CN115093468B - Helicobacter pylori specific antigenic peptide - Google Patents

Helicobacter pylori specific antigenic peptide Download PDF

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CN115093468B
CN115093468B CN202210721353.5A CN202210721353A CN115093468B CN 115093468 B CN115093468 B CN 115093468B CN 202210721353 A CN202210721353 A CN 202210721353A CN 115093468 B CN115093468 B CN 115093468B
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glu
lys
pylori
ala
arg
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CN115093468A (en
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单保恩
赵连梅
李志荣
胡代伦
李晓亚
魏思思
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Hebei Medical University
Fourth Hospital of Hebei Medical University Hebei Cancer Hospital
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Fourth Hospital of Hebei Medical University Hebei Cancer Hospital
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/0208—Specific bacteria not otherwise provided for
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/12—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria
    • C07K16/1203—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-negative bacteria
    • C07K16/121—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-negative bacteria from Helicobacter (Campylobacter) (G)
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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Abstract

The invention relates to helicobacter pylori specific antigenic peptide, which comprises an amino acid sequence shown as SEQ ID No. 1. The antigens of the invention are useful in the preparation of novel antigensH.pyloriVaccines and other usesH.pyloriActive or passive immunotherapy of treatment, forH.pyloriThe prevention and the treatment of infection have important significance.

