of α-L-guluronic acid connected by 1→4, and C in the sugar residue 2 and C 3 bits have at least one SO 3 Na, the content of sulfate is 20%~40%; the weight average molecular weight of polyguluronic acid sulfate is 2 kDa~20 kDa; its general molecular formula can be expressed as [C 12 h 16-m o 12 Na 2 ·(SO 3 Na) m ] n , where m=1~4, n=5~30.

[0033] The carbon NMR spectrum of polyguluronic acid sulfate is as follows figure 1 Shown...

Embodiment 2

[0036] Embodiment 2, the anti-hepatitis B virus effect of polyguluronic acid sulfate PGS in vitro

[0037] 1) Evaluation of the effect of PGS on inhibiting the expression of HBsAg and HBeAg at the cellular level

[0038] Using the HepG2.2.15 cell line (provided by the School of Medicine, Ocean University of China) as a cell model, ELISA kits and thiazolium blue (MTT) colorimetry were used to detect the inhibition of polyguluronic acid sulfate PGS on the expression of HBsAg and HBeAg Effect and cytotoxicity, and calculate the half toxic concentration CC 50 value. Positive control drug selection lamivudine.

[0039] Experimental results such as image 3 and Figure 4 shown. Such as image 3 As shown, PGS (30-250 µg / mL) has no obvious inhibitory activity on the proliferation of HepG2.2.15 cells, and the maximum non-toxic concentration is 250 µg / mL after PGS acts on the cells for 6 days. After 6 and 9 days of PGS, CC 50 The values ​​were 931 µg / mL and 891 µg / mL, respective...

Embodiment 3

[0047] Embodiment 3, the action mechanism of PGS anti-hepatitis B virus in vitro

[0048] 1) Effect of PGS on the expression and secretion of interferon β (IFNβ)

[0049] The effect of PGS on the expression of cytokines and antiviral proteins (such as IFNβ) in HepG2.2.15 cells was evaluated by ELISA method. After HepG2.2.15 cells were treated with different concentrations of PGS (50, 100, 200 and 400 μg / mL) for 6 days, the supernatant was changed every 3 days, and the supernatant and cells were collected on the 6th day. The IFN-β in the cell culture supernatant and cell lysate was determined according to the instructions of the ELISA kit.

[0050] Experimental results such as Figure 6 As shown, compared with the control group, after treatment with different concentrations of PGS (100, 200 and 400 µg / mL), the expression of IFN-β in the cells was significantly increased (P Figure 6 A). At the same time, when the concentration reached 400 µg / mL, PGS significantly increased th...

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Abstract

The invention provides application of polyguluronate sulfate to anti-hepatitis B virus medicine preparation. Experiments prove that the polyguluronate sulfate is capable of well inhibiting expression of an HBV (hepatitis B virus) HBsAg (hepatitis B surface antigen) and an HBV HBeAg (hepatitis Be antigen) in a hepatocellular carcinoma cell line HepG2.2.15, remarkably inhibiting expression of HBV-S mRNA (messenger ribonucleic acid) in the hepatocellular carcinoma cell line HepG2.2.15, enhancing generation and secretion of anti-virus immunity-associated IFN (interferon)-beta in cells and activating NF (nuclear factor)-kappa B and MAPK (mitogen-activated protein kinase) signal pathways. The polyguluronate sulfate which is a marine sulfated polysaccharide compound has the advantages of rich resources, low cost, high safety and the like, and is obviously superior to positive control drug lamivudine in anti-HBV effect, thereby being promising in application prospect of anti-hepatitis B virus medicine preparation.

Description

technical field [0001] The invention belongs to the field of marine drugs, and in particular relates to the application of polyguluronic acid sulfate in preparing anti-hepatitis B virus drugs. Background technique [0002] Hepatitis B virus (HBV) infection is the most widespread and most harmful infectious disease in my country, and it is also one of the most serious public health problems in the world. Hepatitis B virus (HBV) is a DNA virus belonging to the family Hepadnavividae. According to the statistics of the World Health Organization, about 2 billion people in the world have been infected with HBV, of which 350 million people are chronically infected. There are currently 93 million HBV carriers and 20 million chronically infected people in China. Every year, about 280,000 deaths from liver failure, cirrhosis and liver cancer due to HBV infection account for 3.7% of the deaths due to diseases. [0003] At present, the control of hepatitis B is mainly based on vaccina...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/737A61P31/20A61P35/00
CPCA61K31/737
Inventor 赵峡王伟吴丽娟管华诗于广利李春霞
Owner MARINE BIOMEDICAL RES INST OF QINGDAO CO LTD
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