CN104784178B - Application of niacinamide as effective component in preparation of medicine for treating hepatitis B - Google Patents
Application of niacinamide as effective component in preparation of medicine for treating hepatitis B Download PDFInfo
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Abstract
The invention relates to the field of drug research and development and particularly discloses application of niacinamide as an effective component in preparation of a medicine for treating hepatitis B. The experiment firstly reveals that the niacinamide is capable of inhibiting the expression level of the hepatitis B (HBV), including inhibiting the formation of the HBV replication intermediate, inhibiting the pregenome RNA expression, inhibiting the expression of a core protein and inhibiting the secretion of HBeAg and HbsAg. The niacinamide has a function of obviously treating the hepatitis B, can be used for preparing the medicine for treating the hepatitis B and has a wide application future.
Description
Technical field
The present invention relates to Field of Drug Discovery, specifically disclose niacin amide and control preparing hepatitis B as effective ingredient
Treat the purposes in medicine.
Background technology
The existing disease patient populations of chronic viral hepatitis B caused by hepatitis B viruss (Hepatitis B Virus, HBV) infection are huge
Greatly, 20,000,000 patients have been reached in China, virus carrier's radix is then up to 1.2 hundred million.Although the extensive application of vaccine, but make many
Number Susceptible population is protected, but carrier is changed into the potential risk of existing disease patient, it would still be possible to caused in following one period
Hepatitis B patient quantity is growing on and on.The existing disease patient of chronic viral hepatitis B may be developed to liver cirrhosis, hepatocarcinoma, so as to cause death etc. serious
Consequence.In this context, effectively treatment is carried out to existing disease patient, prevents its disease progression, be the master of current Treatment of Hepatitis B
Want task.
At present, the key agents for treating the existing disease patient of hepatitis B include interferon and nucleoside analog.Interferon is only right
Patient outcome less than 30% is obvious, and side reaction is larger, and application is by a definite limitation.The nucleoside analog for having listed
(nucleotide analog, NAs) includes lamivudine, adefovirdipivoxil, Sebivo, Entecavir and tenofovir totally five
Kind.These medicines can reduce the serum HBV carrying capacity of most of patients over a period to come, improve transaminase level and liver histological
Performance, but be finally reached virus cccDNA remove this ideal treatment target ratio it is still relatively low, and, NAs generally needs
Long-term prescription is to maintain effect, but long-term prescription may produce viral resistance problems again.Therefore, current chronic hepatitis B is controlled
Therapeutic effect is still to be improved and improves, it is found that the target of new treatment HBV has the meaning being even more important.
The content of the invention
It is an object of the invention to overcome the defect of prior art, there is provided niacin amide as effective ingredient prepare it is B-mode
Purposes in treating hepatitiss medicine.
Niacin amide, also known as nicotiamide, english name Nicotinamide, is often simply called NAM, also known as Vitamin PP,
It is a kind of water soluble vitamins for belonging to vitamin B3 class.
Niacin amide, can be obtained by existing commercially available approach.
The present invention is achieved by the following technical solutions：
A first aspect of the present invention discloses niacin amide as effective ingredient in therapeutic agent for hepatitis B is prepared
Purposes.
Preferably, niacin amide plays a part of to treat hepatitis B by inhibition HBV replication.
Preferably, niacin amide inhibition HBV replication intermediate is formed.
Preferably, niacin amide suppresses HBV 3.5kb mRNA to produce.
Preferably, niacin amide suppresses HBV core protein levels.
Preferably, niacin amide suppresses the secretion of HBsAg.
Preferably, niacin amide suppresses the secretion of HBeAg.
More preferably, the purposes is preparing hepatitis B as one of effective ingredient or sole active ingredient for niacin amide
Purposes in medicine.
Second aspect present invention discloses a kind of pharmaceutical preparation for treating hepatitis B, the Buddhist nun gram acyl containing safe and effective amount
Amine, balance of pharmaceutically acceptable carrier.
Preferably, niacin amide is one of effective ingredient of the pharmaceutical preparation or sole active ingredient.
Pharmaceutically acceptable carrier is various pharmaceutically conventional adjuvants and/or excipient, including but not limited to sugar
Class (such as Lactose, dextrose and saccharose), starch (such as corn starch and potato starch), cellulose and its derivates are (such as carboxymethyl
Sodium cellulosate, ethyl cellulose and methylcellulose), tragacanth gum powder, Fructus Hordei Germinatus, gelatin, Talcum, kollag is (such as Hard Fat
Acid and magnesium stearate), calcium sulfate, vegetable oil, such as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, Oleum sesami, olive oil, Semen Maydis oil and cupu oil are polynary
Alcohol (such as Propylene Glycol, glycerol, Sorbitol, mannitol and Polyethylene Glycol), alginic acid, emulsifying agent is (such as Tween, Polyethylene oxide
Oleum Ricini), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, tablet agent, stabilizer, antioxidant, preservative, nothing
Pyrogen water, isotonic saline solution and phosphate buffer etc.；The carrier can improve stability, activity and the biology of formula as needed
Effectiveness etc..
