CN111574619B - Lipopeptide Lin-Lf4NH2And Lin-Lf5NH2And uses thereof - Google Patents
Lipopeptide Lin-Lf4NH2And Lin-Lf5NH2And uses thereof Download PDFInfo
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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
- C07K14/79—Transferrins, e.g. lactoferrins, ovotransferrins
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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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- 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
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Abstract
The invention provides a novel lipopeptide Lin-Lf4NH2And Lin-Lf5NH2And applications thereof. Lipopeptide Lin-Lf4NH2/Lin‑Lf5NH2Is obtained by coupling linoleic acid at the N end of antibacterial peptide LfcinB4/LfcinB5 and amidating modification at the C end. Experiments show that the lipopeptide Lin-Lf4NH2And Lin-Lf5NH2Has better inhibiting effect on gram-positive bacteria and gram-negative bacteria, has smaller MIC value than parent peptide, has good thermal stability, can obviously reduce the skin bacterial load and lighten the skin tissue damage in a mouse skin abscess model test, and has the inhibiting effect on gram-positive bacteria and gram-negative bacteria compared with Lf4NH2And Lf5NH2Better treatment effect, is the micromolecular lipopeptide with great application value, can be used for preparing novel antibacterial and anti-infective medicaments and the like, and has wide application prospect.
Description
Technical Field
The invention relates to the technical field of biology, in particular to lipopeptide Lin-Lf4NH2And Lin-Lf5NH2And applications thereof.
Background
Lactoferricin (Lfcin for short) is a segment of multifunctional antibacterial peptide released from the N-terminal of lactoferrin under the action of pepsin in an acidic environment (Gifford et al, 2005), and Lfcin is closely related to the function of lactoferrin, contains most functional domains of lactoferrin, and has strong antibacterial, anticancer, antiviral, antiparasitic and anti-inflammatory activities (Hao et al, 2018). In many cases, Lfcin not only retains the activity of lactoferrin, but is even more potent than the parent protein (Arias et al, 2014). LfcinB, which consists of amino acid residues 17-41 of bovine lactoferrin, is considered to be the most effective of the various Lfcins in cows, mice and goats (Bruni et al, 2016; Ulvatne et al, 2001). The rapid increase in bacterial resistance poses a serious challenge to antibiotics, and compared to traditional antibiotics, because antibacterial peptides have stronger antibacterial activity and different antibacterial mechanisms, are not easy to form resistance, and have the potential to become future antibacterial drugs (Andersson et al, 2016; Seo et al, 2012). However, clinical treatment and application of antibacterial peptides still have problems, and in order to improve the antibacterial activity of Lfcins, develop new functions and resist the emergence of drug-resistant bacteria, various molecular design strategies including amino acid substitution, chemical modification, cyclization, chimerization, polymerization and the like are needed (Hao et al, 2018; Yin et al, 2014).
Disclosure of Invention
The invention aims to provide a novel lipopeptide Lin-Lf4NH2And Lin-Lf5NH2And applications thereof.
The invention has the following conception: in order to further improve the antibacterial activity of polypeptides LfcinB4 and LfcinB5, the N ends of LfcinB4 and LfcinB5 are coupled with linoleic acid, and the C ends of the LfcinB4 and the LfcinB5 are subjected to amidation modification to obtain two lipopeptides Lin-Lf4NH2And Lin-Lf5NH2. Then, Lin-Lf4NH2And Lin-Lf5NH2The antibacterial activity, toxicity and in-vivo efficacy are evaluated, and a theoretical basis is provided for the creation of novel antibacterial drugs.
In order to achieve the object, the invention provides, in a first aspect, a lipopeptide Lin-Lf4NH2The antibacterial peptide is obtained by coupling linoleic acid at the N end of antibacterial peptide LfcinB4 and modifying the C end through amidation. The sequence is as follows: (Linoleic acid) -FKAWRWAWRWKKLAAPS-NH2(SEQ ID NO:1)。
Lipopeptide Lin-Lf4NH2The structure of (A) is shown as formula (I):
in a second aspect, the invention provides the lipopeptide Lin-Lf5NH2Lipopeptide Lin-Lf5NH2Is obtained by coupling linoleic acid at the N end of antibacterial peptide LfcinB5 and amidating and modifying the C end. The sequence is as follows: (Linoleic acid) -FKAFRWAWRWKKLAAPS-NH2(SEQ ID NO:2)。
Lipopeptide Lin-Lf5NH2The structure of (A) is shown as formula (II):
in a third aspect, the present invention provides a lipopeptide-containing Lin-Lf4NH2And/or the lipopeptide Lin-Lf5NH2The broad spectrum antibacterial drug or composition of (1).
