CN110361541A - SFRP2 and PCPE1 is preparing the application in fibrotic disease drug as joint target spot - Google Patents
SFRP2 and PCPE1 is preparing the application in fibrotic disease drug as joint target spot Download PDFInfo
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- CN110361541A CN110361541A CN201910667092.1A CN201910667092A CN110361541A CN 110361541 A CN110361541 A CN 110361541A CN 201910667092 A CN201910667092 A CN 201910667092A CN 110361541 A CN110361541 A CN 110361541A
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- sfrp2
- pcpe1
- target spot
- collagen
- fibrotic disease
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
Abstract
The present invention relates to a kind of sFRP2 and PCPE1 as joint target spot preparing the application in fibrotic disease drug.The present invention is experimentally confirmed sFRP2 and PCPE1 has direct interaction in vitro and in vivo, and the retardance of sFRP2 and PCPE1 interaction can inhibit collagen deposition.Therefore, it is expected to potential target spot is provided, for example prepares fibrotic disease drug for the treatment that abnormal fibrous forms related disease etc. by retardance sFRP2 and PCPE1 interaction.
Description
Technical field
The invention belongs to fibrotic disease drug field, in particular to a kind of sFRP2 and PCPE1 are making as joint target spot
Application in standby fibrotic disease drug.
Background technique
Extracellular matrix plays the part of important role in sustaining life, and some researches show that the specific molecule knots of extracellular matrix
Structure determines the microenvironment and function of cell, such as cell differentiation or metabolism state etc..Numerous researchs confirm that collagen gene is prominent
The defect for becoming or participating in collagen synthesis will lead to many diseases and occur, such as osteogenesis imperfecta, osteochondrodysplasia and
Ehlers-Danlos syndrome etc..In addition, the synthesis rate when collagen is more than degradation rate, collagen deposition increases,
So as to lead to fibrotic disease, such as pulmonary fibrosis, cirrhosis and cardiovascular fibrosis etc..
BMP1 is initially considered as one of bone morphogenetic protein (BMP) family member, has stimulation bone and cartilage-derived growth
Ability [8].BMP belongs to transforming growth factor β family, and different from other BMP, BMP1 belongs to metalloproteinases, is most important
One of C-terminal protease.BMP1 can shear the C-terminal propetide of main procollagen (I, II and type III), so that it is dynamic to generate vertebra
The majority fibers ingredient of object extracellular matrix.BMP1 has metalloproteinase structure domain, including three CUB (complement/Uegf/BMP1)
Structural domain and epidermal growth factor (EGF) spline structure domain, wherein CUB2 structural domain is most important to the activity of C-terminal metalloenzyme.This
Outside, the C-terminal proteinase activity of BMP1 is influenced by certain specific proteins, such as fibronectin, precollagen C-terminal protease enhancer
1 (PCPE1) and secretion frizzled related protein 2 (sFRP2).PCPE1 is a kind of extracellular glycoprotein of secretion, and relative molecular weight is about
55kDa, can be in conjunction with the propetide of I procollagen type PROTEIN C end, and the activity of procollagen C-terminal protease can be improved 20 times
Left and right.SFRP2 is another important regulatory factor of C-terminal protease, belongs to secreted frizzled related protein (sFRP) family.
Then sFRP family can inhibit Wnt signal logical by curling (Fzl) structural domain rich in cysteine in conjunction with Wnt molecule
Road, to regulate and control body development and the pathogenetic correlated process of disease.SFRP2 is there are two major protein structural domain: Fz1 structural domain and
NTR structural domain.In addition to participating in Wnt signal path, the sFRP2 of debita spissitudo can be bound directly by Fz1 structural domain with BMP1, from
And enhance BMP1 to the shear active of collagen.
Although existing research shows that sFRP2 and PCPE1 adjust the process of procollagen by BMP1.However,
Whether whether sFRP2 and PCPE1 have interaction and have synergistic effect unclear the processing of procollagen.
Summary of the invention
Technical problem to be solved by the invention is to provide a kind of sFRP2 and PCPE1, and joint target spot to be used as to prepare fiber
Change the application in disease medicament, is experimentally confirmed sFRP2 and PCPE1 has direct interaction in vitro and in vivo.