Preferably, niacin amide accounts for the 0.0004%～99% of the pharmaceutical preparation gross mass.
The pharmaceutical preparation of the present invention can make any conventional dosage form according to the universal method on pharmaceuticss.
Preferably, the pharmaceutical preparation is ejection preparation.
Beneficial effects of the present invention are：
Jing of the present invention test disclose first niacin amide can inhibition HBV replication intermediate formed, genome before suppressing
Rna expression, suppresses the expression of core protein, and suppresses the secretion of HBeAg and HBsAg.With significantly treatment hepatitis B
Function, can be used to prepare therapeutic agent for hepatitis B, has broad application prospects.
Description of the drawings
Fig. 1：MTS analyzes cytotoxicity of the niacin amide in the cell HepAD38 and HepG2.2.15 that HBV is expressed；Figure
1A：Niacin amide CC50 in the HepAD38 cells of the hbv replication that tetracycline is induced is 36.38mM；Figure 1B：In stable expression
In the cell HepG2.2.15 cells of HBV, CC50 is 44.44mM.
Fig. 2：The impact that fluorescence quantitative PCR detection niacin amide is expressed to hbv replication intermediate；Fig. 2A：In HepAD38
In, to compare with matched group, 8mM, 16mM niacin amide group hbv replication intermediate is reduced to 70%, 60% respectively；Fig. 2 B：
In HepG2.2.15,16mM is compared with matched group, 32mM niacin amide group hbv replication intermediate is reduced to 50% He respectively
30%.
Fig. 3：The impact that Southern Blot detection niacin amide is expressed to hbv replication intermediate；Wherein, rcDNA is
HBV unsaturated cyclic DNA；DsDNA is HBV double-stranded DNAs；SsDNA is HBV single stranded DNAs.
Fig. 4：The impact that fluorescence quantitative PCR detection niacin amide is expressed to HBV3.5kb mRNA；Fig. 4 A：In HepAD38
In, 8mM, 16mM niacin amide group is reduced to 70%, 50% respectively compared with matched group HBV 3.5kb mRNA；Fig. 4 B：
In HepG2.2.15,16mM, 32mM niacin amide group is reduced to 50%, 40% respectively compared with matched group HBV 3.5kb mRNA.
Fig. 5：The impact that Western blot detection niacin amide is expressed to HBc.
Fig. 6：The impact that ELISA detection niacin amide is secreted to HBsAg；Fig. 6 A：In HepAD38,8mM, 16mM Buddhist nun gram
It is 80%, 30% that amide weakens the secretion of HBsAg respectively；Fig. 6 B：In HepG2.2.15,16mM, 32mM niacin amide difference
The secretion for weakening HBsAg is about 70%, 40%.
Fig. 7：The impact that ELISA detection niacin amide is secreted to HBeAg；Fig. 7 A：In HepAD38,8mM, 16mM Buddhist nun gram
Amide weakens the secretion of HBeAg respectively and is about 70%, 60%；Fig. 7 B：In HepG2.2.15,16mM, 32mM niacin amide point
Not Jian Ruo the secretion of HBeAg be about 70%, 50%.
Fig. 8：Impact of the fluorescence quantitative PCR detection niacin amide to mice serum HBV-DNA copy numbers.
Fig. 9：ELISA detects impact of the niacin amide to HBsAg secretions in mice serum.
Figure 10：ELISA detects impact of the niacin amide to HBeAg secretions in mice serum.
Figure 11：Impact of the fluorescence quantitative PCR detection niacin amide to murine liver tissue HBV-DNA copy number.
Figure 12：MST analyzes cytotoxicities of the EX527 in HepAD38 and HepG2.2.15.
Figure 13：The impact that fluorescence quantitative PCR detection EX527 is expressed to hbv replication intermediate；Figure 13 A：In HepAD38,
Compare with matched group, EX527 is had no significant effect to hbv replication intermediate；Figure 13 B：In HepG2.2.15, and matched group phase
Than EX527 is had no significant effect to hbv replication intermediate.
