CN109381463A - Application of the tazarotene in preparation treatment hepatitis B virus infection drug - Google Patents
Application of the tazarotene in preparation treatment hepatitis B virus infection drug Download PDFInfo
- Publication number
- CN109381463A CN109381463A CN201710671770.2A CN201710671770A CN109381463A CN 109381463 A CN109381463 A CN 109381463A CN 201710671770 A CN201710671770 A CN 201710671770A CN 109381463 A CN109381463 A CN 109381463A
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- CN
- China
- Prior art keywords
- tazarotene
- hepatitis
- hbv
- cccdna
- drug
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
Abstract
The invention belongs to pharmaceutical technology fields, are related to tazarotene (Tazarotene) in preparation and inhibit the purposes in hepatitis B drug.The present invention confirms that tretinoin medicines tazarotene has very strong anti-hepatitis B activity through virus transfection and the identification of infection cell model test, and the ability for persistently inhibiting virus is shown after withdrawal, while the acellular poison effect under corresponding antiviral working concentration.There is the activity of relatively special interference cccDNA stability and inhibition cccDNA transcription the invention also discloses tazarotene；And disclose and belong to tretinoin medicines and also there is anti-hepatitis B activity for tazarotene analog Adapalene (Adapalene), the present invention is used for clinical anti-hepatitis virus intervention for tazarotene and the like and provides technology and theoretical basis to prepare the novel hepatitis B drug based on tazarotene and the like and derivative.
Description
Technical field
The invention belongs to field of medicaments technical fields, are related to the new medicine use of tazarotene, and in particular to tazarotene and
Purposes of its analog in preparation treatment hepatitis B virus infection drug, especially reduces or eliminates hepatitis B hepatitis B in preparation
Purposes in the drug of e antigen and surface antigen and targeting hepatitis B virus duplication template DNA.
Background technique
It is one of the important diseases for seriously endangering human health prior art discloses hepatitis B (HBV) infection.According to system
Meter, although the whole world is still in recent years as the implementation of hepatitis B vaccination has significantly reduced the risk of infection of newborn HBV
There are about 2.4 hundred million hepatitis B chronic infections (wherein China exceedes 0.9 hundred million), about a million people dies of hepatitis B every year
Hepatic failure caused by infecting, cirrhosis and primary hepatoma.
Currently, the drug for treating chronic hbv-infection has nucleosides (acid) analog interferon: nucleosides (acid) class
Like object by inhibiting the effect of HBV reverse transcriptase to can significantly reduce serum viral load, but it is still unable to efficient targeting HBV transcription
Template-covalently closed circular DNA (cccDNA) of duplication, therefore, most patient need to take medicine for a long time or even all the life, easily occur resistance to
Hbv replication level easily rebounds after medicine Strain and drug withdrawal；Interferon is that one kind has both direct antiviral effect and is immunized indirectly
The cell factor of regulatory function, according to statistics, though compared with nucleosides (acid) analog have it is relatively high promote HBV e antigen (HBeAg) and
The effect that surface antigen (HBsAg) is turned out cloudy, but 48 weeks interferon therapies are still only capable of that about 30% patient HBeAg is made to turn out cloudy, less than 5%
Patient HBsAg turns out cloudy, and has apparent side effect.Therefore, Present clinical treatment hepatitis B still cannot effectively reach B-type hepatitis
Malicious functionality is cured, therefore the drug molecule for developing the novel efficient targeting HBV infection of searching is very necessary and has realistic meaning.
Tazarotene (Tazarotene) is third generation fragrance tretinoin medicines, mainly optionally combine Tretinoin by
Body (RAR- β；RAR- γ), tazarotene is mainly used for clinical treatment psoriasis, acne, dyskeratosis disease, hair follicle sebum
Gland disease, precancerous skin lesions etc..So far, there is not yet related tazarotene inhibits the report of hepatitis B.
Status based on the prior art, present inventor is quasi- to provide the new medicine use of tazarotene, and in particular to
Application of the tazarotene and the like in preparation treatment hepatitis B virus infection drug.
