CN103127050B - Salvianolic acid B application in preparing anti-H5N1 influenza virus medicine - Google Patents
Salvianolic acid B application in preparing anti-H5N1 influenza virus medicine Download PDFInfo
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- CN103127050B CN103127050B CN201110394891.XA CN201110394891A CN103127050B CN 103127050 B CN103127050 B CN 103127050B CN 201110394891 A CN201110394891 A CN 201110394891A CN 103127050 B CN103127050 B CN 103127050B
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- albumen
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- SNKFFCBZYFGCQN-VWUOOIFGSA-N Lithospermic acid B Natural products C([C@H](C(=O)O)OC(=O)\C=C\C=1C=2[C@H](C(=O)O[C@H](CC=3C=C(O)C(O)=CC=3)C(O)=O)[C@H](OC=2C(O)=CC=1)C=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 SNKFFCBZYFGCQN-VWUOOIFGSA-N 0.000 title claims abstract description 90
- 241000712461 unidentified influenza virus Species 0.000 title claims abstract description 26
- 239000003814 drug Substances 0.000 title claims abstract description 18
- 230000000694 effects Effects 0.000 claims abstract description 29
- 206010064097 Avian influenza Diseases 0.000 claims abstract description 18
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 claims abstract description 17
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 claims abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 5
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- 108090000790 Enzymes Proteins 0.000 claims description 12
- 230000001629 suppression Effects 0.000 claims description 10
- 241000338310 Pseudofabraea citricarpa Species 0.000 claims description 6
- 102000004169 proteins and genes Human genes 0.000 claims description 5
- 108090000623 proteins and genes Proteins 0.000 claims description 5
- 241000700605 Viruses Species 0.000 claims description 4
- 229920000160 (ribonucleotides)n+m Polymers 0.000 claims 1
- 239000000419 plant extract Substances 0.000 claims 1
- 229920002239 polyacrylonitrile Polymers 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 description 12
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- 239000000243 solution Substances 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- 239000005445 natural product Substances 0.000 description 5
- 229930014626 natural products Natural products 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 229940079593 drugs Drugs 0.000 description 4
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
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- 239000012086 standard solution Substances 0.000 description 4
- 108010042407 Endonucleases Proteins 0.000 description 3
- 102000004533 Endonucleases Human genes 0.000 description 3
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- 206010022000 Influenza Diseases 0.000 description 3
- 241001597008 Nomeidae Species 0.000 description 3
- 229920001850 Nucleic acid sequence Polymers 0.000 description 3
- 208000007536 Thrombosis Diseases 0.000 description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Tris Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 230000002785 anti-thrombosis Effects 0.000 description 3
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- 239000003146 anticoagulant agent Substances 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
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- 241000196324 Embryophyta Species 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
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- 210000004185 Liver Anatomy 0.000 description 2
- 229940037179 Potassium Ion Drugs 0.000 description 2
- YMGFTDKNIWPMGF-UCPJVGPRSA-N Salvianolic acid A Chemical class C([C@H](C(=O)O)OC(=O)\C=C\C=1C(=C(O)C(O)=CC=1)\C=C\C=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 YMGFTDKNIWPMGF-UCPJVGPRSA-N 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- 201000009910 diseases by infectious agent Diseases 0.000 description 2
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- 230000004761 fibrosis Effects 0.000 description 2
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- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- JLVVSXFLKOJNIY-UHFFFAOYSA-N magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 2
- 229910001425 magnesium ion Inorganic materials 0.000 description 2
- 230000001717 pathogenic Effects 0.000 description 2
- NPYPAHLBTDXSSS-UHFFFAOYSA-N potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 2
- 229910001414 potassium ion Inorganic materials 0.000 description 2
- 230000000644 propagated Effects 0.000 description 2
- FKNQFGJONOIPTF-UHFFFAOYSA-N sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229910001415 sodium ion Inorganic materials 0.000 description 2
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Abstract
The invention provides salvianolic acid B in preparation for preventing or treating the application in the medicine of H5N1 influenza virus, wherein said salvianolic acid B has a following structural:Salvianolic acid B can effectively suppress the activity of H5N1 influenza virus RNA polymerase subunit PAN albumen.
