CN103601808B - Sodium peptide, preparation method and preparing the application in genetically engineered drug - Google Patents
Sodium peptide, preparation method and preparing the application in genetically engineered drug Download PDFInfo
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Abstract
The invention discloses a kind of sodium peptide, this sodium peptide is connected to form by brain natriuretic peptide and snake sodium peptide; Brain natriuretic peptide is positioned at the N end of sodium peptide, and snake sodium peptide is positioned at the C end of sodium peptide; Wherein, brain natriuretic peptide comprises the disulfide linkage ring texture formed by two cysteine residues.Its preparation method comprises: obtain brain natriuretic peptide gene and snake sodium peptide gene, by PCR method splicing synthesis sodium peptide gene; Build the expression plasmid comprising sodium peptide gene; Expression plasmid is converted in suitable expression strain and carries out inducing culture, the expression of induction sodium peptide.Sodium peptide of the present invention has the characteristic of brain natriuretic peptide and snake sodium peptide simultaneously, and specific effect significantly strengthens, and drug half-life obviously extends; Preparation method's technique of the present invention is simple, practical; The genetically engineered drug with sodium peptide can the effector such as useful effect heart, blood vessel and kidney, and the diseases such as the function of the above-mentioned organ of available protecting, prevention and therapy heart and kidney failure.
Description
Technical field
The invention belongs to biological pharmacy technical field, relate to a kind of sodium peptide prepared based on genetic engineering technique.More specifically, the present invention relates to by brain natriuretic peptide (brainnatriureticpeptide, and snake sodium peptide (dendroaspisnatriureticpeptide, DNP) the genetically engineered sodium peptide (BDNP), the preparation method and for the preparation of the application in the genetically engineered drug in Cardiovarscular and kidney disease etc. that form BNP).
Background technology
Find multiple natriuretic peptide up to now, such as atrial natriuretic peptide, brain natriuretic peptide, C type sodium peptide, urine sodium peptide and snake sodium peptide etc.Although they have some structural differences, but there is following common physiological action: natriuretic peptide is combined by the Peroxisome proliferators activated receptorsΥ on vessel wall, activate guanylate cyclase, cause the concentration rising of the histocyte intramolecular cyclization guanylic acids (cGMP) such as heart, blood vessel, kidney and the diastole of smooth muscle cell; As second messenger, cGMP energy expansion artery and vein, and whole body peripheral arterial pressure, pulmonary capillary wedge pressure, Ppa pulmonary artery pressure, right atrial pressure can be reduced fast, thus reduce the front and back load of ventricle; The cardiac toxic that natriuretic peptide therapeutic energy antagonism endothelin, norepinephrine and aldosterone excessive activation produce, thus the afferent glomerular arteriole of nephrectasia bead, suppression proximal convoluted tubule are to the absorption of sodium, glomerular filtration rate(GFR and sodium excretion are increased, produce obvious diuresis and natriuretic effect, but not increasing kaliuresis, is useful to the direct effect of kidney.Ventricular afterload can be reduced by above-mentioned machine-processed natriuretic peptide, by reducing the secretion of feritin and aldosterone and antagonism vassopressin and sympathetic activity, the effect of the row's of playing sodium, diuresis, step-down, circulating blood volume is reduced, alleviate the preload of ventricle, improve the haemodynamics balance of blood vessel and kidney.In addition, natriuretic peptide suppresses the myocardial fibrosis of transforming growth factor induction, the up-regulated expression suppressing inflammatory factor gene and cardiac muscle fibre parent cell breeding differentiation and collage synthesis, and then reverses remodeling ventricle.
Brain natriuretic peptide (BNP) is separated at first and obtains from pig brain, and the peptide sequence of proBNP has high homology between species.The brain natriuretic peptide of people is made up of (shown in Fig. 1) 32 amino acid, and comprises the disulfide linkage ring texture formed by two cysteine residues.Normal myocardial cells synthesis secretion BNP, pathology cardiac muscle (such as myocardial hypertrophy, myocardial infarction and heart failure) also can induce it to produce.BNP and natriuretic peptide receptor A (NatriureticpeptideAreceptor, NPRA) combines, and activates guanylate cyclase, improves cGMP level in born of the same parents, thus produces multiple physiological effect, comprise sharp sodium, diuresis, vasorelaxation action; Also vascular smooth muscle cell and fibroblast proliferation etc. can be suppressed.But the transformation period of BNP secretion and removing is shorter, is about 2 minutes respectively and 18 minutes.