The present invention provides a kind of sFRP2 and PCPE1 as joint target spot preparing the application in fibrotic disease drug.
The drug inhibits collagen deposition by retardance sFRP2 and PCPE1 interaction.
The drug is equipped with pharmaceutically acceptable auxiliary material or complementary ingredient using sFRP2 and PCPE1 as joint target spot
It is prepared into preparation use.
The preparation is in injection, subdermal implants, tablet, pulvis, granule, capsule, oral solution, sustained release agent
It is a kind of.
Beneficial effect
The present invention is experimentally confirmed sFRP2 and PCPE1 has direct interaction, and sFRP2 in vitro and in vivo
Retardance with PCPE1 interaction can inhibit collagen deposition.Therefore, it is expected to by retardance sFRP2 and PCPE1 interaction
Potential target spot is provided, for example prepares fibrotic disease drug for the treatment that abnormal fibrous forms related disease etc..
Detailed description of the invention
Fig. 1 is the expression of I procollagen type albumen of Western blot experimental analysis different genotype MEF cell；Its
In, A is experimental result, and B is relative quantitative assay statistics；
Fig. 2 is influence of the radioautographic analysis purifying protein sFRP2 and PCPE1 to I procollagen type protein cleavage；Its
In, A is experimental result, and B is relative quantitative assay statistics；
Fig. 3 A-B is the co-immunoprecipitation experiment analysis that sFRP2 and PCPE1 interacts；
Fig. 4 A-B is the external pull-down experimental analysis that sFRP2 and PCPE1 interacts；
Fig. 5 A-B is that western blot detection zebra fish sFRP2 and PCPE1 strike reduction rate；
Fig. 6 is that western blot detection sFRP2 and PCPE1 strikes the expression for subtracting zebrafish embryo Type I collagen albumen；
Wherein, A is experimental result, and B is relative quantitative assay statistics；
Fig. 7 is that sFRP2 and PCPE1 strikes the influence subtracted to zebrafish embryo form.
Fig. 8 A-B is the zebrafish embryo of the different degrees of dorsalization deformity of each group.
Specific embodiment
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In addition, it should also be understood that, after reading the content taught by the present invention, those skilled in the art
Member can make various changes or modifications the present invention, and such equivalent forms equally fall within the application the appended claims and limited
Range.
Embodiment 1
1. experimental method
1. external I procollagen type shear analysis
(1) radioactive I procollagen type protein extraction of 3H- with reference to delivered document [Scott IC, Blitz IL,
Pappano WN,et al.Mammalian BMP-1/Tolloid-related metalloproteinases,including
novel family member mammalian Tolloid-like 2,have differential enzymatic
activities and distributions of expression relevant to patterning and
skeletogenesis[J].Dev Biol,1999,213(2):283-300.].By I procollagen type albumen of purifying protein 3H- and
BMP1 mixing, is then respectively adding 20ng PCPE1,20ng sFRP2 or 10ng PCPE1/10ng sFRP2, buffers in 100 μ l
In liquid A, 37 DEG C of incubation 6h；
(2) SDS sample lysate is added, heats 5min with 95 DEG C of metal baths, makes albuminous degeneration, then place cooled on ice
5min；
(3) protein sample is separated with 7.5%SDS-PAGE glue, is then gone on film；
(4) EN3HANCE (PerkinElmer) is added, is developed using the method for autoradiograph, detects I not be sheared
Procollagen type albumen (Pro- α 1 (I)), the protein expression of the collagen (pN α 1) of Partial Shear and mature collagen (α 1)
It is horizontal.
2. I procollagen type shear analysis of MEF endogenous cellular
(1) WT, Pcolce1 are separately cultured-/-、Sfrp2-/-And Pcolce1-/-/Sfrp2-/-MEF cell；
(2) it collects culture and trains liquid with the cell of 48h for 24 hours, and protease inhibitors is added；
(3) it usesUltra Centrifugal filter concentration trains about 100 times of protein or so of liquid；
(4) cracking of 5 × Laemmli lysate is added into sample, heats 5min with 95 DEG C of metal baths, makes albuminous degeneration；
(5) sample more than is detected for western blot, with specific Pro- α 1 (I), pC/pN α 1 (I) and α 1 (I)
LF67 antibody test collagen relative expression quantity.
