CN102627686B - Polypeptide with effect of inhibiting activity of fibroblast growth factor receptor 3 and application thereof - Google Patents
Polypeptide with effect of inhibiting activity of fibroblast growth factor receptor 3 and application thereof Download PDFInfo
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- CN102627686B CN102627686B CN 201210117618 CN201210117618A CN102627686B CN 102627686 B CN102627686 B CN 102627686B CN 201210117618 CN201210117618 CN 201210117618 CN 201210117618 A CN201210117618 A CN 201210117618A CN 102627686 B CN102627686 B CN 102627686B
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Abstract
The invention discloses polypeptide with an effect of inhibiting activity of fibroblast growth factor receptor 3 (FGFR3). The polypeptide consists of an amino acid sequence shown by Thr-Leu-Gly-Gln-Leu-Leu, can be combined with specificity of an extracellular fragment of the FGFR3, has an obvious inhibition effect on the activity of the extracellular fragment of the FGFR3, has the advantages of low molecular weight, simplicity in preparation, easily controlled quality, low immunogenicity and the like, can be prepared into a medicament for preventing and controlling FGFR3 function enhanced diseases, and has potential good application prospect in prevention and treatment of the FGFR3 function enhanced diseases such as thanatophoric dysplasia and achondroplasia.
Description
Technical field
The invention belongs to biological pharmacy technical field, relate to a kind of active polypeptide and in the application of pharmacy field.
Background technology
Fibroblast growth factor acceptor (fibroblast growth factor receptor, FGFR) be a class have an autophosphorylation activity stride the film tyrosine kinase receptor, with its respective ligand fibroblast growth factor (fibroblast growth factor, FGF) combination plays a significant role in histoorgan growth and injury repairing process.
4 kinds of FGFR have been found at present, i.e. FGFR1, FGFR2, FGFR3 and FGFR4.Wherein, FGFR3 is that the negativity of mediation endochondral ossification is regulated molecule, has vital role in skeleton development.Previously studies show that, FGFR3 function acquisition type transgenation meeting causes the propagation of chondrocyte in the epiphyseal growth plate and differentiation to be suppressed, cause multiple skeleton development defective genetic diseases, as fetal rickets (ACH), hypochondroplasia (HCH) and thanatophoric dysplasia (TD) etc.; And FGFR3 afunction type transgenation meeting causes the delay of epiphyseal growth plate closing, loose cartilage area broadening and long bone hypertrophy etc.
Though found 23 kinds of FGF at present, do not seen the FGF of only being combined with the FGFR3 specificity so far.Because polypeptide has advantages such as molecular weight is little, space structure is simple, immunogenicity is low, so its active polypeptide can is combined and suppress to exploitation with the FGFR3 specificity good prospects for application is arranged, be expected to develop the medicine that becomes anti-FGFR3 increased functionality type disease.
Summary of the invention
In view of this, one of purpose of the present invention is to provide a kind of and can be combined and suppresses its active polypeptide with the FGFR3 specificity; Two of purpose is to provide the application of this polypeptide in pharmacy field.
For achieving the above object, the invention provides following technical scheme:
1, have the polypeptide that suppresses the FGFR3 activity, by Thr-Leu-Gly-Gln-Leu-Leu(TLGQLL) shown in aminoacid sequence form.
2, have the polypeptide that suppresses the FGFR3 activity and prevent and/or treat application in the medicine of FGFR3 increased functionality type disease in preparation.
Further, described FGFR3 increased functionality type disease is ACH and TD.
Beneficial effect of the present invention is: polypeptide of the present invention can be combined with FGFR3 extracellular fragment specificity, and its activity there is the obvious suppression effect, and have advantages such as molecular weight is little, preparation is simple, easy to control the quality, immunogenicity is low, can make the medicine of prevention and treatment FGFR3 increased functionality type disease, have potential good prospects for application aspect the FGFR3 increased functionality type prevention and treatment of diseases such as thanatophoric dysplasia, fetal rickets.
Description of drawings
The ELISA method that shows Fig. 1 detect the peptide C ore1 of different concns and FGFR3 extracellular fragment in conjunction with situation, wherein * * * represents to compare p＜0.001 with the blank group.