Snake sodium peptide (DNP) is a kind of natriuretic peptide extracted from snake venom, is made up of (Fig. 2) 38 amino acid.Owing to also can record the expression of DNP in the blood and tissue of people and rat, prompting DNP may be another kind of endogenous natriuretic peptide.Equally, DNP also has promotion water sodium excretion, the function of inducing vasodilation and suppression vascular smooth muscle cell proliferation.The C-terminal (i.e. C end) of DNP is made up of 15 amino acid, and can increase the stimulatory effect of cGMP, its ability stimulating myocardial cell to produce cGMP is 10 times of ANP.NPRC (NatriureticpeptideCreceptor, NPRC) be cell surface natriuretic peptide remove acceptor, the avidity of DNP and NPRC is lower than ANP and BNP, and centering endopeptidase has stronger resistibility, points out DNP in the circulating cycle and is removed fast unlike other natriuretic peptides.Therefore, the transformation period of DNP is longer.
Had the BNP based on preparation in the market, it is mainly used in treating acute heart failure.But due to the reason such as action site single and transformation period is short, BNP is desirable not enough to the result for the treatment of of acute heart failure.
Summary of the invention
The technical problem to be solved in the present invention is, for when brain natriuretic peptide being applied in prior art treatment acute heart failure, due to its action site specific binding limited use and the short and defect undesirable to acute heart failure prevention effect caused of drug half-life, a kind of sodium peptide prepared based on genetic engineering technique is provided, this sodium peptide has the characteristic of brain natriuretic peptide and snake sodium peptide simultaneously, specific effect significantly strengthens, drug half-life significant prolongation, can useful effect in heart, the effector such as blood vessel and kidney, and available protecting heart, the function of kidney and other organs, reach protection, prevention and therapy heart, the object of kidney and other organ failure diseases.
The technical problem to be solved in the present invention is achieved by the following technical programs: provide a kind of genetically engineered sodium peptide, and described sodium peptide is connected to form by brain natriuretic peptide and snake sodium peptide; Described brain natriuretic peptide is positioned at the N end of described sodium peptide, and described snake sodium peptide is positioned at the C end of described sodium peptide; Described brain natriuretic peptide comprises the disulfide linkage ring texture formed by two cysteine residues.
In said gene engineering sodium peptide, described sodium peptide is made up of 41 amino acid, and the brain natriuretic peptide being wherein positioned at N end has 26 amino acid, and the snake sodium peptide being positioned at C end has 15 amino acid.
In said gene engineering sodium peptide, described brain natriuretic peptide is human brain natriuretic peptide and comprises the ring-type functional zone of a complete human brain natriuretic peptide, and described snake sodium peptide has 15 amino acid of complete snake sodium PEPC end.
In said gene engineering sodium peptide, described sodium peptide has the aminoacid sequence shown in SEQIDNo:7 in sequence table.
According to a further aspect in the invention, a kind of preparation method of said gene engineering sodium peptide is provided, said method comprising the steps of:
A: obtain brain natriuretic peptide gene and snake sodium peptide gene respectively;
B: by PCR method by the described brain natriuretic peptide gene in steps A and snake sodium peptide gene splicing synthesis sodium peptide gene; Described sodium peptide gene is connected to form with the described snake sodium peptide gene being positioned at its C end by the described brain natriuretic peptide gene being positioned at its N end;
C: adopt Prokaryotic expression vector construction to comprise the expression plasmid of described sodium peptide gene; And
D: be converted in expression strain by the expression plasmid formed in step C and carry out inducing culture, expresses described sodium peptide.
In the preparation method of above-mentioned sodium peptide, the described brain natriuretic peptide gene of acquisition is human brain natriuretic peptide gene.