Description

Helicobacter pylori specific antigenic peptide
Technical Field
The invention relates to helicobacter pylori specific antigenic peptides.
Background
About more than 50% of the population worldwide is infected with helicobacter pyloriH.pylori) Among them, it is common in developing countries such as asia and africa. Almost all ofH.pyloriPatients with infection all have chronic gastritis, of which about 10% develop peptic ulcers, and 1% develop in the next decade to decadesIs gastric cancer. Thus, prevention and treatmentH.pyloriInfection is an important means for preventing and treating digestive tract ulcers and chronic gastritis, and preventing gastric cancer.
Clinically directed toH.pyloriThe treatment of infection mainly depends on triple or quadruple therapy based on antibiotics, but has a plurality of problems such as high cost, continuous increase of drug-resistant strains, destruction of normal flora of intestinal tracts, easy recurrence and reinfection after drug withdrawal, and the like. Particularly the problem of increased resistance, results in an increasing difficulty in the treatment of helicobacter pylori infections.
At the position ofH.pyloriPart of membrane proteins or mycoproteins can induce immune response in human body during infection, andH.pyloriis closely related to the adhesion fixation, continuous infection and severity of the disease. Currently, in addition to antibiotic therapy, immunotherapeutic approaches to prepare related vaccines are also used for therapy, targeting membrane proteins and/or other mycoproteinsH.pyloriInfection. Such as byH.pyloriRecombinant urease and subunit thereof, cytotoxin-related protein (CagA), vacuolated toxin-related protein (VacA), adhesin A (HpaA), etcH.pyloriVaccine studies have all been partially advanced.
However, it is currently known thatH.pyloriNone of the vaccines can eradicateH.pyloriIs urgent to search for new immunogenic protein targets for the preparation of effectiveH.pyloriThe vaccine provides the basis.
Disclosure of Invention
The invention aims to provide a novel helicobacter pylori specific antigen peptide with immunogenicity.
The invention adopts the following technical scheme:
a helicobacter pylori-specific antigenic peptide comprising the amino acid sequence as shown in SEQ ID No. 1.
A nucleic acid molecule encoding the helicobacter pylori-specific antigenic peptide described above, comprising a nucleotide sequence as shown in SEQ ID No. 2.
A vector comprising the above nucleic acid molecule.
A monoclonal antibody prepared by using the helicobacter pylori specific antigen peptide.
A vaccine prepared using the helicobacter pylori specific antigenic peptide described above, for stimulating an immune response in a host organism.
A helicobacter pylori specific antigen protein comprising a membrane protein having an amino acid sequence as shown in SEQ ID No. 1.
Further, the helicobacter pylori specific antigen protein is a membrane protein pgbA comprising an amino acid sequence shown as SEQ ID No. 3.
The invention has the beneficial effects that: the antigens of the invention are useful in the preparation of novel antigensH.pyloriVaccines and other usesH.pyloriActive or passive immunotherapy of treatment, forH.pyloriThe prevention and the treatment of infection have important significance.
Drawings
FIG. 1 shows dielectrophoresis and immunoblotting detectionH. pyloriMilk antibody immune membrane protein target.
FIG. 2 is a two-way diffusion test of immune agarH. pyloriMilk antibody immune membrane protein target.
FIG. 3 is an IP testH. pyloriMilk antibody immune membrane protein target.
FIG. 4 is an ELISA validation antigenicity experiment.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
1. Cultivation of helicobacter pylori
Helicobacter pylori clinical isolate HP435 was inoculated in modified campylobacter medium (Campy-BAP) containing 10% defibrinated sheep blood of diameter 9 cm, microaerophilic (5% O) at 37 ℃ 2 ，10% CO 2 ，85% N 2 Humidity 95%) for 3-4 days.
2. Extraction of helicobacter pylori membrane protein
Washing with sterile 0.1 mol/L Phosphate Buffer (PBS)H.pyloriThe bacterial cells were 3 times suspended in 20% glycerol broth and frozen at-80℃until use. For strains producing membrane proteins, a sterile 0.1 mol/L PBS wash should be usedH.pyloriCells were 3 times. EZ-Link Sulfo-NHS-SS-biotin reaction solution with the concentration of 250 mug/ml is prepared, and the freshly washed H.pyri cell membrane protein is marked. The labeled somatic cells were sonicated (3 s on/7s off, intensity 20%,5 min). 4. Centrifuging at 120deg.C for 30 min at 12,000 g, collecting the enriched extractH.pyloriSupernatant of membrane protein. The membrane proteins were then purified using an avidin column.
3. Milk cow immunization and antibody preparation
3.1 Milk cow immunization
Selecting 3-4 years old, and gestating for 6-7 months, and keeping healthy Holstein cow. Preparation of 5mg Membrane protein plus 4×10 9 The whole cells were fixed to 5 ml with 0.1 mol/L PBS, mixed with 5 ml of aluminum hydroxide adjuvant (alum adjuvant) by shaking, and immunized by subcutaneous injection in the cervical subcutaneous and subiliac lymph nodes of the cows 5 times. Wherein the first and second immunizations are separated by 20 days, and the immunization is completed from day 10 to day 10 before calving of the cow.