Summary of the invention
It is an object of the invention in view of there is no in the prior art and meanwhile inhibit viral antigen express and ccc DNA drug
Status, the new medicine use of tazarotene is provided, and in particular to tazarotene and the like preparation treat hepatitis B
Purposes in infection medicine；Especially hepatitis B hepatitis B virus e antigen and surface antigen and targeting hepatitis B are reduced or eliminated in preparation
Purposes in the drug of virus replication template DNA.
The present invention the test shows that, tazarotene tool and the like Adapalene (Adapalene) have Anti-HBV effect
The effect of (including inhibiting viral antigen expression and virus ccc DNA replication dna), tazarotene and the like can be used for preparing suppression
The drug of hepatitis B processed.
The present invention carries out high flux screening, from the U.S. by establishing 384 orifice plate hepatitis B virus infection primary cultured hepatocytes
In drug reservoir 1442 kinds of small molecule compounds of Bureau of Drugs Supervision (FDA) approval listing, screening and identification tazarotene has significant anti-
HBV activity.
The present invention is using primary hepatocyte (PHH) system of HBV infection and the HBV infection model of people's HepaRG cell into one
Step demonstrate,proves tazarotene to the inhibiting effect of HBeAg, HBsAg and HBV DNA, and confirmation tazarotene all has significant suppression to it
System, half effective inhibition concentration (IC50) in tens nanomoles, and to cell without overt toxicity under corresponding antiviral concentration
Effect.
The present invention is the experimental results showed that in the cell line (HepDES19) of the cccDNA containing HBV and in HepG2 HBV transfected
In the cell of circle DNA, tazarotene, which equally has, significantly inhibits HBeAg, the effect of HBsAg, and in host cell
Genome is manually integrated with HBV gene group and has no the activity for finding no in the cell line Hep2.215 of ccc DNA and inhibiting HBV,
Show that tazarotene can specifically target the feature of HBV template DNA in nucleus relatively.
In the present invention, experimental result confirms tazarotene in the primary cell of HBV infection, and tazarotene can partially inhibit
The activity of cccDNA is that template transcription has stronger inhibitory activity for cccDNA.
In the present invention, experimental result also demonstrates the Adapalene etc. for belonging to tretinoin medicines and being tazarotene analog
Also there is stronger Anti-HBV effect, it is shown that tretinoin medicines are preparing the application potential in Anti-HBV drugs.
The invention discloses tazarotenes and the like in the inhibitory activity of targeting HBV cccDNA, provides Ta Zhaluo
Application of the spit of fland and the like in preparation treatment hepatitis B virus infection drug；Especially hepatitis B is reduced or eliminated in preparation
Hepatitis B virus e antigen and surface antigen and target hepatitis B virus duplication template DNA drug in application, the present invention be tazarotene most
The therapeutic intervention for being applied to chronic hbv-infection eventually illustrates extraordinary prospect and provides empirical theory basis.
For ease of understanding, will have below by specific drawings and examples to tazarotene of the present invention preferable
The activity of Anti-HBV activity is illustrated.It is noted that the drawings and examples are merely to explanation, it is clear that this field it is common
Technical staff can be according to illustrating herein, and make modification to the present invention within the scope of the invention, the present invention is also included in these modifications
In the range of.
Detailed description of the invention
The evaluation of Fig. 1 tazarotene Effect of anti-HBV in HBV infection system,
Wherein, Figure 1A is based on the HBV infection model of human primary hepatocyte (PHH)；
HBV infection model of Figure 1B based on HepaRG cell.
The comparison of Fig. 2 tazarotene Effect of anti-HBV in HBV cell line (HepDES19 and Hep2.215 etc.).
Fig. 3 tazarotene is to cccDNA, the influence of HBV RNA and HBc content.
Fig. 4 tazarotene inhibits hbv replication to have persistence activity.
Fig. 5 belongs to tretinoin medicines and evaluates for the Effect of anti-HBV of the Adapalene of tazarotene analog.