3. the pull-down of PCPE1-FLAG and sFRP2-His is tested
1) by 80ng PCPE1-FLAG and the 200ng sFRP2-His of purifying in 100 μ l training liquid B, 4 DEG C of preincubate mistakes
Night；
2) sample is in incubation at room temperature 3h；
3) it is subsequently added into His and FLAG (Sigma) Ago-Gel microballon, is incubated overnight on 4 DEG C of shaking tables；
4) it cleans, is repeated 3 times, each 15min on shaking table after PBS being added；
5) with elution and albumen sample is collected；
6) sample is tested and analyzed for western blot, and antibody is anti-FLAG and His.
4. co-immunoprecipitation experiment
1) WT, Pcolce1 of culture of isolated-/-、Sfrp2-/-And Pcolce1-/-/Sfrp2-/-MEF cell, it is every to collect for 24 hours
Liquid is trained, and protease inhibitors (2.5mM EDTA, 1mM PMSF, 1mM PABA, 1mM NEM) is added；
2) liquid will be trained with Millipore concentrating filter be concentrated more than 50 times；
3) sFRP2 and PCPE1 antibody is added in 4 DEG C of incubation 2h；
4) protein A agarose gel microballon is added to be incubated overnight at 4 DEG C；
5) it is added and contains 50mM Tris, pH 7.4,150mM NaCl, 1%NP-40,50mM EDTA and above-mentioned protease
The training liquid of inhibitor cleans 3 times；
6) antigen antibody complex is eluted from pearl with eluent；
7) Western blot detects the protein expression and protein binding situation of sFRP2 and PCPE1.
2. experimental result
1. sFRP2 and PCPE1 can cooperate with enhancing BMP1 to the shear action of Type I collagen albumen in vivo
It separates and cultivates WT, Pcolce1-/-、Sfrp2-/-And Pcolce1-/-/Sfrp2-/-Mouse embryonic fibroblasts
(MEFs), the culture solution of corresponding cell and concentration are collected, then with for Type I collagen albumen specific antibody LF67 with
The protein expression level of western blot detection collagen.Western blot experimental result (Figure 1A) and its relative quantification
Analysis statistics (Figure 1B) display, Pcolce1-/-/Sfrp2-/-Type I collagen albumen is not sheared in MEF cell and accounts for shearing collagen egg
White ratio is significantly more than WT, Pcolce1 and Sfrp2 MEF cell.
2. sFRP2 and PCPE1 can cooperate with enhancing BMP1 to the shear action of Type I collagen albumen in vitro
In order to further clarify the influence of sFRP2 and PCPE1 to I procollagen type Protein processing, purifying protein is obtained first
Including I procollagen type albumen of PCPE1, sFRP2, BMP1 and 3H-.In vitro by I procollagen type albumen of 400ng 3H- respectively with
20ng BMP1,20ng PCPE1,20ng sFRP2 or 10ng PCPE1/10ng sFRP2 are incubated for 37 DEG C in 100 μ l training liquid A
6h is educated, SDS lysate is then added and collects sample, with 7.5%SDS-PAGE glue separating sample, finally uses the side of autoradiograph
Method development.Autoradiograph experimental result (Fig. 2A) and its relative quantitative assay statistics (Fig. 2 B) display, with BMP1, PCPE1 and
SFRP2 group is compared, and the ratio for the Type I collagen albumen that sFRP2/PCPE1 group is not sheared significantly reduces.The above purification albumen
Result of study prove that sFRP2 and PCPE1 can cooperate with enhancing BMP1 to the shear action of Type I collagen albumen.