3.2 preparation of antibodies
Collecting colostrum of milk cow within one week after calving, centrifuging at 4deg.C for 20 min, adding appropriate amount of hydrochloric acid to adjust pH to 4.6, centrifuging at 12000 rpm 4deg.C for 30 min to remove casein precipitate, and collecting clear supernatant (whey). Antibody purification was performed on the extracted antibody-enriched whey using a GE protein purifier, coupled to a Hitrap Protein G HP 1ml purification column. The obtained purified antibody was subjected to antibody titer detection using an ELISA method. Purified antibodies were obtained with an antibody titer of 1:15000.
4. Identification of immunogenic Membrane proteins Using three methods
4.1 two-dimensional electrophoresis and immunoblotting for detecting immunogenicity positivity of milk antibodyH.pyloriMembrane proteins
Two HP435 strain membrane protein samples (150. Mu.g protein each) were labeled with the same Cy dye and subjected to two-dimensional electrophoresis. And (3) using a Typhoon multicolor fluorescence imaging scanner to image and position the PAGE gel after two-dimensional electrophoresis. Then, one of the plate PAGE gels was subjected to immunoblotting using the purified antibodies prepared according to the present invention as primary antibodies, with Cy5 or Cy3 labeled (as distinguished from the dye labeling the protein sample) goat anti-bovine secondary antibodies. Detecting the immunogenic protein spots.
As a result, 6 to 8 immunoreactive positive protein spots were identified (see FIG. 1). And (3) corresponding to the immunoblotting test result and the position of the immunoreactive positive protein spot on the original gel, digging a protein spot at the corresponding position on the other plate PAGE gel, and carrying out protein mass spectrum identification. As a result, it was found that 112 proteins could be identified.
4.2 Immune agar bidirectional diffusion method for detecting immunogenicity positive of milk antibodyH.pyloriMembrane proteins
The whole bacterial suspension of HP435 strain was subjected to an immunoagar double diffusion assay with the blank antibody and the purified antibody after immunization, respectively (see fig. 2).
As a result, it was found that a clear antigen-antibody precipitation line appeared between the purified antibody and the whole bacterial suspension. The pellet was excised, denatured by boiling with 5 Xprotein loading buffer, and subjected to SDS-PAGE. And (3) after electrophoresis, carrying out coomassie brilliant blue staining on the PAGE gel, cutting off the developed protein bands, and carrying out mass spectrum identification after enzymolysis in the gel. As a result, it was found that 501 proteins could be identified.
4.3 IP assay and protein mass spectrometry identification
Will extractH.pyloriThe membrane proteins were subjected to IP experiments with purified antibodies. The proteins after IP were subjected to SDS-PAGE, stained with Coomassie blue, and the developed protein bands were subjected to in-gel enzymolysis and mass spectrometry (see FIG. 3). As a result, it was found that 403 protein could be identified.
5. Further analysis of the authentication results
5.1 Intersection analysis is carried out on the protein identification results obtained by the detection of the three immunological identification methods, and 13 common proteins are found. Wherein, the pgbA with the amino acid sequence shown as SEQ ID No.2 is a newly discovered membrane protein with immunogenicity.
SEQ ID No.2：
MLRLLIGLLLMSFISLQSASWQEPLRVSIEFVDLPKKIIRFPAHDLQVGEFGFVVTKLSDYEIVNSEVVIIAVENGVATAKFRAFESMKQSHLPTPRMVARKGDLVYFRQFNNQAFLIAPNDEIYEQIRATNTDINFISSDLLVTFLNGFDPKIANLRKACNVYSVGVIYIVTTNTLNILSCESFEILEKRELDTSGVTKTSTPFFSRVEGIDAGTLGKLFSGSQSKNYFAYYDALVKKEKRKEVRIKKQEEKVDAREIKREIKQEAIKEPKKANQGTENAPTLEEKNYQKAERKLDATEERRRLRDERKKANATKKAMEFEEKEKAHDERDERETEERRKALGMDQGNEKVNAKENDQEIKQEAIKEPSNENNATQQGENKLNSKEEKRRLKEEKKKAKAEQRAREFEQRAKEQQERDEKELEERRKALEAGKK。
5.2 The membrane protein was subjected to an immunogenic sequence analysis using Bepipred Linear Epitope Prediction 2.0.0, wherein the SEQ ID No.1 (ATEERRR) score was high, and the peptide fragment with immunogenicity corresponds to the nucleotide sequence SEQ ID No.2: GCTACAGAAGAAAGGCGTCGT.
5.3 To further verify the immunogenicity of the peptide fragment, 5mg (purity 98%) of the polypeptide shown in SEQ ID No.1 was synthesized by the polypeptide synthesis company; non-immunogenic peptide fragments were synthesized as controls.
5.4 ELISA verification
(1) 5mg of the synthetic polypeptide was dissolved in 1mL of PBS and mixed well.
(2) ELISA plates: the polystyrene plate was first irradiated with ultraviolet rays for 2 hours, and then with a coating buffer (coating buffer: na) 2 CO 3 And NaHCO 3 Buffer) the synthetic polypeptide was diluted to 0.1mg/ml, 50. Mu.L was added to each reaction well of the polystyrene plate, overnight at 4℃for the next day, the intra-well solution was discarded, and the buffer was washed 1 time with 1 XTBE at 180. Mu.L per well.