Figure 14：ELISA detects impacts of the EX527 to HBsAg secretions in cell conditioned medium；Figure 14 A：In HepAD38,
Secretions of the EX527 to HBsAg has no significant effect；Figure 14 B：In HepG2.2.15, EX527 is to the secretion of HBsAg without obvious shadow
Ring.
Figure 15：ELISA detects impacts of the EX527 to HBeAg secretions in cell conditioned medium；Figure 15 A：In HepAD38,
Secretions of the EX527 to HBeAg has no significant effect；Figure 15 B：In HepG2.2.15, EX527 is to the secretion of HBeAg without obvious shadow
Ring.
Specific embodiment
Before the specific embodiment of the invention is further described, it should be appreciated that protection scope of the present invention is not limited to down
State specific specific embodiment；It is also understood that the term used in the embodiment of the present invention is specific concrete in order to describe
Embodiment, rather than in order to limit the scope of the invention.
When embodiment provides numerical range, it should be appreciated that except non-invention is otherwise noted, two ends of each numerical range
Between point and two end points, any one numerical value can select.Unless otherwise defined, the present invention used in all technologies and
The same meaning that scientific terminology is generally understood that with those skilled in the art of the present technique.Except the concrete grammar used in embodiment, equipment,
Outside material, the record of grasp and the present invention according to those skilled in the art to prior art can also be used and this
Any method of the similar or equivalent prior art of method, equipment described in inventive embodiments, material, equipment and material come real
The existing present invention.
Unless otherwise indicated, disclosed in this invention experimental technique, detection method, preparation method using this technology lead
The conventional molecular biology in domain, biochemistry, chromatin Structure and analysis, analytical chemistry, cell culture, recombinant DNA technology and
The routine techniquess of association area.The perfect explanation in existing document of these technologies, specifically can be found in Sambrook etc.
MOLECULAR CLONING：A LABORATORY MANUAL, Second edition, Cold Spring Harbor
Laboratory Press, 1989 and Third edition, 2001；Ausubel etc., CURRENT PROTOCOLS IN
The and periodic updates of MOLECULAR BIOLOGY, John Wiley＆Sons, New York, 1987；the
Series METHODS IN ENZYMOLOGY, Academic Press, San Diego；Wolffe, CHROMATIN
STRUCTURE AND FUNCTION, Third edition, Academic Press, San Diego, 1998；METHODS IN
ENZYMOLOGY, Vol.304, Chromatin (P.M.Wassarman and A.P.Wolffe, eds.), Academic
Press, San Diego, 1999；With METHODS IN MOLECULAR BIOLOGY, Vol.119, Chromatin
Protocols (P.B.Becker, ed.) Humana Press, Totowa, 1999 etc..
1 MTS of embodiment is tested
Niacin amide (Nicotinamide, NAM) (Sigma-Aldrich, article No.：N0636) it is dissolved in PBS and is formulated as 1M Buddhist nun
Gram amide solution.
Respectively by 1.5 × 104HepAD38 cells or HepG2.2.15 cells are inoculated in 96 orifice plates, after 24 hours, are used
1M niacin amide solution is diluted to 0mM by MEM culture medium, and 1mM, 2mM, 4mM, 8mM, 16mM, 32mM, 64mM and 108mM are altogether
9 Concentraton gradient, 3 multiple holes of each concentration add the above-mentioned solution of 100 μ l respectively per hole.After 72 hours, MEM culture medium is changed to.After
After continuous culture 48 hours, the 20 μ l MTS reagents of addition per hole, lucifuge, 37 ° are incubated 1 hour, 490nm detection OD values, calculate and paint
Yeast production line.
As a result as shown in figure 1, niacin amide CC50 in the HepAD38 cells of the hbv replication that tetracycline is induced is
36.38mM (Figure 1A), in the cell HepG2.2.15 cells of stable expression HBV, CC50 is 44.44mM (Figure 1B).
Detect in embodiment 2 hbv replication cell HepAD38 and HepG2.2.15 that niacin amide is affected on hbv replication
Respectively by 25 × 104HepAD38 or HepG2.2.15 cells are inoculated in six orifice plates, after 24 hours, prepare 0mM,
8mM, 16mM niacin amide solution, adds the above-mentioned solution of 2ml respectively per hole, processes HepAD38 cells and (prepares 0mM, 16mM, 32mM
Niacin amide solution, per the above-mentioned solution of hole 2ml, processes HepG2.2.15 cells).After 72 hours, it is changed to MEM culture medium and continues training
After supporting 48 hours, cell is digested and counted respectively, extract hbv replication intermediate in cell, extract cell RNA, extract cell total
Albumen, and collect cell culture medium and carry out HBsAg, HBeAg detections.
