CN106580995B - Purposes of the phenazine-1-carboxylic acid as medusocongestin fibrinogenase inhibitor - Google Patents
Purposes of the phenazine-1-carboxylic acid as medusocongestin fibrinogenase inhibitor Download PDFInfo
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- CN106580995B CN106580995B CN201611138998.7A CN201611138998A CN106580995B CN 106580995 B CN106580995 B CN 106580995B CN 201611138998 A CN201611138998 A CN 201611138998A CN 106580995 B CN106580995 B CN 106580995B
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- phenazine
- carboxylic acid
- medusocongestin
- fibrinogenase
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
Abstract
Purposes the invention discloses phenazine-1-carboxylic acid as medusocongestin fibrinogenase inhibitor, the structural formula of the phenazine-1-carboxylic acid is as shown in formula I.Phenazine-1-carboxylic acid is by inhibiting the B β chains of medusocongestin fibrinogenase hydrolysis of fibrin original to play the role of inhibiting medusocongestin fibrinogenase vigor.The present invention provides theoretical reference to screen the micromolecular compound of water resistant parent toxin, and the development that drug is also stung for jellyfish lays the foundation.
Description
Technical field
The present invention relates to field of marine biotechnology, and in particular to a kind of phenazine-1-carboxylic acid is as medusocongestin fiber egg
The purposes of white original hydrolase inhibitor.
Background technology
Scyphomedusa is under the jurisdiction of Cnidaria, widely distributed.Divide there are mainly two types of people jellyfish is bitten in Northern Coastal Region of China
Be not the sea of sand bite with rosy clouds jellyfish, they belong to Scyphozoa.Nearly ten years, jellyfish quantity is increased sharply, and jellyfish bites occurrences in human life part and causes
Extensive concern.Nematoblast is the weapon that jellyfish is used to defend and prey on.When nematoblast contact skin, can release immediately out one thin
Long ecthoaeum, includes the venom being made of albumen and polypeptide, and ecthoaeum is pierced into skin histology and jellyfish is caused to sting.Jellyfish stings disease
Shape is mainly that part is red and swollen, pierces itching and pain, death can be caused when serious.
Medusocongestin is the chemical fundamentals for causing jellyfish to sting symptom.Medusocongestin complicated component and have a variety of biologies
Learn activity, such as hemolytic activity, neurotoxicity, Cardiovascular Toxicity, cytotoxic activity etc..In addition, medusocongestin also has fiber egg
White original hydrolysing activity, can quickly remove the B β chains of fibrinogen.Fibrinogen is protein related with coagulation function,
Under physiological condition, fibrinogen by binding the GpIIb/IIIa albumen of platelet surface to connect blood platelet,
Fibrin can also be converted to by fibrin ferment to work in coagulation cascade reaction.The study found that fibrinogen
It is the important target spot that some biotoxins (such as snake venom) act on organism.Such as during snake bite, the fiber egg in snake venom
White hydrolase enters blood circulation system by local capillary, and internal fibrinogen of degrading causes patient locally to coagulate
Blood obstacle, The blood streamed down, to the degree of intoxication of making patients.Medusocongestin can fibrin degradation it is former, show in toxin
Fibrinogenase may also work in jellyfish stings.
Phenazine-1-carboxylic acid can inhibit various agricultural disease fungus, mainly as antiseptic application.We send out in an experiment
Existing, phenazine-1-carboxylic acid can effectively inhibit the fibrinogenase in medusocongestin.This discovery, has not only widened pheno
The application range of piperazine -1- carboxylic acids also provides reference to screen the micromolecular compound of water resistant parent toxin, while being bitten to develop jellyfish
Vulnerary object lays the foundation.
Invention content
Use the object of the present invention is to provide phenazine-1-carboxylic acid as medusocongestin fibrinogenase inhibitor
On the way.
The present invention realizes that the scheme of purpose is as follows：
Purposes of the phenazine-1-carboxylic acid as medusocongestin fibrinogenase inhibitor, the phenazine-1-carboxylic acid
Structural formula is as shown in formula I.
Preferably, the inhibition agent compounding method：After phenazine-1-carboxylic acid is dissolved with dimethyl sulfoxide (DMSO) (DMSO), then use
The dilution of 50mMTris-HCl (pH 7.6) buffer solution is made.