Description
Technical field
The present invention relates to pharmaceutical field, be specifically related to the application of salvianolic acid B.
Background technology
Influenza is that a class is propagated, pathogenic, variability is relatively strong, and involves wider popular of scope
Property disease, is caused by different subtype virus, is broadly divided into A type, Type B and c-type three major types,
Especially based on A type.Influenza A RNA polymerase PA subunit N end protein (PAN) participating in
Stablize the function aspects such as PA structure, endonuclease activity, cap-like structure combination, promoter combination
Play a crucial role, simultaneously because of its well-conserved in A type, Type B, c-type strain RNA sequence,
The most become an important target spot of research and development broad spectrum type influenza virus inhibitor.The most highly pathogenic
Bird flue virus H 5 N 1 subtype just belongs to influenza A, although H5N1 will not be by birds at present
It is propagated directly to the mankind, but has human infection's bird flu and the report of many people death, its hazardness
The most serious.
More existing influenza compound medicine action target spots are indefinite, and action component complexity is various.And
It is currently used for treating medicine such as Buddha's warrior attendant gastral cavity amine, the oseltamivir phosphate capsule etc. of influenza, also deposits in clinical practice at present
At certain drug resistance.RNA polymerase PANAlbumen is as brand-new, a popular research wide spectrum
The target spot of type influenza virus inhibitor, the inhibitor currently for this target spot is less, and lists without finished product
Medicine.The inhibitor in the natural product source reported also is very few.
It is long-standing that natural product and derivant thereof are used for treating various disease.Compared with synthetic drug
For, natural product has structure diversity, functional diversity, the advantages such as side effect is low, Qi Zhongchuan
Medical treatment checking in thousand of years gone through especially by system Chinese medicine, it is most likely that therefrom filter out novel structure, effect side
The compound of the anti-H5N1 influenza virus that formula is unique.
Salvianolic acid B (Salvianolic acid B) is a kind of naturalization extracted from plant amedica (such as Radix Salviae Miltiorrhizae)
Compound, can scavenging activated oxygen, anti-lipid peroxidation reaction, be to be currently known antioxidant activity
One of strong natural product；It may also suppress platelet aggregation, inhibition thrombosis simultaneously.To the heart,
The organs such as brain, liver, kidney have valuable pharmacological effect.
Within 2000, Liu's equality salvianolic acid B magnesium disclosed in patent CN1270809A has lipotropism matter mistake
The effect of oxidation anti-liver injury, has the function alleviating extent of liver fibrosis, and points out to can be used for controlling
Treating and prevent the diseases such as hepatic fibrosis, liver cirrhosis and fatty liver, salvianolic acid B magnesium can be used to prepare to be controlled
Treat the medicament of chronic hepatopathy；The salvianolic acid class disclosed in patent CN1378837A such as Zhang Juntian in 2002
Compound has the effect of suppression mammal HIV (human immunodeficiency virus) infection；Within 2003, thank to sky training etc. in patent
The application in preparation tumor of the salvianolic acid B disclosed in CN1408353A, and point out red phenol
Tumor cell is had by acid B and its esters (iron ion, sodium ion, potassium ion, calcium ion and magnesium ion)
Lethal effect, and animal experiment in vivo prove there is antitumous effect；Within 2005, the prosperous grade of Xiao Ming is specially
Salvianolic acid B disclosed in profit CN1578668A can be drawn as treatment or prevention OxLDL ELISA
The purposes of the medicament of the disease sent out；Wang Sheng in 2008 opens etc. red disclosed in patent CN101239057A
The pharmaceutical composition of phenolic acid B and its esters (potassium ion, sodium ion, calcium ion and magnesium ion) has anti-
Parkinson disease purposes；2009 Nian Ni power armies etc. disclose salvianolic acid B in patent CN101362741A
The derivant of structural modification and synthetic method thereof；Within 2010, he is public in patent CN101627988A again
Open structure modified outcome of salvianolic acid B application in pharmacy, and point out that these modified outcomes can be as anti-
Myocardial ischemia drug, anti-cerebral ischemia, atherosclerosis, antithrombotic, antitumor, defying age,
Anti-liver cirrhosis and anti-hepatic fibrosis medicines；Zhang Zuoguang is salvianolic acid disclosed in patent CN101375844A
B can be as the raw material of antidepressant drug；Really Dean etc. are a kind of disclosed in patent CN101496798A
There is the compound of the salvianolic acid B mother nucleus structure purposes in preparing MMP-9 activity inhibitor；
The salvianolic acid B disclosed in patent CN101530409A such as Han Jingyan can extend thrombosis initial time, presses down
The mesentery thrombosis that photochemistry processed causes, has antithrombotic application.