In a fourth aspect, the present invention provides a polypeptide comprising the lipopeptide Lin-Lf4NH2And/or the lipopeptide Lin-Lf5NH2A preservative, bactericide or surfactant.
In a fifth aspect, the invention provides the lipopeptide Lin-Lf4NH2And/or the lipopeptide Lin-Lf5NH2Any of the following uses:
1) for the preparation of an antibacterial medicament or composition;
2) for the preparation of preservatives;
3) is used for preparing bactericide;
4) is used for preparing the surfactant.
The bacteria include gram positive bacteria and gram negative bacteria. Preferably including Staphylococcus (Staphylococcus), Escherichia (Escherichia), Salmonella (Salmonella) bacteria. More preferably, Staphylococcus suis (Staphylococcus hyicus), Staphylococcus aureus (Staphylococcus aureus), Escherichia coli (Escherichia coli), Salmonella pullorum (Salmonella pullorum), and Salmonella enteritidis (Salmonella enteritidis).
By the technical scheme, the invention at least has the following advantages and beneficial effects:
lipopeptide Lin-Lf4NH of the invention2And Lin-Lf5NH2Is artificially designed and synthesized active polypeptide, which comprises 17 amino acid residues and has 5 positive charges, the N end is coupled with linoleic acid, the C end is amidated and modified, and the molecular weights are 2450.09 Da and 2411.05Da respectively. With the parent peptide Lf4NH2And Lf5NH2In contrast, Lin-Lf4NH2And Lin-Lf5NH2Has higher antibacterial activity and thermal stability, and has little cytotoxicity in a low concentration range.
Experiments show that the lipopeptide Lin-Lf4NH2And Lin-Lf5NH2The peptide has better inhibition effect on gram-positive bacteria and gram-negative bacteria, has a smaller MIC value than that of parent peptide, has good thermal stability, can obviously reduce the skin bacterial load and relieve skin tissue damage in a mouse skin abscess model test, has better effect than that of the antibiotic mupirocin, is a micromolecular lipopeptide with high application value, can be used for preparing novel antibacterial anti-infective drugs and the like, and has wide application prospect.
Drawings
FIG. 1 shows the lipopeptide Lin-Lf4NH of the present invention2And Lin-Lf5NH2Mass spectrum of (2).
FIG. 2 shows the lipopeptide Lin-Lf4NH in example 3 of the present invention2And Lin-Lf5NH2The cytotoxicity of (a).
FIG. 3 shows the lipopeptide Lin-Lf4NH in example 5 of the present invention2And Lin-Lf5NH2The mouse skin charge after treatment of (1).
FIG. 4 shows the lipopeptide Lin-Lf4NH in example 5 of the present invention2And Lin-Lf5NH2After treatment mice skin tissue sections.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art, and the raw materials used are commercially available products.
Experimental materials used in the following examples: MEM high-sugar cell culture fluid, trypsin digestion fluid, PBS for cells, fetal bovine serum and streptomycin mixture were purchased from Gibco, USA, ELISA plate and sterile 96-well culture plate were purchased from Thermo Scientific, antibiotic 2% mupirocin ointment was purchased from China veterinary medicine institute, human immortalized epidermal cells (Hacat) were purchased from Beijing collaborating Hospital, and six-week-old SPF-grade BALB/c mouse Beijing Wintolite laboratory animals Co. Other conventional reagents are imported and subpackaged or domestic analytically pure.
Media and buffer formulations referred to in the following examples:
MH liquid medium: dissolving 2.4g in 80mL of distilled water, dissolving completely, diluting to 100mL, and autoclaving at 121 deg.C for 20 min.