Phenazine-1-carboxylic acid inhibits medusocongestin fibrinogenase vigor to pass through electrophoresis technique determining.
After phenazine-1-carboxylic acid is dissolved with dimethyl sulfoxide (DMSO) (DMSO), then it is dilute with 50mM Tris-HCl (pH 7.6) buffer solution
It releases to obtain phenazine-1-carboxylic acid solution.Then into medusocongestin solution be added phenazine-1-carboxylic acid solution, make phenazine-1-carboxylic acid with
The mass ratio of medusocongestin (with protein refractometer) is greater than or equal to 0.1:After pre-processing 30min under the conditions of 1,37 DEG C, substrate is added
Fibrinogen solution starts reaction.After reacting 6h, 20 μ l reaction mixtures is taken to be placed on ice, and immediately plus isometric 2 ×
Sample buffer solutions (containing beta -mercaptoethanol) terminate reaction.Sample takes 20 μ l to add in loading hole after 100 DEG C are boiled 10min,
Then the electrophoresis on 12%SDS-PAGE running gels.Electrophoresis is completed, and is taken out gel, is placed in 0.25% Coomassie brilliant blue and dyes
After 3h, with destainer (methanol：Water：Glacial acetic acid=5:4:1) it decolourizes to gel.It is fine by checking after obtaining clear band
Fibrillarin original band changes to analyze inhibition of the phenazine-1-carboxylic acid to medusocongestin fibrinogenase vigor.
Advantages of the present invention：
1), the present invention provides the new applications of phenazine-1-carboxylic acid, and phenazine-1-carboxylic acid is to medusocongestin fibrin raw water
Solve the B that enzyme is inhibited, and phenazine-1-carboxylic acid passes through inhibition medusocongestin fibrinogenase hydrolysis of fibrin original
β chains play the role of inhibiting medusocongestin fibrinogenase vigor, therefore phenazine-1-carboxylic acid can be used as medusocongestin fibre
The inhibitor of fibrillarin original hydrolase uses.
2), the present invention provides theoretical reference to screen the micromolecular compound of water resistant parent toxin, also stings drug for jellyfish
Development lay the foundation.
Description of the drawings
Fig. 1 be in the embodiment of the present invention phenazine-1-carboxylic acid and medusocongestin (with protein refractometer) under the conditions of different quality ratio,
Phenazine-1-carboxylic acid inhibits the electrophoretogram of medusocongestin fibrinogenase vigor.
Specific implementation mode
The following examples are further illustrations of the invention, rather than limiting the invention.
Phenazine-1-carboxylic acid inhibits medusocongestin fibrinogenase vigor to pass through electrophoresis technique determining.
Phenazine-1-carboxylic acid solution preparation method：1.00g phenazine-1-carboxylic acids are taken, are dissolved with DMSO, then with 50mM Tris-
HCl (pH 7.6) buffer solution is diluted to 100mL, and 10mg/mL phenazine-1-carboxylic acid solution is made；Then by 10mg/mL azophenlyene -1-
Carboxylic acid solution with 50mM Tris-HCl (pH 7.6) buffer solution dilute, be respectively configured a concentration of 0.10mg/mL, 0.31mg/mL,
The phenazine-1-carboxylic acid solution of 0.63mg/mL, 1.2mg/mL, 2.5mg/mL, 5mg/mL.
1mg/mL medusocongestin solution manufacturing methods：The jellyfish tentacle tissue of frost is placed in after being taken out in -80 DEG C of refrigerators
Defrosting, self-dissolving 2-4 days in 4 DEG C of refrigerators.Period is to accelerate the dissolving of jellyfish tentacle, is added after every other day carefully toppling over upper ocean water
Enter fresh seawater, ecthoaeum bladder cell is accelerated to fall off from tentacle.After jellyfish organizes complete self-dissolving, upper layer self-dissolving is slowly outwelled
Liquid is collected lower layer with precipitation from solution, is then filtered respectively with the sub-sieve of 60 mesh and 100 mesh.Filtered fluid is collected,
3000g centrifuges 15min, collects lower sediment, then is washed 2-3 times and centrifuged with clean seawater to get to more pure nematocyst.