3. there are direct interactions by endogenous sFRP2 and PCPE1
Enhance the mechanism that BMP1 acts on Type I collagen protein cleavage to understand sFRP2 and PCPE1 in depth, by isolated WT,
Pcolce1-/-And Sfrp2-/-MEF cell is cultivated for 24 hours in the DNEM training liquid containing 10%FBS, then collects culture supernatant,
Filter protein concentrate is used after protease inhibitors is added.Take 1ml WT, Pcolce1-/-And Sfrp2-/-Each two parts of sample, point
It Jia Ru not sFRP2 and PCPE1 antibody progress co-immunoprecipitation experiment.The results show that PCPE1 can precipitate sFRP2 (Fig. 3 A),
SFRP2 can also precipitate PCPE1 (Fig. 3 B), illustrate that endogenous PCPE1 and sFRP2 have interaction.
4. there is direct interaction in vitro in purifying protein sFRP2 and PCPE1
It is clear sFRP2 and PCPE1 with the presence or absence of direct interaction, by purifying protein PCPE1-FLAG and sFRP2-
His carries out drop-down experiment in vitro.The results show that sFRP2 can illustrate sFRP2 and PCPE1 in conjunction with PCPE1 (Fig. 4 A and 4B)
In the presence of direct interaction.
5. MO inhibits Sfrp2 and Pcpe1 that zebra fish is caused to form significant dorsalization deformity simultaneously
A.Sfrp2-MO and Pcpe1-MO strikes reduction rate
It is research sFRP2 and PCPE1 in body function, inhibits zebra fish using morpholine oligonucleotides (MO)
Sfrp2 and Pcpe1 gene expression, the variation that the form and collagen for observing zebrafish embryo are formed.To 1~2 cell stage
Zebrafish embryo microinjection 0.5mM StCon-MO, 0.5mM Sfrp2-MO, 0.5mM Pcpe1-MO and 0.5mM Sfrp2-
MO/0.5mM Pcpe1-MO collects zebrafish embryo for 24 hours, after embryo is homogenized carry out western blot detection Sfrp2 and
The protein expression of Pcpe1.The results show that the Pcpe1 albumen of Pcpe1-MO zebra fish is almost suppressed (Fig. 5 A) entirely, Sfrp2-MO
The Sfrp2 protein level of zebra fish is obviously lowered (Fig. 5 B), the egg of the Sfrp2 and Pcpe1 of Sfrp2-MO/Pcpe1-MO zebra fish
It is white to express while being significantly down-regulated (Fig. 5 A and Fig. 5 B).
B.sfrp2 and pcpe1 is lowered simultaneously causes collagen deposition to reduce
Collect Stcon-MO, Sfrp2-MO, Pcpe1-MO and Sfrp2-MO/Pcpe1-MO for 24 hours with 48h zebra fish embryo
Then tire carries out the expression of western blot detection Type I collagen albumen using the antibody LF67 of specific Type I collagen albumen
Amount.The experimental results showed that zebrafish embryo Type I collagen protein expression is less for 24 hours for after fertilization, and 48h zebrafish embryo Type I collagen
Protein expression compared with horn of plenty (Fig. 6 A), and Sfrp2 and Pcpe1 be not sheared in repressed 48h zebrafish embryo simultaneously I
The content of collagen type is apparently higher than other groups (Fig. 6 B).
C.sfrp2 and pcpe1 is lowered simultaneously causes zebra fish significant dorsalization deformity occur
To 1~2 cell stage zebrafish embryo microinjection Stcon-MO, Sfrp2-MO, Pcpe1-MO and Sfrp2-MO/
After Pcpe1-MO, the form of observation fertilization zebrafish embryo for 24 hours under a dissecting microscope.The study found that individually injecting Sfrp2-
There is campylorrhachia in the zebrafish embryo of MO or Pcpe1-MO, and injects the zebra of Pcpe1-MO/Sfrp2-MO simultaneously
Fish embryo's deformity is significant to aggravate (Fig. 7).Therefore, the present embodiment expands the quantity of zebra fish, further observes the change of its form
Change (Fig. 8 A), and (Fig. 8 B) for statistical analysis to the quantity of fertilization zebrafish embryo difference degree of deformity for 24 hours.The results show that
About 20% zebra fish generation mild malformation in independent injection Pcpe1-MO Sfrp2-MO zebrafish embryo, 10% or so
Severe deformities occur for zebra fish, and inject has about 40% zebra fish generation molten at the same time in Pcpe1-MO/Sfrp2-MO zebra fish
More serious deformity occurs for solution, about 30% zebra fish.Therefore it is reasonable to speculate Sfrp2 and Pcolce1 to zebrafish embryo
The influence of development has synergistic effect.
