CN114395026A - Broad-spectrum antibacterial peptide constructed based on rational design strategy - Google Patents
Broad-spectrum antibacterial peptide constructed based on rational design strategy Download PDFInfo
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- CN114395026A CN114395026A CN202210098946.0A CN202210098946A CN114395026A CN 114395026 A CN114395026 A CN 114395026A CN 202210098946 A CN202210098946 A CN 202210098946A CN 114395026 A CN114395026 A CN 114395026A
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Images
Classifications
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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
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/463—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from amphibians
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- 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
Abstract
The invention discloses a broad-spectrum antibacterial peptide CA-1, the amino acid sequence of which is GLLSVLGSVAKHVLPHVVPVIAEHLWKKLFKK-NH2. The broad-spectrum antibacterial peptide is obtained by modifying natural antibacterial peptide Caerin1.1 from Australian tree frog through rational molecular design by combining the related theoretical knowledge of the existing antibacterial peptide. The antibacterial peptide CA-1 has a broad-spectrum antibacterial effect, has a good inhibition effect on gram-positive bacteria and gram-negative bacteria, and has an antibacterial concentration of 1-8 mug/ml. According to the determination of circular dichroism chromatogram, the antibacterial peptide CA-1 has a negative value absorption peak at 205-220 nm, and can form an alpha helical structure in a TFE solution.
Description
Technical Field
The invention relates to a broad-spectrum antibacterial peptide CA-1, in particular to a broad-spectrum antibacterial peptide CA-1 obtained by modifying a natural antibacterial peptide derived from skin glands of Australian Rana japonica skin gland based on a rational design strategy on a certain theoretical basis by using the natural antibacterial peptide Caerin1.1 as a template, and belongs to the technical field of biomedicine.
Background
By 2050, 1000 million people are expected to die globally from bacterial infections. Traditional antibiotics have remarkable effect on treating bacterial infectious diseases, but due to the abuse of antibiotics, microorganisms have stronger and stronger resistance to the traditional antibiotics, and the appearance of some superbacteria is a great test for public health. There is an urgent need for additional antimicrobial approaches to alleviate the public health concerns associated with microbial resistance. The antibacterial peptide is considered to be the most potential antibiotic substitute due to the excellent characteristics of good antibacterial activity, broad-spectrum antibacterial action, small molecular weight, simple structure, difficult generation of drug resistance and the like, so that the research and development of the antibacterial peptide have very important significance.
The action mechanism of the current antibacterial peptide can be mainly divided into two types: one is interaction with cell membrane, and is bound to cell membrane by electrostatic interaction, so as to destroy the integrity of cell membrane, leak the cell contents such as nucleic acid, protein and ion, or block cell wall synthesis, and the bacteria finally die. Such as the well-known melittin, Cecropin a. The other is to enter the cell interior through membrane permeation, destroy the normal physiological metabolism of the cell, cause dysfunction and inactivate the cell. For example, the bee-derived antibacterial peptide Abaecin passes through cell membranes when exerting an antibacterial effect, enters the interior of cells and is combined with biological functions DnaK and Hsp70 which influence protein folding and ribosome in the interior of bacterial cells. The mechanism influences the normal physiological metabolism and the service function of bacterial cells, indirectly leads to the increase of the permeability of bacterial cell membranes, and triggers the death of bacteria, thereby exerting the bacteriostatic effect. The unique bacteriostasis mechanism of the antibacterial peptide makes the antibacterial peptide not easy to generate drug resistance.
The difference of the cell membranes of prokaryotes and eukaryotes in the composition of phospholipid is utilized, so that the antibacterial peptide has selective toxicity and can have toxic action on external pathogenic bacteria without damaging host cells. The peptidoglycan layer in the cell wall of gram-positive bacteria is thick and contains negatively charged teichoic acid. Gram-negative bacteria contain negatively charged Lipopolysaccharide (LPS) in their cell walls, and negatively charged phospholipid substances such as Phosphatidylglycerol (PG), Cardiolipin (CL), and Phosphatidylserine (PS) are present in both cell membranes. Is favorable for electrostatic interaction with the antibacterial peptide with positive electricity, so that the antibacterial peptide can be adsorbed on the surface of bacteria. And the phospholipids on the mammalian cell membrane mainly comprise neutral Phosphatidylcholine (PC), Phosphatidylethanolamine (PE) and Sphingomyelin (SM). The phospholipids are asymmetrically distributed, the zwitterionic phospholipids are distributed in the outer layer, and the negatively charged phospholipids of the head group are in the inner layer and face the cytoplasm. It acts with antimicrobial peptides primarily through hydrophobic interactions, which are weaker than electrostatic interactions. The membrane surface contains cholesterol capable of keeping a phospholipid bilayer stable. These factors are the basis of the selectivity of the antibacterial peptide, so that the antibacterial peptide has good antibacterial effect and has little or no toxicity to mammalian cells within a certain concentration range.