Fig. 2 shows that Western blot method detects the variation that peptide C ore1 handles ATDC5 cell ERK phosphorylation level after 5,10,30,45,60 minutes.
Fig. 3 shows that Western blot method detects the variation that peptide C ore1 handles ATDC5 cell p38 phosphorylation level after 5,10,30,45,60 minutes.
Fig. 4 shows that Western blot method detects the variation that peptide C ore1 handles ATDC5 cell Jnk phosphorylation level after 5,10,30,45,60 minutes.
Fig. 5 shows that mtt assay detects the cell proliferation situation of peptide C ore1 processing ATDC5 cell after 24 hours of different concns, and wherein * represents to compare p＜0.05 with the blank group.
Fig. 6 shows the effect of the ACH model mice bone growth of the vitro culture of peptide C ore1, wherein A is 7 days metatarsal photo of vitro culture, B is that the length of 7 days metatarsal of vitro culture increases percentage, Blank is normal mouse C57BL/6 control group, ACH is ACH model mice control group, and ACH+Core1 is ACH model mice Core1 treatment group; * represent to compare p＜0.05 with normal mouse C57BL/6 control group, * * represents to compare p＜0.01 with normal mouse C57BL/6 control group, and ## represents to compare p＜0.01 with ACH model mice control group.
Fig. 7 shows the effect of the TD model mice survival of injection peptide C ore1, and wherein TDII Core1 (-) is TD model mice control group, and TDII Core1 (+) is TD model mice Core1 treatment group, and WT is EIIa-Cre mouse control group.
Fig. 8 shows the effect of the TD model mice of injection peptide C ore1 alveolar, and wherein TDII Core1 (-) is TD model mice control group, and TDII Core1 (+) is TD model mice Core1 treatment group, and WT is EIIa-Cre mouse control group.
Fig. 9 shows the effect of the TD model mice of injection peptide C ore1 shin bone, and wherein TDII Core1 (-) is TD model mice control group, and TDII Core1 (+) is TD model mice Core1 treatment group, and WT is EIIa-Cre mouse control group.
Embodiment
In order to make the purpose, technical solutions and advantages of the present invention clearer, below in conjunction with accompanying drawing the present invention is described in detail.The experimental technique of unreceipted actual conditions among the embodiment, usually according to normal condition, the condition described in the molecular cloning experiment guide (third edition, J. Sa nurse Brooker etc. work) for example, or the condition of advising according to manufacturer.
One, polypeptide core1's is synthetic
Entrusting Hua Datian source, Shanghai biotech company to adopt standard Fmoc scheme solid phase synthesis aminoacid sequence is Thr-Leu-Gly-Gln-Leu-Leu(TLGQLL, SEQ ID No.1) polypeptide, with this polypeptide called after Core1.Synthetic polypeptide purity is higher than 95%, puts temperature-70 ℃ preservation.
Two, the ELISA method detects the combination of peptide C ore1 and FGFR3 extracellular fragment
Adopt indirect elisa method, in 96 well culture plates, every hole adds concentration and is respectively 1,10,100, the peptide C ore1 solution 100 μ L of 1000 μ M, blank group (solvent with preparation peptide C ore1 solution substitutes peptide C ore1 solution) is set simultaneously, 4 ℃ of bags of temperature are spent the night, discard coating buffer, it is the calf serum solution (PBS with pH7.4 is solvent) of 50g/L that full hole adds concentration, 37 ℃ of sealings of temperature 40 minutes, discard confining liquid, contain the PBS that concentration is the tween 20 of 0.5mL/L with PBST(, pH7.4) washing is 3 times, adding concentration is the FGFR3 extracellular fragment solution 30 μ L of 100 μ g/mL and the PBS 70 μ L of pH7.4, temperature was hatched 1 hour for 37 ℃, with PBST washing 3 times, add the mouse-anti FGFR3 extracellular fragment antibody (U.S. Sigma company by dilution in 1: 500, be that 1% bovine serum albumin solution is diluting solvent with massfraction) 100 μ L, temperature was hatched 1 hour for 37 ℃, discard primary antibodie solution, with PBST washing 5 times, rabbit anti-mouse igg (middle China fir Golden Bridge biological reagent company) the 100 μ L that add horseradish peroxidase-labeled, temperature was hatched 30 minutes for 37 ℃, discard two anti-solution, with PBST washing 5 times, add tetramethyl biphenyl diamines-hydrogen peroxide urea solution 100 μ L, 37 ℃ of lucifuge colour developings of temperature 10 minutes, adding concentration is the sulphuric acid soln termination reaction of 2M, measures the OD450 value at wavelength 450nm place, and each organizes the result with the equal value representation in 3 multiple holes.The results are shown in Figure 1, peptide C ore1 and the FGFR3 extracellular fragment of different concns all have higher combination rate, compare with the blank group to have utmost point significant difference.