Specific embodiment
Embodiment 1HBV infects system embodiment
PHH or HepaRG cell by tazarotene processing infected with hepatitis B particle, Hepatitis B virus e antigen
(HBeAg), the generation of hepatitis B surface antigen (HBsAg) and HBV DNA is inhibited in various degree.
(1) culture of HepaRG cell: HepaRG cell line derives from the terminally differentiated cells of people's liver precursor system, protects
The many characteristics for having stayed primary human liver cell, can support HBV infection after differentiation；1) grown cultures liquid: 15% fetal calf serum,
100U/L penicillin, 0.1mg/L streptomysin, glutamine, 0.023IU/ml insulin, 4.7 μ g/ml hydrocortisones, 80 μ
L/ml gentamicin；2) break up culture solution: grown cultures liquid+2%DMSO, need to continue differentiation two weeks or more to carry out HBV infection；
(2) culture of PHH cell: purchased from the auspicious moral biology in Shanghai and dedicated commercial medium culture is used；It is noted that
Human primary hepatocyte in research process of the present invention using two kinds of Different Individual sources has carried out testing and verifying correlated results,
As a result with uniformity；
(3) after PHH cell infection 2 days, the tazarotene of various concentration is added to cell, carries out changing liquid and locate again within every 3 days
Reason；The 8th day after infection, collects cell conditioned medium ELISA and detect HBV antigen markers HBeAg and HBsAg, with specific HBV primer
QPCR detects the production of viral DNA in supernatant；HBV antigen markers and HBV can be greatly reduced in Zha Luoting as the result is shown
The content of DNA, and cytotoxicity (as shown in Figure 1A) is not detected under relevant work concentration；
The tazarotene of various concentration is added to cell after 5 days by the HepaRG cell infection HBV of differentiation, and every incubation 72 is small
Shi Jinhang changes liquid and reprocessing；The 15th day after infection, collect cell conditioned medium ELISA detection HBV antigen markers HBeAg and
HBsAg, with the production of viral DNA in specific HBV primer qPCR detection supernatant；Tazarotene can significantly press down as the result is shown
The content of HBV biology antigen markers and DNA processed, and concentration dependent (as shown in Figure 1B) is presented；
Similar, the present invention comments Effect of anti-HBV of the tazarotene analog Adapalene in HBV infection system
Valence, the results show that the Adapalene can effectively inhibit HBV biology antigen markers HBsAg and HBeAg, and cell-free
Toxicity (as shown in Figure 5)；
(4) in PHH infection model, cell, the withdrawal after dosing three times, measuring and calculating are handled with the tazarotene of various concentration
Antiviral index calculates half effective inhibition concentration (IC after dosing and after withdrawal50), IC after withdrawal as the result is shown50Compared with withdrawal
It is preceding about the same (as shown in Figure 4), show tazarotene with superior Anti-HBV effect and inhibits hbv replication with holding
Ability；
(5) tazarotene is further detected to influence (such as Fig. 4 of HBV cccDNA and RNA with qPCR and qRT-PCR respectively
It is shown), tazarotene has certain inhibition to cccDNA as the result is shown, while having to HBV rna transcription and lowering effect；It is immunized glimmering
Light experiment display tazarotene has very strong inhibitory effect to hepatitis B virus core protein (HBc) expression.