Real time PCR detections show that the obvious inhibition HBV replication intermediate of niacin amide is formed.In HepAD38,
Compare with matched group, 8mM, 16mM niacin amide group hbv replication intermediate is reduced to 70%, 60% (Fig. 2A) respectively,
In HepG2.2.15,16mM is compared with matched group, 32mM niacin amide group hbv replication intermediate is reduced to 50% and 30% respectively
(Fig. 2 B)；Southern Blot further demonstrate that this phenomenon (Fig. 3).
Real time PCR results show that niacin amide significantly inhibits HBV 3.5kb mRNA generations.In HepAD38,
8mM, 16mM niacin amide group is reduced to 70%, 50% (Fig. 4 A) respectively compared with matched group HBV 3.5kb mRNA,
In HepG2.2.15,16mM, 32mM niacin amide group is reduced to 50% respectively compared with matched group HBV 3.5kb mRNA, 40% (figure
4B)。
Western Blot results show that niacin amide can significantly inhibit HBV in HepAD38 and HepG2.2.15
Core protein levels (Fig. 5).
Diagnostic Test Kit for Hepatitis B Surface Antigen(Elisa) (Shanghai section China) testing result shows, Ni Ke
Amide suppresses the secretion of HBsAg, and in HepAD38, it is 80% that 8mM, 16mM niacin amide weakens the secretion of HBsAg respectively,
30% (Fig. 6 A), in HepG2.2.15,16mM, 32mM niacin amide weakens the secretion of HBsAg respectively and is about 70%, 40%
(Fig. 6 B).
Hepatitis B virus e antigen diagnostic kit (euzymelinked immunosorbent assay (ELISA)) (Shanghai section China) testing result shows, Buddhist nun gram acyl
Amine suppresses the secretion of HBeAg.In HepAD38,8mM, 16mM niacin amide weakens the secretion of HBeAg respectively and is about 70%,
60% (Fig. 7 A), in HepG2.2.15,16mM, 32mM niacin amide weakens the secretion of HBeAg respectively and is about 70%, 50%
(Fig. 7 B).
In 3 HBV transgene mouse models of embodiment, niacin amide can inhibition HBV replication
Selection 15 is female, and age 12-16 is all, the HBV transgenic mice (HBV-Tg of 28.12 ± 2.57g of weight
C57BL/6).Tail vein blood 100-300 μ l, 37 ° are incubated 1 hour, are centrifuged 4000rpm, 10min, 4 DEG C, and transfer serum is to dry
In net EP pipes (about 50-200 μ l).Blood is extracted using virus genom DNA/RNA extracts kits (TIANGEN, article No. DP315)
HBV DNA in clear, detect HBV DNA copy numbers.Hepatitis B virus surface antigen diagnostic kit (enzyme linked immunological is used respectively
Method) and hepatitis B virus e antigen diagnostic kit (euzymelinked immunosorbent assay (ELISA)) (China of Shanghai section) detection HBsAg in serum and HBeAg.
The higher mice 12 of HBV DNA copy numbers and HBsAg and HBeAg is chosen, mice is randomly divided into into 4 groups, 3 per group, point
The 500 μ l of niacin amide solution of the 0 μ g/g not prepared by tail vein injection Sodium Chloride, 10 μ g/g, 100 μ g/g, 200 μ g/g,
Continuous use 5 days.After last time medication 24 hours, eye socket about 500 μ l of blood sampling, cervical dislocation put to death mice, separate liver ,-
80 ° of preservations.Serum is separated, serum HBV DNA copy number is extracted and detect, is contrasted with the front level of administration, is detected serum
Contrasted before middle HBsAg and HBeAg, with administration, using wizard genomic DNA purification kits (promega, A1120)
DNA in murine liver tissue is extracted, and detects HBV DNA copy numbers.
Real time PCR detection serum HBV DNA copy numbers find, compare with 0 μ g/g groups, 10 μ g/g, 100 μ g/
G, after 200 μ g/g niacin amide group medications, HBV DNA copy numbers reduce about 60%, 40% respectively, 30% (Fig. 8).
Testing result shows Diagnostic Test Kit for Hepatitis B Surface Antigen(Elisa) (China of Shanghai section), and 0 μ
G/g groups are compared, 10 μ g/g, 100 μ g/g, and the secretion of HBsAg after 200 μ g/g niacin amide group medications reduces about 60% respectively,
50%, 40% (Fig. 9).
Testing result shows hepatitis B virus e antigen diagnostic kit (euzymelinked immunosorbent assay (ELISA)) (China of Shanghai section), and 0 μ g/g
Group is compared, 10 μ g/g, 100 μ g/g, and the secretion of HBeAg after 200 μ g/g niacin amide group medications reduces about 80% respectively,
50%, 40% (Figure 10).