Three, Western blot method detects the activation of signaling molecule among the main downstream signal path of the FGFR3 of the peptide C ore1 MAPK
Research at present is clear and definite, and mitogen-activated protein kinase signal path MAPK is one of topmost signal path in FGFR3 downstream, and the activation situation of MAPK directly or indirectly influences propagation, differentiation, conversion and the apoptosis etc. of cell.In mammalian cell, found to exist three parallel MAPK signal paths at present, be respectively ERK signal path, p38MAPK signal path and JNK/SAPK signal path.Same stimulus can activate many MAPK signal paths simultaneously, can activate ERK, p38MAPK and JNK/SAPK three signal paths simultaneously as stress stimulation, and EGF can activate ERK and JNK/SAPK two signal paths simultaneously.Mechanism by complexity between the parallel MAPK signal path not only can distinguish mutually, but also can regulate mutually.
In 12 well culture plates, every hole inoculation 1 * 10
5Individual precartilage cell ATDC5(is given by New York Univ USA, expresses FGFR3), be that the DMEM/F12 substratum of the foetal calf serum of 50g/L is 37 ℃, CO in temperature with containing concentration
2Gas concentration is to cultivate 24 hours under the condition of 50mL/L, after treating cell attachment, absorb substratum, wash cell 2 times with serum-free DMEM/F12 substratum, add serum-free DMEM/F12 substratum 1mL, cultivated 24 hours, absorb substratum, adding and containing concentration is that DMEM/F12 substratum and the final concentration of the foetal calf serum of 50g/L is the peptide C ore1 of 10 μ M, and blank group (not adding peptide C ore1) is set simultaneously, handles 5 respectively, 10,30,45,60 minutes, collecting cell, blow and beat lysing cell with cell pyrolysis liquid, in collecting cell homogenate on ice, adopt BCA protein quantification kit measurement protein concentration.The protein sample of having surveyed concentration adds equal-volume 2 * sample-loading buffer, boiled 5 minutes, carrying out SDS-PAGE(employing concentration after the room temperature cooling is the concentrated glue of 50g/L, concentration is the separation gel of 90g/L, the electrophoresis parameter is 80V 20 minutes, 120V 80 minutes), after electrophoresis finishes, with albumen electricity transfer printing (constant current 300mA 60 minutes) to PVDF membrane, be the sealing 1 hour under room temperature of the skim-milk solution (be solvent with TBST) of 50g/L with concentration, the primary antibodie (β-actin is interior reference) and the p-ERK1/2(phosphorylation ERK1/2 that add β-Actin again), p-p38(phosphorylation P38) or p-Jnk(phosphorylation Jnk) primary antibodie, 4 ℃ of overnight incubation of temperature, wash film 5 times with TBST, it is anti-to add horseradish peroxidase-labeled two, temperature was hatched 1 hour for 37 ℃, wash film 5 times with TBST, colour developing, exposure, photographic fixing detects ERK, P38, the variation of Jnk phosphorylation level.The results are shown in Figure 2 ~ 4, the phosphorylation level of signaling molecule ERK, p38 and Jnk all has the obvious suppression effect in the MAPK signal path of peptide C ore1, and prompting peptide C ore1 regulates the cells physiological process by regulating the FGFR3 main signal path MAPK in downstream.