In the preparation method of above-mentioned sodium peptide, described steps A comprises following sub-step:
Obtain full length human brain sodium peptide gene;
The N-terminal gene fragment of described human brain natriuretic peptide gene is obtained: build primer sequence 3:5 '-GAATTCGTTCGTGGTCCGCGTAGCCCGAAGATGGTGCAA-3 ' and primer sequence 4:5 '-AGCGTTCGGACGCGGGTCACGCAGGCTCGGGCAGCCCAGGCCACTGGA-3 ' from described full length human brain sodium peptide gene: and
Obtain the C-terminal gene fragment of described snake sodium peptide gene: build primer sequence 5:5 '-GTGGATCCTCAAGCGCTAGTGCTCGGAGCGTTCGGACGCGGGTCACG-3 '.
In the preparation method of above-mentioned sodium peptide, after described step D, described method also comprises step e: the thalline of expression strain described in collected by centrifugation, obtains described sodium peptide after carrying out purifying.
In the preparation method of above-mentioned sodium peptide, in described step C, described prokaryotic expression carrier is pGEX-4T-1 or pCW; In described step D, described expression strain is DH5 α, BL21, Rosetta or Rosetta-gami.
According to a further aspect in the invention, the application of a kind of said gene engineering sodium peptide in the genetically engineered drug for the preparation of protection, Prevention and Curation cardiovascular disorder and kidney disease is provided.
Implement technical scheme of the present invention, following technique effect can be obtained: BDNP has the N end be made up of BNP and the C end be made up of DNP, by force, the enzymolysis of DNP centering endopeptidase has stronger resistibility simultaneously for the BNP of formation N end and the binding ability of natriuretic peptide receptor A; Intensity and the action time of specific binding and biological action significantly increase, thus significantly increase the stimulatory effect of cGMP, realize the physiology of dual enhancing natriuretic peptide, pharmacology usefulness; The effectors such as sodium Toplink useful effect heart of the present invention, blood vessel and kidney, and the function of available protecting heart and kidney and other organs; Preparation method's technique of the present invention is simple, practical; Have sodium peptide gene engineering medicine of the present invention can useful effect in effector, reach the object of prevention and therapy heart and kidney and other organ failure diseases.Sodium peptide gene engineering medicine of the present invention can also be used for the treatment of acute respiratory distress syndrome (ARDS), and the disease such as hypertension (comprising gestational hypertension), diabetes, obesity.
Accompanying drawing explanation
Below with reference to the drawings and specific embodiments, the present invention is described in further details.In accompanying drawing:
Fig. 1 is the schematic diagram of human brain natriuretic peptide;
Fig. 2 is the schematic diagram of snake sodium peptide; And
Fig. 3 is the schematic diagram of the sodium peptide prepared in the embodiment of the present invention.
Embodiment
In order to make object of the present invention, technical scheme and advantage clearly understand, below in conjunction with drawings and Examples, the present invention is further elaborated.Should be appreciated that specific embodiment described herein only in order to explain the present invention, be not intended to limit the present invention.
Genetically engineered sodium peptide (BDNP) of the present invention is connected to form by brain natriuretic peptide and snake sodium peptide.See Fig. 3, brain natriuretic peptide is positioned at the N end of this sodium peptide, and snake sodium peptide is positioned at the C end of this sodium peptide, and wherein brain natriuretic peptide comprises the disulfide linkage ring texture formed by two cysteine residues.More specifically, sodium peptide of the present invention is made up of 41 amino acid, and wherein N end is 26 amino acid of brain natriuretic peptide N end, and C end is 15 amino acid of snake sodium PEPC end.The enzymolysis of this C end structure centering endopeptidase has stronger resistibility, can extend the transformation period of the sodium peptide finally prepared.Genetically engineered sodium peptide of the present invention can be used for preparing can protect, the genetically engineered drug of Prevention and Curation cardiovascular disorder and kidney disease; Certainly it also can be applicable to the preparation of the medicine for the treatment of other multiple organ dysfunctions.