(3) Closing: each well was blocked with 60. Mu.L of 1% BSA (TBST formulation) and incubated at 37℃for 1 hour. After which the blocking solution is discarded.
(4) Sample adding: after gradient dilution of the collected immune whey (see step 3.2), 50. Mu.L/well was incubated at 37℃for 1 hour, after which the blocking solution was discarded and washed 2 times with 1 XTBE buffer at 180. Mu.L/well.
(5) Adding enzyme-labeled antibody: freshly diluted goat anti-bovine secondary antibody-HRP (diluted 1:5000 with 1% BSA) was added to the wells of the microplate at 50. Mu.L/well, incubated at 37℃for 45min, after which the blocking solution was discarded and washed 3 times with 180. Mu.L/well of 1 XTBST buffer.
(6) Adding a substrate solution for color development: 100. Mu.L of the TMB substrate solution prepared temporarily was added to each reaction well, and the mixture was allowed to react at 37℃for 5 minutes, as shown in FIG. 4.
(7) Terminating the reaction: to each reaction well was added 90. Mu.L of 2M sulfuric acid.
(8) Measuring absorbance at 450nm wavelength on enzyme-labeled instrument with OD 450 The maximum dilution factor of 0.5 is the antibody titer (more than 2.1 times the OD value of the negative well). The antibody titer of the immunogenic peptide (1:12000) was 2 times that of the control peptide (1:6000).
5.4 mouse verification
Full emulsification of the polypeptide shown in SEQ ID No.1, BSA and Freund's complete adjuvant, and subcutaneous multipoint injection of 50 mug/mouse BALB/c in four limbs and back; immunization 2 was performed after 2 weeks, and the polypeptide shown in SEQ ID No. 1+BSA+Freund's incomplete adjuvant was thoroughly mixed, and four limbs and back were subcutaneously injected at 25. Mu.g/dose, followed by immunization 3 rd after 2 weeks, and the same as 2 nd. Serum antibody titers (1:4000) were determined by indirect ELISA (experimental procedure was as for the pre-milk antibodies) from 7-10 d eyeballs after the 3 rd immunization. Control groups were injected with PBS.
SEQUENCE LISTING
<110> fourth Hospital of university of Hebei medical science, university of Hebei medical science
<120> helicobacter pylori-specific antigenic peptide
<130> 2021
<160> 3
<170> PatentIn version 3.3
<210> 1
<211> 7
<212> PRT
<213> Synthesis
<400> 1
Ala Thr Glu Glu Arg Arg Arg
1 5
<210> 2
<211> 21
<212> DNA
<213> Synthesis
<400> 2
gctacagaag aaaggcgtcg t 21
<210> 3
<211> 435
<212> PRT
<213> Helicobacter pylori
<400> 3
Met Leu Arg Leu Leu Ile Gly Leu Leu Leu Met Ser Phe Ile Ser Leu
1 5 10 15
Gln Ser Ala Ser Trp Gln Glu Pro Leu Arg Val Ser Ile Glu Phe Val
20 25 30
Asp Leu Pro Lys Lys Ile Ile Arg Phe Pro Ala His Asp Leu Gln Val
35 40 45
Gly Glu Phe Gly Phe Val Val Thr Lys Leu Ser Asp Tyr Glu Ile Val
50 55 60
Asn Ser Glu Val Val Ile Ile Ala Val Glu Asn Gly Val Ala Thr Ala
65 70 75 80
Lys Phe Arg Ala Phe Glu Ser Met Lys Gln Ser His Leu Pro Thr Pro
85 90 95
Arg Met Val Ala Arg Lys Gly Asp Leu Val Tyr Phe Arg Gln Phe Asn
100 105 110
Asn Gln Ala Phe Leu Ile Ala Pro Asn Asp Glu Ile Tyr Glu Gln Ile
115 120 125
Arg Ala Thr Asn Thr Asp Ile Asn Phe Ile Ser Ser Asp Leu Leu Val
130 135 140
Thr Phe Leu Asn Gly Phe Asp Pro Lys Ile Ala Asn Leu Arg Lys Ala
145 150 155 160
Cys Asn Val Tyr Ser Val Gly Val Ile Tyr Ile Val Thr Thr Asn Thr
165 170 175
Leu Asn Ile Leu Ser Cys Glu Ser Phe Glu Ile Leu Glu Lys Arg Glu
180 185 190
Leu Asp Thr Ser Gly Val Thr Lys Thr Ser Thr Pro Phe Phe Ser Arg
195 200 205
Val Glu Gly Ile Asp Ala Gly Thr Leu Gly Lys Leu Phe Ser Gly Ser
210 215 220
Gln Ser Lys Asn Tyr Phe Ala Tyr Tyr Asp Ala Leu Val Lys Lys Glu
225 230 235 240
Lys Arg Lys Glu Val Arg Ile Lys Lys Gln Glu Glu Lys Val Asp Ala
245 250 255
Arg Glu Ile Lys Arg Glu Ile Lys Gln Glu Ala Ile Lys Glu Pro Lys
260 265 270
Lys Ala Asn Gln Gly Thr Glu Asn Ala Pro Thr Leu Glu Glu Lys Asn
275 280 285
Tyr Gln Lys Ala Glu Arg Lys Leu Asp Ala Thr Glu Glu Arg Arg Arg
290 295 300
Leu Arg Asp Glu Arg Lys Lys Ala Asn Ala Thr Lys Lys Ala Met Glu
305 310 315 320
Phe Glu Glu Lys Glu Lys Ala His Asp Glu Arg Asp Glu Arg Glu Thr
325 330 335
Glu Glu Arg Arg Lys Ala Leu Gly Met Asp Gln Gly Asn Glu Lys Val
340 345 350
Asn Ala Lys Glu Asn Asp Gln Glu Ile Lys Gln Glu Ala Ile Lys Glu
355 360 365
Pro Ser Asn Glu Asn Asn Ala Thr Gln Gln Gly Glu Asn Lys Leu Asn
370 375 380
Ser Lys Glu Glu Lys Arg Arg Leu Lys Glu Glu Lys Lys Lys Ala Lys
385 390 395 400
Ala Glu Gln Arg Ala Arg Glu Phe Glu Gln Arg Ala Lys Glu Gln Gln
405 410 415
Glu Arg Asp Glu Lys Glu Leu Glu Glu Arg Arg Lys Ala Leu Glu Ala
420 425 430
Gly Lys Lys
435

Claims (3)

1. A helicobacter pylori specific antigen peptide is characterized in that the amino acid sequence is shown as SEQ ID No. 1.
2. A nucleic acid molecule encoding a helicobacter pylori specific antigenic peptide according to claim 1, characterized in that the nucleotide sequence is shown in SEQ ID No. 2.
3. A vector comprising the nucleic acid molecule of claim 2.
CN202210721353.5A 2021-08-25 2022-06-24 Helicobacter pylori specific antigenic peptide Active CN115093468B (en)

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WO2005023851A1 (en) * 2003-09-05 2005-03-17 Karolinska Innovations Ab Plasminogen/plasmin binding polypeptides and nucleic acids therefore
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