Four, mtt assay detects the influence of the FGFR3 express cell propagation of peptide C ore1 of different concns
In 96 well culture plates, inoculation 8000 ATDC5 cells in every hole are that the DMEM/F12 substratum of the foetal calf serum of 50g/L is 37 ℃, CO in temperature with containing concentration
2Gas concentration is to cultivate 24 hours under the condition of 50mL/L, after treating cell attachment, absorb substratum, wash cell 2 times with serum-free DMEM/F12 substratum, add serum-free DMEM/F12 substratum 1mL, cultivated 24 hours, absorb substratum, add again and contain the DMEM/F12 substratum of foetal calf serum that concentration is 50g/L and the peptide C ore1 solution that final concentration is respectively 1,5,10,20,50,100,200 μ M, blank group (not adding peptide C ore1) is set simultaneously, handling 24 hours, and added cell proliferation detection reagent 20 μ L, is 37 ℃, CO in temperature
2Gas concentration is that lucifuge was hatched 2 ~ 6 hours under the condition of 50mL/L, treat that liquid becomes pink colour by purple in the hole after, measure OD490 value at wavelength 490nm place, each organizes the result with 3 equal value representations of answering holes.The results are shown in Figure 5, peptide C ore1 propagation to the ATDC5 cell under 20 μ M, 50 μ M concentration has significant promoter action.
Five, external metatarsal is cultivated the effect that detects the ACH model mice of peptide C ore1 cartilage-derived growth
Adopt relative intravital mouse simple controllable, relatively cell more can analogue body in the vitro tissue culture technique of situation.Normal mouse C57BL/6 control group, ACH model mice control group and ACH model mice Core1 treatment group are set, every group of sample number 4 ~ 6, the ACH model mice is set up at America NI H by first contriver; Under aseptic condition, get the newborn mice metatarsal, clip tire mouse mouse tail 2mm is used for the evaluation of tire musculus cdna type simultaneously, machinery is removed most cartilage adventitias and periosteum under dissecting microscope, the metatarsal of separator well is adopted earlier figure (* 20) under dissecting microscope, after using aseptic PBS rinsing again, immersion contains 0.2% bovine serum albumin, 2mM L-glutamic acid, 50 μ g/ml vitamins Cs, in 10mM sodium and the antibiotic BGJb substratum, ACH model mice Core1 treatment group also adds the peptide C ore1 that final concentration is 20 μ M in the BGJb substratum, normal mouse C57BL/6 control group and ACH model mice control group all do not add peptide C ore1, are 37 ℃ in temperature, CO
2Gas concentration is to hatch under the condition of 50mL/L, changed liquid in per 2 days, through external cultivation in 7 days, under dissecting microscope, adopt figure (* 20), measure bone total length (TL), computational length increases percentage: length increases percentage=(0 day length of length-vitro culture of 7 days of vitro culture)/0 day length of vitro culture * 100%.The results are shown in Figure 6, ACH newborn rat metatarsal after giving 20 μ M peptide C ore1 and handling, do not give ACH newborn rat metatarsal that peptide C ore1 handles under its growth rate and the same culture conditions and compare and significantly improve.