Embodiment 2.HBV science cell line model embodiment
It tests tazarotene and inhibits situation in HBV cell line:
(1) culture of hepatic cell line Hep2.215: using DMEM/F12 culture solution, (Gibco company adds 10% tire ox blood
Clearly, 100U/ml penicillin, 100mg/ml streptomysin and 400mg/ml G418) in 5%CO2Lower 37 DEG C of saturated steam environment
Constant temperature incubation；
(2) culture of hepatic cell line HepDES19: using DMEM/F12 culture solution, (Gibco company adds 10% tire ox blood
Clearly, 100U/ml penicillin, 100mg/ml streptomysin and 400mg/ml G418) in 5%CO2Lower 37 DEG C of saturated steam environment
Constant temperature incubation；
(3) in Hep2.215 cell and HepDES19 cell, various concentration is added is added various concentration to cell
Tazarotene collects cell conditioned medium ELISA after processing 5 days and detects HBV antigen markers HBeAg or HBsAg；He pricks as the result is shown
Luo Ting no activity (as shown in Figure 2 A) in Hep2.215 cell, and the tazarotene in the HepDES19 containing cccDNA
Then there is the activity figure (as shown in 2B) for inhibiting HBeAg, in the system of HepG2 HBV transfected circle DNA, tazarotene energy
Inhibit HBsAg and HBeAg, further illustrates that tazarotene may affect the stability of HBV cccDNA or inhibit HBV
The transcription of cccDNA.
Above-described embodiment illustrates screening and identification of the present invention tretinoin medicines tazarotene and the like in anti-hepatitis B disease
Effect in poison shows that tazarotene has significant Effect of anti-HBV in HBV natural infection system, and this kind of effect can be held
Long property is kept without rebounding；In addition, tazarotene shows Anti-HBV effect in the cell line containing HBV cccDNA, and
Host genome is manually integrated in the cell line of HBV gene group and does not show Anti-HBV effect but；It is further thin in the primary liver of people
In born of the same parents tazarotene have must cccDNA inhibition, and show in cccDNA transcription with stronger inhibitory activity
Tazarotene has the biological effect of opposite special target HBV cccDNA.
Claims (5)
1. purposes of the tazarotene in preparation treatment hepatitis B virus infection drug, the tazarotene further includes its analog
And derivative.
2. purposes according to claim 1, which is characterized in that described tazarotene and the like and derivative are for making
The drug of disease caused by standby clinic control and treating hepatitis B poison infect.
3. purposes according to claim 1, which is characterized in that described tazarotene and the like and derivative are for making
The drug of standby targeting cccDNA stability and cccDNA transcriptional activity.
4. by purposes described in claims 1 or 2 or 3, which is characterized in that described tazarotene and the like and derivative
To hepatitis B HBeAg, HBsAg, the generation of HBcAg virus protein and cccDNA transcriptional activity and cccDNA content.
5. purposes according to claim 1, which is characterized in that described tazarotene and the like and derivative are for making
Purposes in the composition of medicine of standby treatment hepatitis B virus infection in the composition of medicine, tazarotene and the like and is spread out
Biology is combined with other antiviral and immunoregulation medicaments.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710671770.2A CN109381463A (en) | 2017-08-08 | 2017-08-08 | Application of the tazarotene in preparation treatment hepatitis B virus infection drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710671770.2A CN109381463A (en) | 2017-08-08 | 2017-08-08 | Application of the tazarotene in preparation treatment hepatitis B virus infection drug |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109381463A true CN109381463A (en) | 2019-02-26 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710671770.2A Pending CN109381463A (en) | 2017-08-08 | 2017-08-08 | Application of the tazarotene in preparation treatment hepatitis B virus infection drug |
Country Status (1)
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| CN (1) | CN109381463A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023221361A1 (en) * | 2022-05-16 | 2023-11-23 | 重庆医科大学 | Use of small-molecule inhibitor bay87-2243 in preparing drug for treating hepatitis b |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008157394A2 (en) * | 2007-06-13 | 2008-12-24 | La Jolla Institute For Allergy And Immunology | Regulatory t cells and methods of making and using same |
-
2017
- 2017-08-08 CN CN201710671770.2A patent/CN109381463A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008157394A2 (en) * | 2007-06-13 | 2008-12-24 | La Jolla Institute For Allergy And Immunology | Regulatory t cells and methods of making and using same |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023221361A1 (en) * | 2022-05-16 | 2023-11-23 | 重庆医科大学 | Use of small-molecule inhibitor bay87-2243 in preparing drug for treating hepatitis b |
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| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20190226 |
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| WD01 | Invention patent application deemed withdrawn after publication |