Disclosure of Invention
The invention aims to provide a broad-spectrum strong antibacterial peptide CA-1 constructed based on a rational design strategy aiming at the defects of the prior art.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention firstly provides a broad-spectrum antibacterial peptide CA-1, the amino acid sequence of which is as follows: Gly-Leu-Leu-Ser-Val-Leu-Gly-Ser-Val-Ala-Lys-His-Val-Leu-Pro-His-Val-Val-Pro-Val-Ile-Ala-Glu-His-Leu-Trp-Lys-Lys-Leu-Phe-Lys-Lys-NH2Expressed in single letter as GLLSVLGSVAKHVLPHVVPVIAEHLWKKLFKK-NH2。
Further, the broad-spectrum antibacterial peptide CA-1 is obtained by rational molecular design based on a natural antibacterial peptide Caerin1.1 derived from skin glands of Australian Rana japonica; wherein the amino acid sequence of the natural antibacterial peptide Caerin1.1 is as follows: Gly-Leu-Leu-Ser-Val-Leu-Gly-Ser-Val-Ala-Lys-His-Val-Leu-Pro-His-Val-Val-Pro-His-Val-Pro-Val-Ile-Ala-Glu-His-Leu-NH2Expressed in single letter as GLLSVLGSVAKHVLPHVVPVIAEHL-NH2。
Furthermore, the broad-spectrum antibacterial peptide CA-1 has the molecular weight of 3543.34 and the charge amount of + 4.
The invention also provides application of the broad-spectrum antibacterial peptide CA-1 in preparing broad-spectrum antibacterial medicaments for treating gram-positive bacteria and gram-negative bacteria infection.
Specifically, the antibacterial peptide CA-1 has a strong broad-spectrum antibacterial activity, and shows good antibacterial activity on 19 strains such as Escherichia coli ATCC 8739, Escherichia coli ATCC 25922, Escherichia coli ATCC 8099, Escherichia coli CMCC 44102, Salmonella typhimurium CICC 51005, Fusobacterium formosanum CMCC 51571, Vibrio parahaemolyticus ATCC 17802, Pseudomonas fluorescens ATCC 13525, Enterobacter sakazakii ATCC 29544, Salmonella choleraesuis CICC 13312, Staphylococcus aureus ATCC6538, Staphylococcus aureus ATCC29213, Staphylococcus aureus ATCC12600, Staphylococcus aureus ATCC25923, Staphylococcus aureus CMCC (B)26003, methicillin-resistant Staphylococcus aureus N315, Bacillus cereus CMCC63301, Micrococcus luteus CMCC28001, Bacillus pumilus CMCC63202 and the like.
The invention has the advantages that:
the invention takes natural antimicrobial peptide Caerin1.1 from skin gland of Australian tree frog as a template, and carries out rational design and modification on the template on the basis of a certain theory to obtain the novel antimicrobial peptide CA-1. The antibacterial peptide CA-1 contains 4 positive charge amino acids and 13 hydrophobic amino acids, and has an absorption peak at 205-220 nm as determined by circular dichroism chromatography, and an alpha helical structure is formed in a TFE solution. Due to strong hydrophobicity, the antibacterial peptide CA-1 can be combined with a hydrophobic region of a phospholipid molecule in a bacterial cell membrane, so that the bacterial cell membrane is damaged to play a bactericidal effect.
Description of the drawings:
FIG. 1: the helix diagram and the three-dimensional structure diagram of the antibacterial peptide CA-1 and the Caerin1.1. A, helix structure diagram of Caerinn 1.1; b, a spiral structure diagram of CA-1; c, simulating a three-dimensional structure diagram of the Caerinn 1.1; d, a simulated three-dimensional structural diagram of CA-1.
FIG. 2: high performance liquid chromatogram of antibacterial peptide CA-1.
FIG. 3: liquid chromatography mass spectrometry of antimicrobial peptide CA-1 is combined with the figure.
FIG. 4: circular dichroism chromatogram of antibacterial peptide CA-1 in TFE solution.