MH solid medium: dissolving 3.65g in 80mL of distilled water, dissolving completely, diluting to 100mL, and autoclaving at 121 deg.C for 20 min.
Cell complete culture solution: 10% fetal bovine serum, 100U/mL streptomycin (diabody), 90% MEM high sugar base medium.
PBS phosphate buffer: 4.25g of NaCl, KH2PO4 0.12g，Na2HPO4Dissolving 1.825g and KCl 0.1g in distilled water, dissolving completely, diluting to 500mL, and autoclaving at 121 deg.C for 20 min.
The species referred to in the following examples are shown in table 1:
TABLE 1 strains and sources
Example 1 lipopeptide Lin-Lf4NH2And Lin-Lf5NH2Design and synthesis of
The amino acid sequences of the polypeptides LfcinB4 and LfcinB5 are respectively shown in SEQ ID NO 1 and 2, and the structures of the two polypeptides are respectively optimized and designed in order to further improve the antibacterial activity of LfcinB4 and LfcinB 5.
Dissolving Fmoc-Phe-OH, HOBT, HBTU and DIEA in DMF, mixing uniformly, and carrying out condensation reaction with the MBHA resin with the Fmoc protecting group removed to obtain Fmoc-Phe-resin; sequentially condensing subsequent amino acids according to the same method to respectively obtain Fmoc-Lf4-resin and Fmoc-Lf5-resin, and removing side chain protecting groups by DCM solution containing 1% by volume fraction of TFA to obtain Lf4NH2-resin and Lf5NH2-a resin; respectively adding fatty acid LDissolving in, HOBT, HBTU and DIEA in DMF, mixing, and mixing with Lf4NH2-resin、Lf5NH2Carrying out condensation reaction on-resin to obtain Lin-Lf4NH2-resin、Lin-Lf5NH2-a resin; mixing Lin-Lf4NH2、Lin-Lf5NH2Cutting from resin, purifying to obtain fatty acid modified antibacterial peptide Lin-Lf4NH2And Lin-Lf5NH2。
Purity of synthetic peptide measured by reverse phase high performance liquid chromatography C18 column>95%), ESI-MS Mass Spectrometry confirmation of Lin-Lf4NH2And Lin-Lf5NH2Molecular weight of (1).
Example 2 lipopeptide Lin-Lf4NH2And Lin-Lf5NH2Detection of antibacterial Activity
The antibacterial peptide and lipopeptide obtained according to example 1 (Lf4 NH)2,Lf5NH2,Lin-Lf4NH2And Lin-Lf5NH2) Antimicrobial peptide solutions with a concentration of 2560. mu.g/mL were prepared with ultrapure water, diluted 2-fold to a final concentration of 2. mu.g/mL, and antimicrobial peptide solutions of different concentrations were added to sterile 96-well cell culture plates, 10. mu.L per well, three replicates per sample, with the same amount (10. mu.L) of PBS as a negative control and a blank control of sterile MH medium. MIC plates were prepared. The strain is cultured in MH culture medium, and is subjected to shaking culture at 37 ℃ until the logarithmic growth phase (OD)600nm0.4-0.6), preparing the bacterial liquid into bacterial suspension with the concentration equivalent to 0.5 McLeod turbidity standard, and diluting the bacterial suspension to 10 ℃ by using a sterile MH liquid culture medium incubated at 37 DEG C5And after CFU/mL, adding 90 mu L of bacterial suspension into each prepared MIC plate sample hole, incubating at the constant temperature of 37 ℃ for 16-18h until obvious turbid bacterial liquid visible to the naked eye appears in the negative control hole, wherein the lowest concentration capable of completely inhibiting the bacterial growth is the MIC value of the peptide to the tested strain. And if the hole jumping or the result inconsistency among the parallel samples occurs, retesting. Three replicates were processed each. Minimum Inhibitory Concentration (MIC) determination was made with reference to the broth microdilution method established by Tian et al, with minor modifications as the case may be (Tian et al, 2009).