Although salvianolic acid B and derivant thereof are at antioxidation, anti-liver injury, antitumor, antidepressant, anti-ageing
The aspects such as old and antithrombotic have stronger pharmacological action, but it is sick in prevention or treatment H5N1 influenza to there is no it
Application in terms of Du.
Summary of the invention
The present invention provides salvianolic acid B in preparation for preventing or treat the medicine of H5N1 influenza virus
Application in thing, wherein said salvianolic acid B has a following structural:
In the application, the molecular formula of salvianolic acid B is C36H30O16, molecular weight is 718.62.
In the application, salvianolic acid B can be by various methods known in the art or accommodation side
Method separation and Extraction, synthesis or semisynthetic method from plant prepare, it is also possible to be directly purchased
Obtain.
In the application, salvianolic acid B is for suppressing the activity of H5N1 influenza virus RNA polymerase.
In the application, salvianolic acid B is used for suppressing H5N1 influenza virus RNA polymerase subunit
PANThe activity of albumen.Wherein, described H5N1 influenza virus RNA polymerase subunit PANAlbumen is
One of target spot of suppression H5N1 influenza virus.
The present invention chooses H5N1 type influenza virus RNA polymerase hypotype PA subunit N terminal nucleotide sequence
PA expressed by rowNAlbumen, as target proteins, is commented using vitro enzyme high flux alive as the activity of screening
Valency method, finds that salvianolic acid B has and significantly suppresses PANProtein active, measures its IC50Value is 16.3
μM.Salvianolic acid B can suppress the activity of H5N1 influenza virus RNA polymerase.May be used for system
Standby prevention or the medicine for the treatment of H5N1 influenza virus.
Accompanying drawing explanation
When reading in conjunction with the accompanying drawings, the present invention may be better understood according to the following detailed description.
Fig. 1 shows salvianolic acid B standard solution (50mg/mL) and the feminine gender of embodiments of the invention
Comparison, positive control are to H5N1 type influenza virus RNA polymerase hypotype PANProtease activity curve.
Fig. 2 shows salvianolic acid B suppression H5N1 type influenza virus according to an embodiment of the invention
RNA polymerase hypotype PANThe IC of albumen50Value curve chart.
Detailed description of the invention
In order to the present invention is better described, will be described specific embodiments of the present invention below.
The present invention chooses H5N1 type influenza virus RNA polymerase hypotype PA subunit N terminal nucleotide sequence
PA expressed by rowNAlbumen, as target proteins, utilizes the endonuclease activity that this albumen is had,
Live high flux as the activity rating method screened, natural product list existing to this laboratory using vitro enzyme
Body storehouse is screened, and finds that salvianolic acid B is at suppression PANProtein active aspect is had outstanding performance, Ke Yifa
Generated is the medicine of anti-H5N1 influenza virus.