3. discussion of results
Separate and cultivate WT, Pcolce1-/-, Sfrp2-/- and Pcolce1-/-/Sfrp2-/- MEF cell, collect culture
Supernatant for western blot detection Type I collagen albumen expression.Experimental result finds Pcolce1-/-/Sfrp2-/-
The ratio that MEF cell is not sheared Type I collagen albumen is apparently higher than other groups.This results show PCPE1 and sFRP2 pairs
There is synergistic effect in the shearing of Type I collagen albumen.In addition, in vitro by purifying protein PCPE1 and sFRP2 alone or in combination with
BMP1 and Type I collagen albumen are incubated for, and research confirms that PCPE1 and sFRP2 plays collaboration to the shearing of Type I collagen albumen by BMP1
Effect.Potential target is provided by the treatment that retardance sFRP2 and PCPE1 interaction is expected to be formed related disease for abnormal fibrous
Point, for example prepare fibrotic disease drug etc..
Claims (4)
1. a kind of sFRP2 and PCPE1 is preparing the application in fibrotic disease drug as joint target spot.
2. application according to claim 1, it is characterised in that: the drug passes through retardance sFRP2 and PCPE1 interaction
Inhibit collagen deposition.
3. application according to claim 1, it is characterised in that: the drug using sFRP2 and PCPE1 as joint target spot,
It is equipped with pharmaceutically acceptable auxiliary material or complementary ingredient is prepared into preparation use.
4. application according to claim 3, it is characterised in that: the preparation be selected from injection, subdermal implants, tablet,
One of pulvis, granule, capsule, oral solution, sustained release agent.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6037139A (en) * | 1997-06-03 | 2000-03-14 | Wisconsin Alumni Research Foundation | System for assaying modulators of procollagen maturation |
| CN1318549A (en) * | 2000-04-19 | 2001-10-24 | 上海生元基因开发有限公司 | Precollagen C terminal proteinase enhancing protein and polynucleotide sequence for encoding it |
| CN1387537A (en) * | 1999-09-13 | 2002-12-25 | 惠氏公司 | Pharmaceutical compositions and methods of using secreted frizzled related protein |
| US20120270246A1 (en) * | 2008-04-02 | 2012-10-25 | Ramot At Tel-Aviv University Ltd. | Procollagen c-proteinase enhancer (pcpe) biomarker for bone formation |
| CN107034305A (en) * | 2017-06-19 | 2017-08-11 | 上海市第十人民医院 | A kind of diagnosis marker of glioblastoma |
-
2019
- 2019-07-23 CN CN201910667092.1A patent/CN110361541A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6037139A (en) * | 1997-06-03 | 2000-03-14 | Wisconsin Alumni Research Foundation | System for assaying modulators of procollagen maturation |
| CN1387537A (en) * | 1999-09-13 | 2002-12-25 | 惠氏公司 | Pharmaceutical compositions and methods of using secreted frizzled related protein |
| CN1318549A (en) * | 2000-04-19 | 2001-10-24 | 上海生元基因开发有限公司 | Precollagen C terminal proteinase enhancing protein and polynucleotide sequence for encoding it |
| US20120270246A1 (en) * | 2008-04-02 | 2012-10-25 | Ramot At Tel-Aviv University Ltd. | Procollagen c-proteinase enhancer (pcpe) biomarker for bone formation |
| CN107034305A (en) * | 2017-06-19 | 2017-08-11 | 上海市第十人民医院 | A kind of diagnosis marker of glioblastoma |
Non-Patent Citations (1)
| Title |
|---|
| QIN ZHU等: "Synergistic effect of PCPE1 and sFRP2 on the processing of procollagens via BMP1", 《FEBS LETTERS》 * |
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