The preparation method of genetically engineered sodium peptide (BDNP) of the present invention comprises the following steps: A: obtain brain natriuretic peptide gene and snake sodium peptide gene respectively; B: by PCR method by the brain natriuretic peptide gene in steps A and snake sodium peptide gene splicing synthesis sodium peptide gene; Sodium peptide gene is connected to form with the snake sodium peptide gene being positioned at its C end by the brain natriuretic peptide gene being positioned at its N end; C: adopt Prokaryotic expression vector construction to comprise the expression plasmid of sodium peptide gene; D: be converted in expression strain by the expression plasmid formed in step C and carry out inducing culture, expresses sodium peptide.After abduction delivering, aforesaid method also comprises step e: the thalline of collected by centrifugation expression strain, obtains genetically engineered sodium peptide after carrying out purifying.The method extension easy and simple to handle, that be convenient to realize said gene engineering sodium peptide (BDNP) is produced.
Preferably, brain natriuretic peptide of the present invention is human brain natriuretic peptide.Below will illustrate the present invention and how to build said gene engineering sodium peptide by human brain natriuretic peptide and snake sodium peptide.
Further, above-mentioned steps A specifically comprises the following steps:
A1: the fishing of people's total length brain natriuretic peptide gene is got
Design suitable primer, fish from human heart cDNA and get full length human brain sodium peptide gene (pre-BNP).In the database such as US National Bioinformatics Institute (NCBI), European Bioinformatics center (EBI), find human brain natriuretic peptide (BNP) gene order, and carry out corresponding bioinformatic analysis.
The fishing of full length human brain sodium peptide gene (pre-BNP) is got: in the database such as US National Bioinformatics Institute (NCBI), European Bioinformatics center (EBI), search human brain natriuretic peptide gene order, design upstream and downstream primer, is respectively:
Primer sequence the 1:5 '-ATGGATCCCCAGACAGCACCTTCCCGGGCG-3 ' of upstream primer,
Primer sequence the 2:5 '-TTAATGCCGCCTCAGCACTTTGCAGCCCAGGCC-3 ' of downstream primer.
With human heart cDNA for template, with the upstream and downstream primer amplification of full length human brain sodium peptide gene (pre-BNP), obtain the gene fragment of about 400bp size.Subsequently, the gene fragment obtained increasing loads carrier T, confirms that gene fragment is required goal gene through gene sequencing analysis.
A2: the fishing of human brain natriuretic peptide gene (BNP) N-terminal gene fragment is got
Design suitable primer, fish from the full length human brain sodium peptide gene (pre-BNP) that steps A 1 obtains and get human brain natriuretic peptide gene (BNP) N-terminal gene fragment.The upstream and downstream primer of design containing restriction enzyme site, is respectively:
Upstream primer sequence 3:5 '-GAATTCGTTCGTGGTCCGCGTAGCCCGAAGATGGTGCAA-3 ',
Downstream primer sequence 4:5 '-AGCGTTCGGACGCGGGTCACGCAGGCTCGGGCAGCCCAGGCCACTGGA-3 ',
In upstream primer, introduce EcoRI restriction enzyme site, introduce thrombin proteins cleavage site simultaneously, target protein (i.e. BDNP) and fusion protease are cut.The partial sequence (5 '-AGCGTTCGGACGCGGGTCACGCAGGCTCGG-3 ') of snake sodium peptide gene has been introduced as subsequent PCR amplification splicing synthesis sodium peptide (BDNP) in downstream primer.
A3: the synthesis of snake sodium peptide gene C-terminal gene fragment
In the database such as US National Bioinformatics Institute (NCBI), European Bioinformatics center (EBI), find snake sodium peptide (DNP) gene order, and carry out corresponding bioinformatic analysis.Synthesis snake sodium peptide (DNP) gene/C terminal sequence, design contains gene order and the restriction enzyme site of part brain natriuretic peptide (BNP) gene simultaneously, and the primer sequence of design is
Primer sequence 5:5 '-GTGGATCCTCAAGCGCTAGTGCTCGGAGCGTTCGGACGCGGGTCACG-3 ',
BamHI restriction enzyme site and part brain natriuretic peptide (BNP) gene order (5 '-AGCGTTCGGACGCGGGTCACGCAGGCTCGG-3 ') is introduced as subsequent PCR amplification splicing synthesis sodium peptide (BDNP) in primer.