Ecthoaeum bladder cell is placed in -80 DEG C of refrigerators and is preserved, it is spare.3g nematocysts are taken, the 20mM phosphoric acid that 18mL is pre-chilled in 4 DEG C is added
Salt buffer (PBS, pH 7.4) extracts toxin using ultrasonication nematocyst.Extraction conditions are set as：400W, 90 are followed
Ring.Each cycle is broken comprising 15s, 10s intervals.4 DEG C, 15000g refrigerated centrifuge 30min after the completion of broken, supernatant are
With the medusocongestin solution of a concentration of 1mg/mL of protein refractometer.The measurement of medusocongestin concentration, using Forint phenol method (Zhang Lei, Liu Yu,
Jiang Da and the low-priced Biochemistry Experiments guidance of Yang Mingyuan, Cao Zhi;M]Wuhan：Publishing house of Wuhan University, 2011.95~98.) with
Bovine serum albumin(BSA) (BSA) is standard.
1mg/mL fibrinogen solution preparation methods：30.0mg fibrinogens are taken to be dissolved in 3mL 0.9%NaCl (w/v)
In solution, 1.5ml centrifuge tubes are distributed into, this is standby reservoir, -20 DEG C of preservations.Used time is diluted with 50mM Tris-HCl (pH 7.6)
To 1mg/mL.
Embodiment 1：
Take 10 μ L phenazine-1-carboxylic acids solution (0.10mg/mL) pre- at 37 DEG C with 10 μ L medusocongestins solution (1mg/mL)
The mass ratio of processing 30min, phenazine-1-carboxylic acid and medusocongestin (with protein refractometer) is 0.1:1.Then into the above reaction system
50 μ L fibrinogen solutions (1mg/mL) are added and start reaction.After reacting 6h at 37 DEG C, 20 μ L reaction mixtures is taken to be placed in ice
On, and isometric 2 × Sample buffer solutions (containing beta -mercaptoethanol) is added to terminate reaction immediately.This sample is immediately placed in -20 DEG C
It saves backup.Sample adds after boiling 10min in 20 μ L to loading duct, then the electrophoresis on 12%SDS-PAGE running gels,
Deposition condition is 120V, about 90min.After the completion of electrophoresis, gel is taken out, is placed in 0.25% coomassie brilliant blue R_250 and dyes
After 3h, with destainer (methanol：Water：Glacial acetic acid=5:4:1) it decolourizes to gel.It is fine by checking after obtaining clear band
Inhibition of the fibrillarin original band mutation analysis phenazine-1-carboxylic acid to medusocongestin fibrinogenase vigor, is as a result shown in figure
1。
Embodiment 2：
Take 10 μ L phenazine-1-carboxylic acids solution (0.31mg/mL) pre- at 37 DEG C with 10 μ L medusocongestins solution (1mg/mL)
The mass ratio of processing 30min, phenazine-1-carboxylic acid and medusocongestin (with protein refractometer) is 0.3:1.Then into the above reaction system
50 μ L fibrinogen solutions (1mg/mL) are added and start reaction.After reacting 6h at 37 DEG C, 20 μ L reaction mixtures is taken to be placed in ice
On, and isometric 2 × Sample buffer solutions (containing beta -mercaptoethanol) is added to terminate reaction immediately.This sample is immediately placed in -20 DEG C
It saves backup.Sample adds after boiling 10min in 20 μ L to loading duct, then the electrophoresis on 12%SDS-PAGE running gels,
Deposition condition is 120V, about 90min.After the completion of electrophoresis, gel is taken out, is placed in 0.25% coomassie brilliant blue R_250 and dyes
After 3h, with destainer (methanol：Water：Glacial acetic acid=5:4:1) it decolourizes to gel.It is fine by checking after obtaining clear band
Inhibition of the fibrillarin original band mutation analysis phenazine-1-carboxylic acid to medusocongestin fibrinogenase vigor, is as a result shown in figure
1。
Embodiment 3：
Take 10 μ L phenazine-1-carboxylic acids solution (0.63mg/mL) pre- at 37 DEG C with 10 μ L medusocongestins solution (1mg/mL)
The mass ratio of processing 30min, phenazine-1-carboxylic acid and medusocongestin (with protein refractometer) is 0.6:1.Then into the above reaction system
50 μ L fibrinogen solutions (1mg/mL) are added and start reaction.After reacting 6h at 37 DEG C, 20 μ L reaction mixtures is taken to be placed in ice
On, and isometric 2 × Sample buffer solutions (containing beta -mercaptoethanol) is added to terminate reaction immediately.This sample is immediately placed in -20 DEG C