FIG. 5: cytotoxicity of antimicrobial peptide CA-1 to Caco-2.
The specific implementation case is as follows:
in order to make the present invention more comprehensible, the technical solutions of the present invention are further described below with reference to specific embodiments, but the following examples are only examples of the present invention and do not represent the scope of the present invention defined by the claims.
Example 1
The invention modifies natural antibacterial peptide Caerin1.1 on the basis of the existing theory so as to improve the antibacterial activity and reduce the cytotoxicity of the antibacterial peptide.
The Caerin1.1 is an antibacterial peptide separated from mucus secreted by skin glands of Rana catesbeiana, the antibacterial peptide has the charge of 0 and higher hydrophobicity of 0.734, and the amino acid sequence is as follows: GLLSVLGSVAKHVLPHVVPVIAEHL-NH2And the proline residue at position 15/19 in the sequence has a great influence on the antibacterial activity of the antibacterial peptide, which can affectThe alpha helix structure of the antimicrobial peptide. The antibacterial peptide Caerin1.1 does not exert a bacteriostatic action through a membrane rupture mechanism, but penetrates through a cell membrane to destroy the physiological process in bacteria, so that the bacteria die and the bactericidal effect is achieved. In previous researches, it is found that the removal of the 5 amino acid sequence at the terminal of the antibacterial peptide Caerin1.1 does not affect the bacteriostatic activity of the antibacterial peptide Caerin1.1. On the basis, the Cecropin A sequence (WKKLFKK) is spliced on the original antibacterial peptide Caerin1.1, the Cecropin A is a famous peptide which plays a role in bacteriostasis through a membrane rupture mechanism, the two peptides of the Caerin1.1 and the Cecropin A are expected to be combined with the completely different bacteriostasis characteristics, the membrane penetration capacity of the antibacterial peptide is improved on the basis of not damaging the original antibacterial activity, a novel antibacterial peptide CA-1 with stronger antibacterial activity is designed, and certain properties of the antibacterial peptide CA-1 are predicted through prediction websites, such as physicochemical properties: antibiotic Peptide Database-DBAASP, secondary structure: home | PBIL (ibcp. fr), spirogram: https:// www.donarmstrong.com/cgi-bin/wheel. pl, 3D structural prediction: the Yang Zhang Lab (zhangggroup. org). The predicted results are as follows (table 1): from the prediction result of physicochemical properties, the charge amount of the antibacterial peptide CA-1 is greatly improved compared with that of Caerinn 1.1; from the view of the helix structure (fig. 1), the hydrophobicity and amphiphilicity of CA-1 are lower compared to that of cairin 1.1, but it can be seen that the reason for the decrease of amphiphilicity is that the terminally spliced segment carries more charges, that is, one end of the antibacterial peptide CA-1 with the charges mainly concentrated, which may make the antibacterial peptide CA-1 adsorbed on the bacterial cell membrane at one end by electrostatic interaction, and the other end destroys the bacterial cell membrane by hydrophobic interaction, thereby enhancing the bacteriostatic effect. The prediction result shows that the secondary structure of the antibacterial peptide CA-1 is mainly alpha helical structure, alpha helical structures are formed at two ends of the antibacterial peptide, and the middle part of the antibacterial peptide is a random coil structure.
TABLE 1 prediction of physicochemical Properties of antimicrobial peptides CA-1 and Caerin1.1
Example 2
The antimicrobial peptide CA-1 was synthesized by Gill Biochemical company (Shanghai). The method adopts a solid phase chemical synthesis method, the polypeptide is purified to the purity of more than 95 percent through reversed phase high performance liquid chromatography, and the amino acid sequence of the polypeptide is further identified through electrospray mass spectrometry to obtain the molecular weight of 3543.34, the prediction result of the amino acid sequence and the designed sequence GLLSVLGSVAKHVLPHVVPVIAEHLKKFLKKW-NH of the antibacterial peptide CA-12And (4) the same.
The chromatographic conditions are as follows: the chromatographic column is 4.6X 250 mm, Kromasil C185 um; liquid chromatography conditions: mobile phase: and (B) pump A: trifluoroacetic acid acetonitrile solution with volume percentage of 0.1%, B pump: 0.1% by volume of aqueous trifluoroacetic acid solution. The flow rate is 1 ml/min; the sample injection amount is 5 mu L; the detection wavelength is 220 nm; elution time: 30 min; the elution mode is gradient elution: the sample amount at the beginning is 36% A +64% B, the sample amount at 25.0min is 61% A +39% B, the sample amount at 25.1min is 100% A +0% B, and the method is stopped when the sample amount is maintained for 30 min. The HPLC chromatogram of antibacterial peptide CA-1 is shown in FIG. 2.