Pharmacological evaluation part
1. enzyme test philosophy alive
Utilize FRET (fluorescence resonance energy transfer) (fluorescence resonance energy transfer, FRET)
Technical measurement is for PANThe activity of the inhibitor of albumen.According to PANThe endonuclease that albumen is had
Enzymatic activity, designs one section of nucleic acid fragment as substrate: 5 ' FAM--AA--3 ' BHQ1, when inhibitor pair
PANWhen albumen does not act on, PANAlbumen can play the activity of its Cobra venom endonuclease and be cut by substrate,
Quenching group (BHQ1) is away from fluorophor (FAM), after fluorophor absorbs the transmitting light of 494nm,
Inspire the light wave of 526nm, by the change of detector fluorescence intensity；If inhibitor pair
PANAlbumen has inhibitory action, then quenching group will not be cut out, and fluorophor absorbs sending out of 494nm
Penetrating light wave rear portion energy and can be transferred to quenching group, the excitation light wave intensity of 526nm will weaken,
Inhibitor is detected to PA with thisNThe inhibition of albumen.
2. enzyme method of testing alive
The vitro enzyme that the present invention uses appraisement system composition of living is shown in Table 1:
Table 1. vitro enzyme appraisement system alive
Wherein, PANAlbumen is bird flu virus A/goose/Guangdong/1/1996 (H1N5) strain
RNA polymerase PA subunit 1-256 amino acids residue, PAN protein storage solution is: 20mM Tris
PH 8.0,150mM NaCl, pH=8.0, final PANProtein concentration is 1mg/mL；Substrate is
5 ' FAM--AA--3 ' BHQ1 (are purchased from Shanghai Sheng Gong biological engineering company limited), are dissolved in buffer (20
MM Tris pH 8.0,150mM NaCl, pH=8.0) in, concentration is 50 μMs；The concentration of EDTA
For 200mM, its preparation method is: takes 14.97 grams of EDTA and is dissolved in 150 milliliters of distilled waters, so
After be settled to 200 milliliters；In experimental group, the concentration of standard solution of salvianolic acid B is 50.00mg/mL,
Successively with the salvianolic acid B solution of the available variable concentrations of qdx dilution.
Appraisement system sets negative and positive comparison.Positive controls is for add 1.00 μ L 200mM in system
EDTA solution, negative control group is molten for adding 1.00 μ L 200mM Tris (pH=8.0) in system
Liquid.Experimental group is the salvianolic acid B solution adding 1.00 μ L variable concentrations in system,.
After system described in table 1 is hatched 10 minutes at 37 DEG C, utilize microplate reader (Fluoroskan
Ascent, Thermo Scientific company, optical filter is that machine carries), measure exciting of being used
Light and transmitting light are respectively 494nm and 526nm, record first order fluorescence strength values every 30 seconds,
Record 200 times altogether.Enzyme curve alive, standard salvianolic acid B solution is drawn according to obtained florescent intensity value
Curve alive with the enzyme that positive control and negative control measure is shown in Fig. 1, and calculates PANThe residue of albumen is lived
Property (RA), parallel is repeated 3 times, and averages.
3. the computational methods of residual activity (RA):
Living in curve at enzyme, taking negative control slope of curve maximum value is V0, drug profile slope is
General goal is V1, then PANThe residual activity RA=V of albumen1/V0。
The following example is only used for illustrating the present invention, does not has any restriction to the present invention.
Embodiment 1 salvianolic acid B is to H5N1 type influenza virus RNA polymerase subunit PANAlbumen presses down
The mensuration of system activity
By 5.00mg salvianolic acid B, (purchased from Chengdu Man Site reference substance company limited, HPLC analyzes and contains
Amount ＞ 98%) it is dissolved completely in the double steaming solution of 100.00 μ L 95%DMSO, being configured to concentration is
50.00mg/mL standard solution.