It saves backup.Sample adds after boiling 10min in 20 μ L to loading duct, then the electrophoresis on 12%SDS-PAGE running gels,
Deposition condition is 120V, about 90min.After the completion of electrophoresis, gel is taken out, is placed in 0.25% coomassie brilliant blue R_250 and dyes
After 3h, with destainer (methanol：Water：Glacial acetic acid=5:4:1) it decolourizes to gel.It is fine by checking after obtaining clear band
Inhibition of the fibrillarin original band mutation analysis phenazine-1-carboxylic acid to medusocongestin fibrinogenase vigor, is as a result shown in figure
1。
Embodiment 4：
10 μ L phenazine-1-carboxylic acids solution (1.2mg/mL) are taken to locate in advance at 37 DEG C with 10 μ L medusocongestins solution (1mg/mL)
The mass ratio of reason 30min, phenazine-1-carboxylic acid and medusocongestin (with protein refractometer) is 1.2:1.Then add into the above reaction system
Enter 50 μ L fibrinogen solutions (1mg/mL) and starts reaction.After reacting 6h at 37 DEG C, 20 μ L reaction mixtures is taken to be placed on ice,
And isometric 2 × Sample buffer solutions (containing beta -mercaptoethanol) is added to terminate reaction immediately.This sample, which is immediately placed in -20 DEG C, to be preserved
It is spare.Sample adds after boiling 10min in 20 μ L to loading duct, then electrophoresis, electrophoresis on 12%SDS-PAGE running gels
Condition is 120V, about 90min.After the completion of electrophoresis, gel is taken out, is placed in after dyeing 3h in 0.25% coomassie brilliant blue R_250,
With destainer (methanol：Water：Glacial acetic acid=5:4:1) it decolourizes to gel.After obtaining clear band, by checking fibrin
Inhibition of the former band mutation analysis phenazine-1-carboxylic acid to medusocongestin fibrinogenase vigor, the result is shown in Figure 1.
Embodiment 5：
10 μ L phenazine-1-carboxylic acids solution (2.5mg/mL) are taken to locate in advance at 37 DEG C with 10 μ L medusocongestins solution (1mg/mL)
The mass ratio of reason 30min, phenazine-1-carboxylic acid and medusocongestin (with protein refractometer) is 2.5:1.Then add into the above reaction system
Enter 50 μ L fibrinogen solutions (1mg/mL) and starts reaction.After reacting 6h at 37 DEG C, 20 μ L reaction mixtures is taken to be placed on ice,
And isometric 2 × Sample buffer solutions (containing beta -mercaptoethanol) is added to terminate reaction immediately.This sample, which is immediately placed in -20 DEG C, to be preserved
It is spare.Sample adds after boiling 10min in 20 μ L to loading duct, then electrophoresis, electrophoresis on 12%SDS-PAGE running gels
Condition is 120V, about 90min.After the completion of electrophoresis, gel is taken out, is placed in after dyeing 3h in 0.25% coomassie brilliant blue R_250,
With destainer (methanol：Water：Glacial acetic acid=5:4:1) it decolourizes to gel.After obtaining clear band, by checking fibrin
Inhibition of the former band mutation analysis phenazine-1-carboxylic acid to medusocongestin fibrinogenase vigor, the result is shown in Figure 1.
Embodiment 6：
10 μ L phenazine-1-carboxylic acids solution (5mg/mL) are taken to be pre-processed at 37 DEG C with 10 μ L medusocongestins solution (1mg/mL)
The mass ratio of 30min, phenazine-1-carboxylic acid and medusocongestin (with protein refractometer) is 5:1.Then 50 are added into the above reaction system
μ L fibrinogen solutions (1mg/mL) start reaction.After reacting 6h at 37 DEG C, takes 20 μ L reaction mixtures to be placed on ice, exist side by side
I.e. plus isometric 2 × Sample buffer solutions (containing beta -mercaptoethanol) terminate reaction.This sample be immediately placed in -20 DEG C preserve it is standby
With.Sample adds after boiling 10min in 20 μ L to loading duct, then electrophoresis, electrophoresis strip on 12%SDS-PAGE running gels
Part is 120V, about 90min.After the completion of electrophoresis, gel is taken out, is placed in after dyeing 3h in 0.25% coomassie brilliant blue R_250, is used
Destainer (methanol：Water：Glacial acetic acid=5:4:1) it decolourizes to gel.After obtaining clear band, by checking fibrinogen
Inhibition of the band mutation analysis phenazine-1-carboxylic acid to medusocongestin fibrinogenase vigor, the result is shown in Figure 1.