The results are shown in Table 2, where the lipopeptide Lin-Lf4NH2And Lin-Lf5NH2Has broad-spectrum antibacterial activity. The MIC value for gram-positive bacteria staphylococcus aureus and staphylococcus suis was 3.27-6.64 mu M, superior to the parent peptide Lf4NH2And Lf5NH2(7.31-59.57. mu.M). The MIC value of the salmonella strain to gram-negative bacteria is 3.27 to 3.32 mu M and is superior to that of the parent peptide Lf4NH2And Lf5NH2(7.31-14.89. mu.M), which indicates that the lipopeptide Lin-Lf4NH2And Lin-Lf5NH2Shows different degrees of bacteriostatic effects on gram-positive bacteria and gram-negative bacteria.
TABLE 2 MIC value determination of antimicrobial peptides and lipopeptides
Example 3 lipopeptide Lin-Lf4NH2And Lin-Lf5NH2Cell toxicity test of
MTT method for detecting antibacterial peptide and lipopeptide (Lf4 NH)2，Lf5NH2，Lin-Lf4NH2And Lin-Lf5NH2) And is cytotoxic to Hacat cells. MTT can be reduced to insoluble blue-violet crystalline formazan by succinate dehydrogenase in mitochondria of living cells, deposited in cells, while dead cells do not. DMSO can dissolve blue-purple formazan crystal in cells, and the number of living cells can be indirectly reflected by the absorbance of the solution after the dissolution. Within a certain range of cell number, the amount of crystal formation is directly proportional to the number of cells.
37℃，5％CO2And saturated humidity conditions, Hacat cells were cultured in MEM complete medium. Cells were blown on with a pipette, suspended in MEM in complete medium and 2.5 × l05cells/mL density were seeded in 96-well plates at 100. mu.L per well in 3 replicates. After 24h the medium was removed and 100. mu.L of sample peptide at 1, 2, 4, 8, 16, 32, 64, 128, 256. mu.g/mL was added to each well in a concentration gradient and an equal amount of PBS solution was added to the control wells. After a further 24h incubation, the medium was removed, washed twice with PBS and 100. mu.L of MTT at a concentration of 5mg/mL was added to each well (protected from light). The 96-well plate was moved to an incubator for further 4 h. And (3) discarding the MTT solution, adding 150 mu L DMSO into each well, oscillating for 10min by an oscillator, and measuring the absorbance of each well at the wavelength of 570nm after the crystals at the bottom of the well are completely dissolved. Cell viability was calculated according to the following formula: survival (%) — treated group OD value/control groupOD value × 100% (Li et al, 2017).
The results are shown in FIG. 2, where the lipopeptide Lin-Lf4NH2And Lin-Lf5NH2There was almost no cytotoxicity in the low concentration range of 1-16. mu.g/mL.
Example 4 lipopeptide Lin-Lf4NH2And Lin-Lf5NH2Thermal stability test of
Incubating the sample peptide solution at 4 deg.C, 20 deg.C, 40 deg.C, 60 deg.C, 80 deg.C and 100 deg.C for 1h, cooling, and collecting 10 μ L sample peptide and 90 μ L log phase (10 μ L log phase)5CFU/mL) of Staphylococcus suis NCTC10350, the negative control group was a test bacterial liquid in which PBS was used instead of antibacterial peptide, and the blank control group was a sterile MH medium. Three replicates were processed each. The culture plate is placed at 37 ℃ and incubated for 16-18h at constant temperature until visible obvious turbid bacterial liquid appears in the negative control hole, and the MIC change condition of the peptide after different temperature treatment is observed (Chen et al, 2017).
The results are shown in Table 3, and the lipopeptide Lin-Lf4NH was obtained under different temperature conditions2And Lin-Lf5NH2The MIC value of (A) was unchanged, indicating that it had good thermal stability.