Six, detect the effect of the FGFR3 increased functionality of peptide C ore1 associated diseases TD in the body
EIIa-Cre mouse control group, TD model mice control group and TD model mice Core1 treatment group are set, every group of sample number 4 ~ 6, EIIa-Cre mouse and TD model mice are given by America NI H; With Fgfr3
+/K644EneoMouse and the mating of EIIa-Cre mouse, look into cloudy bolt and be designated as E0.5 the same day, the 16.5th day (E16.5) afterwards, the pregnant mouse of TD model mice Core1 treatment group is according to the dosage abdominal injection peptide C ore1 of 100 μ g/kg/day, the pregnant mouse abdominal injection equivalent water for injection of TD model mice control group, observe the postnatal survival condition of mouse, newborn mice be gene recombination +/the K644E mouse is the TDII model mice; Survival mice is got shin bone and the internal organ of putting mutually when corresponding, fix 12 ~ 16 hours with 4% Paraformaldehyde 96 after row HE dyeing.The results are shown in Figure 7 ~ 9, from mouse survival condition and phenotype, cyanosis of the skin namely appears in the newborn TDII mouse birth of the TD model mice control group same day (P0), final hypoxia death, and the newborn TDII mouse birth of TD model mice Core1 treatment group survival on the same day, skin and skin mucosa are ruddy, identical with the EIIa-Cre newborn mice, the TDII mouse build at TD model mice Core1 1 monthly age for the treatment of group (P30) is obviously less than normal than the EIIa-Cre mouse at 1 monthly age, the head circle is blunt, the TDII mouse of survival all shows the phenotype of similar ACH mouse from childhood substantially to growing up, and the head circle is blunt, four limbs are short, individuality is obviously less than normal; Form quantity and form from alveolar, the alveolar of TD model mice control group TDII mouse forms quantity than TD model mice Core1 treatment group and EIIa-Cre mouse control group is few and alveolus wall becomes, and the alveolar size and form of TD model mice Core1 treatment group TDII mouse approaches normally; From the shin bone structure, the shin bone growth plate structure disturbance of TD model mice control group TDII mouse, and the shin bone growth plate chondrocyte of TD model mice Core1 treatment group TDII mouse arrangement approaches normally.
Based on above-mentioned experimental result, can draw as drawing a conclusion: peptide C ore1 of the present invention can be combined with FGFR3 extracellular fragment specificity, and its activity there is the obvious suppression effect, can be used as activeconstituents, use separately or use with other compound and/or extract composition compound with pharmacologically active, make the medicine of various formulations with pharmaceutically acceptable carrier according to the conventional formulation method of pharmaceutical field again, be used for prevention and treatment FGFR3 increased functionality type disease such as thanatophoric dysplasia, fetal rickets etc.
Explanation is at last, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although by invention has been described with reference to the preferred embodiments of the present invention, but those of ordinary skill in the art is to be understood that, can make various changes to it in the form and details, and not depart from the spirit and scope of the present invention that appended claims limits.
＜110〉No.3 Hospital Attached to No.3 Military Medical Univ., P.L.A.
＜120〉have polypeptide and the application thereof that suppresses the fibroblast growth factor receptor3 activity
<160> 1
<210> 1
<211> 6
<212> PRT
＜213〉artificial sequence
<220>
＜223〉has the polypeptide that suppresses the fibroblast growth factor receptor3 activity
<400> 1
Thr Leu Gly Gln Leu Leu
1 5
Claims (2)
1. have the polypeptide that suppresses the fibroblast growth factor receptor3 activity, formed by the aminoacid sequence shown in the Thr-Leu-Gly-Gln-Leu-Leu.
2. claim 1 is described has the polypeptide that suppresses the fibroblast growth factor receptor3 activity and prevents and/or treats application in the medicine of FGFR3 increased functionality type disease in preparation, and described FGFR3 increased functionality type disease is fetal rickets and thanatophoric dysplasia.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101619093A (en) * | 2009-05-26 | 2010-01-06 | 中国人民解放军第三军医大学野战外科研究所 | Polypeptide with function of promoting activity of fibroblast growth factor receptor 3 and screening method and application thereof |
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| CN101619093A (en) * | 2009-05-26 | 2010-01-06 | 中国人民解放军第三军医大学野战外科研究所 | Polypeptide with function of promoting activity of fibroblast growth factor receptor 3 and screening method and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| Bacterial Synthesis and Purification of Normal and Mutant Forms of Human FGFR3 Transmembrane Segment;Goncharuk SA等;《Acta Naturae.》;20110731;第3卷(第3期);77-84 * |
| Goncharuk SA等.Bacterial Synthesis and Purification of Normal and Mutant Forms of Human FGFR3 Transmembrane Segment.《Acta Naturae.》.2011,第3卷(第3期),77-84. |
| 余瑛等.FGFR3胞外区在酵母中的表达.《重庆工学院学报（自然科学）》.2009,第23卷(第5期),45-49. * |
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