Embodiment 7：
10 μ L phenazine-1-carboxylic acids solution (10mg/mL) are taken to locate in advance at 37 DEG C with 10 μ L medusocongestins solution (1mg/mL)
The mass ratio of reason 30min, phenazine-1-carboxylic acid and medusocongestin (with protein refractometer) is 10:1.Then add into the above reaction system
Enter 50 μ L fibrinogen solutions (1mg/mL) and starts reaction.After reacting 6h at 37 DEG C, 20 μ L reaction mixtures is taken to be placed on ice,
And isometric 2 × Sample buffer solutions (containing beta -mercaptoethanol) is added to terminate reaction immediately.This sample, which is immediately placed in -20 DEG C, to be preserved
It is spare.Sample adds after boiling 10min in 20 μ L to loading duct, then electrophoresis, electrophoresis on 12%SDS-PAGE running gels
Condition is 120V, about 90min.After the completion of electrophoresis, gel is taken out, is placed in after dyeing 3h in 0.25% coomassie brilliant blue R_250,
With destainer (methanol：Water：Glacial acetic acid=5:4:1) it decolourizes to gel.After obtaining clear band, by checking fibrin
Inhibition of the former band mutation analysis phenazine-1-carboxylic acid to medusocongestin fibrinogenase vigor, the result is shown in Figure 1.
F in Fig. 1：Blank control, in fibrinogen solution plus medusocongestin and phenazine-1-carboxylic acid processing；
NnNV：Positive control, medusocongestin fibrin degradation is former, and medusocongestin does not add phenazine-1-carboxylic acid to handle；
Bβ：The B β chains of fibrinogen.
Fig. 1 analysis results：B β chain bands are had no in positive control, in electrophoretogram, show the B β chains of fibrinogen by water
Parent toxin complete hydrolysis；When the mass ratio of phenazine-1-carboxylic acid and medusocongestin (with protein refractometer) is 0.1:1-0.3:When 1, with sun
Property control compare, although the B β chains of fibrinogen are fuzzy but still as it can be seen that show that phenazine-1-carboxylic acid part inhibits jellyfish malicious
Cellulose fiber proteinogen hydrolytic enzyme activities；When the mass ratio of phenazine-1-carboxylic acid and medusocongestin (with protein refractometer) is 0.6:1-10:1
When, the B β chains of fibrinogen are stabilized, and indicate that phenazine-1-carboxylic acid completely inhibits medusocongestin fibrinogenase
Activity.
Claims (2)
1. phenazine-1-carboxylic acid prepares the purposes as medusocongestin fibrin degradation original inhibitor, the phenazine-1-carboxylic acid
Structural formula is as shown in formula I；
The mass ratio of the phenazine-1-carboxylic acid and medusocongestin is 0.6:1-10:1, wherein medusocongestin is with protein refractometer.
2. purposes according to claim 1, which is characterized in that the inhibition agent compounding method：By phenazine-1-carboxylic acid with two
After methyl sulfoxide dissolving, then the 50mM Tris-HCl buffer solutions dilution for being 7.6 with pH is made.
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| 基于蛋白质组学和转录组学的沙海蜇毒素蜇伤成分研究;李荣锋 等;《全国第九届海洋生物技术与创新药物学术会议摘要集》;20140810;第185页 * |
| 水母蜇伤治疗药物的研制;于华华 等;《全国第九届海洋生物技术与创新药物学术会议摘要集》;20140810;第181页 * |
| 蛋白酶抑制剂对霞水母毒素溶血活性的影响;李荣锋;《中国海洋药物杂志》;20110430;第30卷(第2期);第39-43页 * |
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