Above-mentioned steps B specifically comprises the following steps---the PCR splicing amplification of sodium peptide (BDNP) gene.With people's total length brain natriuretic peptide gene (pre-BNP) for template, be upstream and downstream primer amplification with primer sequence 3 and primer sequence 4 respectively, obtain the gene fragment of about 108bp size, wherein containing BNPN end 78bp fragment and DNPC end 30bp fragment.Subsequently, with above-mentioned 108bp fragment for template, be upstream and downstream primer amplification with primer sequence 3 and primer sequence 5 respectively, obtain the gene fragment of about 123bp size, wherein containing BNPN end 78bp fragment and DNPC end 45bp fragment, be sodium peptide (BDNP) gene fragment (see sequence in sequence table 6).The BDNP gene fragment obtained increasing loads carrier T, confirms that each gene fragment is required goal gene through gene sequencing analysis.
Above-mentioned steps C specifically comprises following flow process---construction expression plasmid: the PCR primer of sodium peptide BDNP gene fragment is connected after EcoRI with BamHI enzyme is cut and inserts in prokaryotic expression carrier pGEX-4T-1 or pCW that cut of same enzyme, be built into recombinant plasmid pGEX-BDNP or pCW-BDNP containing BDNP gene; Consider follow-up purifying, preferably use recombinant plasmid pGEX-BDNP.
Due to the expression level of genetically engineered drug and expression strain closely related, therefore, in the present invention expression strain choose also very important, consider the growth conditions of the output of expression product, solubility and host strain, the present invention have selected multiple expression strain DH5 α, BL21, Rosetta or Rosetta-gami as Host Strains, and preferably uses BL21 and Rosetta to set up expression strain.
How to adopt prokaryotic expression carrier pGEX-4T-1 and pCW to build prokaryotic expression plasmid pGEX-BDNP and pCW-BDNP by describing in detail and in expression strain BL21 and Rosetta, realize the high expression of sodium peptide (BDNP) in following embodiment.
Embodiment 1:
By sodium peptide (BDNP) gene clone through PCR splicing amplification and through checking order in prokaryotic expression carrier pGEX-4T-1, be built into the prokaryotic expression plasmid pGEX-BDNP containing sodium peptide (BDNP).Adopt BL21 and Rosetta as expression strain.Extract the prokaryotic expression plasmid pGEX-BDNP of high quality high density, utilize cold CaCl
2method transforms host bacteria, is transformed into respectively by above-mentioned plasmid in BL21 and Rosetta bacterial strain, 37 DEG C of incubated overnight; Then picking expression strain, inoculation LB substratum (add penbritin, final concentration is 100 μ g/ml), collects bacterium liquid after 37 DEG C of incubated overnight, extracts albumen after ultrasonic disruption, carry out WesternBlot detection.
Embodiment 2:
By sodium peptide (BDNP) gene clone through PCR splicing amplification and through checking order in prokaryotic expression carrier pCW, be built into the prokaryotic expression plasmid pCW-BDNP containing sodium peptide (BDNP).Adopt BL21 and Rosetta as expression strain.Extract the prokaryotic expression plasmid pCW-BDNP of high quality high density, utilize cold CaCl
2method transforms host bacteria, is transformed into respectively by above-mentioned plasmid in BL21 and Rosetta bacterial strain, 37 DEG C of incubated overnight; Then picking expression strain, inoculation LB substratum (add penbritin, final concentration is 100 μ g/ml), collects bacterium liquid after 37 DEG C of incubated overnight, extracts albumen after ultrasonic disruption, carry out WesternBlot detection.
In above-mentioned steps E, carrying out purifying to the sodium peptide of embodiment 1-2 comprises by collected by centrifugation expression strain, then gone out the fusion rotein of sodium peptide by affinity protein purification, utilize zymoplasm enzyme to cut except label protein, last separation and purification obtains sodium peptide (BDNP).
In sum, sodium peptide of the present invention has the characteristic of brain natriuretic peptide and snake sodium peptide simultaneously, and specific effect significantly strengthens, drug half-life significant prolongation; Preparation method's technique of the present invention is simple, practical; The genetically engineered drug with sodium peptide can the effector such as useful effect heart, blood vessel and kidney, and the function of available protecting heart and kidney, the diseases such as prevention and therapy heart and kidney failure.