The mass spectrum conditions are as follows: mobile phase: water: acetonitrile =1:1, nebulizer gas flow: 1.5L/min, sample size: 0.2ml/min, the CDL and Block temperatures were 250 ℃ and 400 ℃ respectively. The antibacterial peptide CA-1 liquid chromatogram mass spectrum is shown in figure 3.
Example 3
And (3) determining the secondary structure of the antibacterial peptide CA-1.
And (3) determining the secondary structure of the antibacterial peptide CA-1 by adopting a circular dichroism method. The antibacterial peptide CA-1 is dissolved in sterile water, and the sample and trifluoroethanol (Aladdin) are mixed uniformly in a volume ratio of 1:1, so that the final concentration of the antibacterial peptide CA-1 is 128 mug/mL. The circular dichroism spectrum (lambda 190-250 nm) of the antibacterial peptide CA-1 is determined by adopting J-1500 spectropolimeter (Jasco, Tokyo, Japan), the optical path is 0.1 cm, the temperature is 25 ℃, and the frequency is 50 nm/min. 3 replicates were measured. The results are shown in FIG. 4. The antibacterial peptide CA-1 forms a negative peak at 205-220 nm, and the CA-1 is an alpha helical structure, which has great influence on the antibacterial activity of the antibacterial peptide CA-1.
Example 4
And (3) measuring the bacteriostatic activity of the antibacterial peptide CA-1.
Minimum Inhibitory concentration (Minimum Inhibitory Con)center) measurement: escherichia coli ATCC 8739, Escherichia coli ATCC 25922, Escherichia coli ATCC 8099, Escherichia coli CMCC 44102, Salmonella typhimurium CICC 51005, Shigella flexneri CMCC 51571, Vibrio parahaemolyticus ATCC 17802, Pseudomonas fluorescens ATCC 13525, Enterobacter sakazakii ATCC 29544, Salmonella choleraesuis CICC 13312, Staphylococcus aureus ATCC6538, Staphylococcus aureus ATCC29213, Staphylococcus aureus ATCC12600, Staphylococcus aureus ATCC25923, Staphylococcus aureus CMCC (B)26003, methicillin-resistant Staphylococcus aureus N315, Bacillus cereus CMCC63301, Micrococcus luteus CMCC28001, Bacillus pumilus CMCC63202, 19 strains were selected as indicator bacteria. Inoculating the strains stored in the frozen tube into MHB liquid culture medium one by one for activation culture, culturing in a shaking table at 37 ℃ and a rotating speed of 180 r/min to logarithmic phase, transferring the activated strains to fresh MHB liquid culture medium for secondary culture, performing shake culture in the shaking table at 37 ℃ to logarithmic phase, and then diluting the strain culture solution cultured to logarithmic phase to 1 × 10 with the fresh MHB liquid culture medium5cfu/ml is ready for use.
Adding 90 mu l of MHB liquid culture medium and 10 mu l of 2560 mu g/ml of antimicrobial peptide CA-1 into the first column of a 96-well plate, adding 2-9 into 50 mu l of culture medium, uniformly mixing the first column, sucking 50 mu l of mixed liquid of the MHB liquid culture medium and the CA-1 into the second column, continuously and uniformly mixing the second column, removing 50 mu l of sample into the third column, and repeating the steps until the third column reaches 9; and adding the diluted bacterial liquid into 2-9 rows in an addition amount of 50 mul. Column 10 was blanked with 100. mu.l of MHB broth. In column 11, 100. mu.l of the bacterial suspension was added as a positive control.
Finally, the 96-well plate was placed in an incubator at 37 ℃ and incubated overnight for 12 hours with slow shaking, and the light absorption was measured at a wavelength of 600 nm. The minimum inhibitory concentration is the lowest sample concentration at which no bacterial growth is visible. The results are shown in Table 2.
According to the literature (FERANDEZ D I, GEHMAN J D, SEPAROVIC F. Membrane interactions of antimicrobial peptides from Australian proteins, 2009, 1788(8): 1630-. As can be seen from Table 2, the antibacterial peptide CA-1 obtained by modification shows extremely strong antibacterial activity, the MIC for gram-positive bacteria is 2-4 mug/ml, the MIC for gram-negative bacteria is 1-8 mug/ml, and compared with the original antibacterial peptide Caerin1.1, the antibacterial activity of the antibacterial peptide CA-1 is obviously improved.