The salvianolic acid B standard solution DMSO of 95% taking 10.00 μ L carries out what 2 times amount were incremented by
Gradient dilution, is diluted to variable concentrations as shown in table 2 solution to be measured altogether.Use such as pharmacological evaluation portion
Enzyme described in point method of testing alive measures the enzyme curve alive of solution to be measured, and calculates PANThe residue of albumen
Activity, parallel is repeated 3 times.The residual activity measured the results are shown in Table 2.
The compound concentration of dilution divided by the molecular weight of respective compound and is taken denary logarithm
Being worth as X-axis, corresponding residual activity is Y-axis, maps with GraphPad Prism 5 and calculates
Corresponding IC50Value.IC50Value curve chart is shown in Fig. 2.The IC measured50Value is 16.3 μMs.
Table 2. salvianolic acid B residual activity under different diluted concentrations
| Test concentrations (mg/mL) | Residual activity | Test concentrations (mg/mL) | Residual activity |
| 1.00 | 0.002896 | 0.015625 | 0.3597 |
| 0.50 | 0.04234 | 0.007813 | 0.6117 |
| 0.25 | 0.05906 | 0.003906 | 0.8417 |
| 0.125 | 0.08515 | 0.001953 | 0.9574 |
| 0.0625 | 0.08398 | 0.000977 | 0.9625 |
| 0.03125 | 0.2011 | 0.000488 | 0.9647 |
According to above-described embodiment, it will be appreciated that salvianolic acid B has and suppresses PA wellNProtein active
Effect, its IC50Value is 16.3 μMs.In consideration of it, salvianolic acid B can suppress H5N1 influenza virus
The activity of RNA polymerase, such that it is able to for preparing prevention or the medicine for the treatment of H5N1 influenza virus
Thing.
For clear and understandable purpose, it is illustrated with describe in detail with embodiment
State invention.Can be changed and modified in the range of subsidiary claim, this is to this area
It is apparent from for technical staff.It is, therefore, to be understood that description above is intended to for saying
Bright rather than be used for limiting.Therefore, the scope of the present invention should not determine with reference to description above, and
Determined by the doctrine of equivalents should enjoyed with reference to following appended claims and these claim
Four corner determines.
Claims (7)
1. salvianolic acid B is used for preventing or treat H5N1 influenza in preparation as unique active component
Application in the medicine of virus, wherein said salvianolic acid B has a following structural:
Application the most according to claim 1, the molecular formula of wherein said salvianolic acid B is
C36H30O16, molecular weight is 718.62.
Application the most according to claim 1, wherein said salvianolic acid B uses and separates from plant
Extract or synthesize or the acquisition of semisynthetic method.
Application the most according to claim 1, wherein said salvianolic acid B is used for suppressing H5N1 to flow
The activity of Influenza Virus RNA polymerase.
Application the most according to claim 1, wherein said salvianolic acid B is used for suppressing H5N1 to flow
Influenza Virus RNA polymerase subunit PANThe activity of albumen.
Application the most according to claim 4, wherein said H5N1 Influenza Virus RNA is polymerized
Enzyme subunit PANAlbumen is one of target spot of suppression H5N1 influenza virus.
Application the most according to claim 4, wherein said salvianolic acid B suppression H5N1 influenza is sick
Poison RNA polymerase subunit PANThe IC of protein active50Value is 16.3 μMs.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110394891.XA CN103127050B (en) | 2011-12-02 | Salvianolic acid B application in preparing anti-H5N1 influenza virus medicine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110394891.XA CN103127050B (en) | 2011-12-02 | Salvianolic acid B application in preparing anti-H5N1 influenza virus medicine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103127050A CN103127050A (en) | 2013-06-05 |
| CN103127050B true CN103127050B (en) | 2016-12-14 |
Family
ID=
Non-Patent Citations (1)
| Title |
|---|
| Crystal structure of an avian influenza polymerase PAN reveals an endonuclease active site;Puwei Yuan et al.;《nature》;20090416;第458卷;第909-913页 * |
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