Claims (5)
1. a genetically engineered sodium peptide, is characterized in that, described sodium peptide is connected to form by brain natriuretic peptide and snake sodium peptide; Described brain natriuretic peptide is positioned at the N end of described sodium peptide, and described snake sodium peptide is positioned at the C end of described sodium peptide; Described brain natriuretic peptide comprises the disulfide linkage ring texture formed by two cysteine residues; Described brain natriuretic peptide is human brain natriuretic peptide and comprises the ring-type functional zone of a complete human brain natriuretic peptide, and described snake sodium peptide has 15 amino acid of complete snake sodium PEPC end;
Wherein, the gene fragment of described sodium peptide is the nucleotide sequence shown in the SEQIDNo:6 in sequence table, and described sodium peptide is the aminoacid sequence shown in the SEQIDNo:7 in sequence table.
2. a preparation method for the genetically engineered sodium peptide of claim 1, is characterized in that, said method comprising the steps of:
A: obtain brain natriuretic peptide gene and snake sodium peptide gene respectively, wherein said brain natriuretic peptide gene is human brain natriuretic peptide gene;
B: by PCR method by the described brain natriuretic peptide gene in steps A and snake sodium peptide gene splicing synthesis sodium peptide gene; Described sodium peptide gene is connected to form with the described snake sodium peptide gene being positioned at its C end by the described brain natriuretic peptide gene being positioned at its N end;
C: adopt Prokaryotic expression vector construction to comprise the expression plasmid of described sodium peptide gene; And
D: be converted in expression strain by the expression plasmid formed in step C and carry out inducing culture, expresses described sodium peptide;
Described steps A comprises following sub-step:
Obtain full length human brain sodium peptide gene;
The N-terminal gene fragment of described human brain natriuretic peptide gene is obtained: build primer sequence 3:5 '-GAATTCGTTCGTGGTCCGCGTAGCCCGAAGATGGTGCAA-3 ' and primer sequence 4:5 '-AGCGTTCGGACGCGGGTCACGCAGGCTCGGGCAGCCCAGGCCACTGGA-3 ' from described full length human brain sodium peptide gene: and
Obtain the C-terminal gene fragment of described snake sodium peptide gene: build primer sequence 5:5 '-GTGGATCCTCAAGCGCTAGTGCTCGGAGCGTTCGGACGCGGGTCACG-3 '.
3. preparation method according to claim 2, is characterized in that, after described step D, described method also comprises step e: the thalline of expression strain described in collected by centrifugation, obtains described sodium peptide after carrying out purifying.
4. preparation method according to claim 2, is characterized in that, in described step C, described prokaryotic expression carrier is pGEX-4T-1 or pCW; In described step D, described expression strain is DH5 α, BL21, Rosetta or Rosetta-gami.
5. the application of genetically engineered sodium peptide in the genetically engineered drug for the preparation of protection, Prevention and Curation cardiovascular disorder and kidney disease of claim 1.
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| CN110278941B (en) * | 2019-07-11 | 2021-05-28 | 西安国际医学中心有限公司 | Isolated heart protection solution containing natriuretic peptide |
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Non-Patent Citations (6)
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| A new member of the natriuretic peptide family is present in the venom of the Green Mamba (Dendroaspis angusticeps);Hugues Schweita, et al.;《JBC》;19920715;第267卷(第20期);第13928-13932页 * |
| Chain C, Crystal Structure Of Human Insulin-Degrading Enzyme (Ide) In Complex With Human B-Type Natriuretic Peptide (Bnp);Ralat L.A., et al.;《GenBank》;20121010;参见ORIGIN序列部分 * |
| Natriuretic peptide receptors and neutral endopeptidase in mediating the renal actions of a new therapeutic synthetic natriuretic peptide dendroaspis natriuretic peptide;Horng H., et al.;《Journal of the American College of Cardiology》;20021231;第40卷(第6期);第1186-1191页 * |
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| RecName: Full=Natriuretic peptide DNP;Schweitz H., et al.;《GenBank》;20120905;参见ORIGIN序列部分 * |
| Renal actions of synthetic Dendroaspis natriuretic peptide;Ondrej Lisy, et al.;《Kidney International》;19991231;第56卷;第502-508页 * |
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