TABLE 2 antibacterial Activity of antibacterial peptide CA-1
Example 5
The cytotoxicity of the antimicrobial peptide CA-1 was determined.
The cytotoxicity of the antibacterial peptide CA-1 is determined by adopting an MTT method, and the specific steps are as follows:
plate paving: digesting the caco-2 cells in logarithmic phase with 0.25% pancreatin, washing with PBS buffer (0.01M, pH 7.2), centrifuging (2000 r/min, centrifuging for 3 min), collecting the cells, making into cell suspension, and adjusting the concentration to 1 × 10 by cell counting method5 Per ml; aspirate the cell suspension into a 96-well plate (100. mu.l/well) and place in a cell incubator at 37 ℃ C, CO2Culturing for 24 h under the conditions of concentration of 5% and humidity of 95%.
Sample adding: the pre-prepared 96-well plate was removed from the incubator, the old cell culture medium was aspirated, and 90. mu.l of fresh cell culture medium was added. Column 1 was blanked with 100. mu.l PBS buffer (0.01M, pH 7.2). Antimicrobial peptide CA-1 samples were diluted with PBS buffer (0.01M, pH 7.2) to concentrations of 128, 64, 32, 16, 8, 4, 2, 1. mu.g/ml, with a sample addition of 10. mu.l per well, with 5 sets of replicates for each concentration. The 96-well plate was then placed in an incubator for further 24 h.
Adding MTT: mu.l MTT with a concentration of 5 mg/mL was added to each well in the dark and placed in the incubator for further incubation for 4 h.
Terminating the culture, dissolving and crystallizing: sucking out the culture medium from the well plate, adding 150 μ l dimethyl sulfoxide, incubating in metal bath at 37 deg.C and 600 r/min for 10 min to dissolve the crystal, and performing OD detection in an ELISA detector570The absorbance of each well was measured at nm. The results are shown in FIG. 5.
SEQUENCE LISTING
<110> Fuzhou university
<120> broad-spectrum antibacterial peptide constructed based on rational design strategy
<130>
<160> 2
<170> PatentIn version 3.3
<210> 1
<211> 32
<212> PRT
<213> Artificial sequence
<400> 1
Gly Leu Leu Ser Val Leu Gly Ser Val Ala Lys His Val Leu Pro His
1 5 10 15
Val Val Pro Val Ile Ala Glu His Leu Trp Lys Lys Leu Phe Lys Lys
20 25 30
<210> 2
<211> 25
<212> PRT
<213> Artificial sequence
<400> 2
Gly Leu Leu Ser Val Leu Gly Ser Val Ala Lys His Val Leu Pro His
1 5 10 15
Val Val Pro Val Ile Ala Glu His Leu
20 25
Claims (3)
1. A broad-spectrum antibacterial peptide CA-1, which is characterized in that: the amino acid sequence is as follows: Gly-Leu-Leu-Ser-Val-Leu-Gly-Ser-Val-Ala-Lys-His-Val-Leu-Pro-His-Val-Val-Pro-Val-Ile-Ala-Glu-His-Leu-Trp-Lys-Lys-Leu-Phe-Lys-Lys-NH2Expressed in single letter as GLLSVLGSVAKHVLPHVVPVIAEHLWKKLFKK-NH2。
2. The broad spectrum antimicrobial peptide CA-1 of claim 1, wherein: the broad-spectrum antibacterial peptide CA-1 is obtained by rational molecular design based on a natural antibacterial peptide Caerin1.1 derived from skin glands of Rana temporaria chensinensis David, wherein the amino acid sequence of the natural antibacterial peptide Caerin1.1 is as follows: Gly-Leu-Leu-Ser-Val-Leu-Gly-Ser-Val-Ala-Lys-His-Val-Leu-Pro-His-Val-Val-Pro-His-Val-Pro-Val-Ile-Ala-Glu-His-Leu-NH2Expressed in single letter as GLLSVLGSVAKHVLPHVVPVIAEHL-NH2。
3. The use of the broad-spectrum antibacterial peptide CA-1 of claim 1 in the preparation of a broad-spectrum antibacterial medicament for treating gram-positive and gram-negative bacterial infections.
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| WO2023142449A1 (en) * | 2022-01-27 | 2023-08-03 | 福州大学 | Broad-spectrum antibacterial peptide constructed on basis of rational design strategy |
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