Real time PCR detection murine liver tissue HBV DNA copy numbers find, compared with 0 μ g/g groups, 10 μ g/g, and 100
μ g/g, 200 μ g/g niacin amide groups suppress murine liver tissue HBV DNA to be about 47%, 30% respectively, 16% (Figure 11).
4 EX527 of embodiment is had no significant effect to hbv replication
EX527 (Santa Cruz, article No.：CAS 49843-98-3) it is dissolved in DMSO and is formulated as 1mM EX527 solution.
1.MTS is tested
Respectively by 1.5 × 104HepAD38 cells or HepG2.2.15 cells are inoculated in 96 orifice plates, after 24 hours, are used
1M EX527 solution is diluted to 0,0.5,1,2,4,8,16,32uM totally 7 Concentraton gradient by MEM culture medium, and each concentration 3 is multiple
Hole, adds the above-mentioned solution of 100 μ l respectively per hole.After 72 hours, MEM culture medium is changed to.After continuing culture 48 hours, 20 are added per hole
μ l MTS reagents, lucifuge, 37 ° are incubated 1 hour, 490nm detection OD values, calculate and draw curve.
As a result as shown in figure 12, EX527 CC50 in the HepAD38 cells of the hbv replication that tetracycline is induced are 5 μM of (figures
12A), in the cell HepG2.2.15 cells of stable expression HBV, CC50 is 5 μM (Figure 12 B).
Detect in 2.HBV replicating cell HepAD38 and HepG2.2.15 that EX527 is affected on hbv replication
Respectively by 25 × 104HepAD38 or HepG2.2.15 cells are inoculated in six orifice plates, after 24 hours, prepare 0 μM, 1 μ
M, 2 μM of EX527 solution add the above-mentioned solution of 2ml respectively per hole, process HepAD38 and HepG2.2.15 cells.After 72 hours, change
After continuing culture 48 hours for MEM culture medium, cell is digested and count respectively, extract hbv replication intermediate in cell, and collect
Cell culture medium carries out HBsAg, HBeAg detections.
As a result find, EX527 is had no significant effect to hbv replication in hbv replication cell HepAD38 and HepG2.2.15 have
Body：
Real time PCR detection show, EX527 in HepAD38 and HepG2.2.15, to hbv replication intermediate
Expression has no significant effect (Figure 13 A, B).
Cell conditioned medium is collected, is shown by hepatitis B virus surface antigen diagnostic kit testing result, EX527 pair
The secretion of HBsAg does not make significant difference (Figure 14 A, B) yet.Hepatitis B virus e antigen diagnostic kit testing result shows,
EX527 does not equally make significant difference (Figure 15 A, B) to the secretion of HBeAg yet.
Embodiment above is, in order to illustrate embodiment disclosed by the invention, can not to be interpreted as the limit to the present invention
System.Additionally, method, the change of compositionss in various modifications listed herein and invention, without departing from the scope of the present invention
With for those skilled in the art be obvious on the premise of spirit.Although having combined the various concrete of the present invention
Preferred embodiment has carried out specific description to the present invention, it is to be understood that, the present invention should not be limited only to these specific embodiments.
In fact, various modifications obvious for those skilled in the art as above should all include obtaining invention
Within the scope of the invention.
Claims (7)
1. purposes of the niacin amide as sole active ingredient in therapeutic agent for hepatitis B is prepared.
2. purposes according to claim 1, it is characterised in that niacin amide plays treatment second by inhibition HBV replication
The effect of type hepatitis.
3. purposes according to claim 1, it is characterised in that niacin amide inhibition HBV replication intermediate is formed.
4. purposes according to claim 1, it is characterised in that niacin amide suppresses HBV 3.5kb mRNA to produce.
5. purposes according to claim 1, it is characterised in that niacin amide suppresses HBV core protein levels.
6. purposes according to claim 1, it is characterised in that niacin amide suppresses the secretion of HBsAg.
7. purposes according to claim 1, it is characterised in that niacin amide suppresses the secretion of HBeAg.
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| CN109507430B (en) * | 2018-09-06 | 2022-03-11 | 重庆医科大学 | Function and application of SIRT7 |
| CN109364074B (en) * | 2018-11-01 | 2021-05-07 | 重庆医科大学 | Application of 6-aminonicotinamide as effective component in preparing medicament for treating hepatitis B |
| CN110859840A (en) * | 2019-11-29 | 2020-03-06 | 湖南大学 | Application of nicotinic acid in preparing medicine for treating chronic hepatitis B |
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