TABLE 3 MIC values of antimicrobial peptides and lipopeptides after treatment at different temperatures
Example 5 lipopeptide Lin-Lf4NH2And Lin-Lf5NH2Therapeutic effect on mouse skin abscess induced by staphylococcus suis
SPF-grade BALB/c mice (15 g/mouse) at 6 weeks of age, the mice were randomly divided into 7 groups of 15 mice each, abdominal hairs of the mice were shaved off with a razor, and Staphylococcus suis NCTC10350 (7.5X 10) was subcutaneously injected in log phase of growth8CFU/mL, 200. mu.L/single). After 48h of infection, the abdominal skin of the mice developed abscesses. The mice were anesthetized and subsequently treated with the peptide Lf4NH2,Lf5NH2,Lin-Lf4NH2And Lin-Lf5NH2(concentration is 10mg/mL) is applied to the abscess part of the mouse twice a day, and the abscess part is taken to be homogenized after seven continuous days of observation to measure the skin loadAnd observing skin tissue sections. Uninfected mice served as blank control group with buffer only (10% Na)3PO445% PEG and 45% glycerol) and 2% Mupirocin (Mupirocin) were used as negative and positive controls, respectively.
The results are shown in FIGS. 3 and 4, Lin-Lf4NH2(percentage of reduction in the amount of bacteria-carrying capacity: 28.13%) and Lin-Lf5NH2(the percentage of reduction of the bacterial load is 33.07 percent), can obviously reduce the bacterial load of the skin of the abscess of the mouse, and is better than Lf4NH2(percentage of reduction in bacterial load of 18.77%), Lf5NH2(percentage reduction in the amount of charged bacteria was 18.93%) and the antibiotic mupirocin (percentage reduction in the amount of charged bacteria was 24.93%). In addition, the lipopeptide Lin-Lf4NH was observed from mouse skin tissue sections2And Lin-Lf5NH2Can remarkably reduce skin tissue damage. These results indicate that the lipopeptide Lin-Lf4NH2And Lin-Lf5NH2The external treatment effect on a mouse abscess model is better than that of the parent peptide Lf4NH2And Lf5NH2。
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Reference documents:
1.Gifford,J.L.,Hunter,H.N.,Vogel，H.J.,2005a.Lactoferricin.Cellular and Molecular Life Sciences 62,2588.
2.Arias,M.,McDonald,L.J.,Haney,E.F.,Nazmi,K.,Bolscher,J.G.M.,Vogel,H.J.,2014.Bovine and human lactoferricin peptides:chimeras and new cyclic analogs.Biometals:an international journal on the role of metal ions in biology， biochemistry，and medicine 27，935-948.
3.Bruni，N.,Capucchio，M.T.，Biasibetti，E.,Pessione,E.,Cirrincione,S.,Giraudo,L.,Corona，A.，Dosio，F.，2016. Antimicrobial Activity of Lactoferrin-Related Peptides and Applications in Human and Veterinary Medicine.Molecules 21.
4.Ulvatne，H.,Haukland,H.H.,Olsvik,O.,Vorland,L.H.,2001.Lactoferricin B causes depolarization of the cytoplasmic membrane of Escherichia coli ATCC 25922and fusion of negatively charged liposomes.FEBS letters 492,62-65.
5.Andersson，D.I.，Hughes，D.，Kubicek-Sutherland，J.Z.，2016.Mechanisms and consequences of bacterial resistance to antimicrobial peptides.Drug resistance updates:reviews and commentaries in antimicrobial and anticancer chemotherapy 26, 43-57.
6.Seo,M.D.,Won，H.S.，Kim，J.H.，Mishig-Ochir,T.,Lee,B.J.,2012.Antimicrobial peptides for therapeutic applications: a review.Molecules 17,12276-12286.
7.Yin,C.,Wong，J.H.,Ng,T.B.，2014.Recent studies on the antimicrobial peptides lactoferricin and lactoferrampin. Current molecular medicine 14,1139-54.
8.Tian Z.,Dong T.,Yang Y.,Teng,D.,Wang,J.,2009.Expression of antimicrobial peptide LH multimers in Escherichia coli C43(DE3).Appl Microbiol Biotechnol,2009,83(1):143-149.
9.Li,Z.，Mao，R.，Teng，D.,Hao，Y.，Chen，H.，Wang，X.，Wang，X.，Yang，N.,Wang,J.,2017.Antibacterial and immunomodulatory activities of insect defensins-DLP2 and DLP4 against multidrug-resistant Staphylococcus aureus.Sci Rep 7,12124.
10.Chen，H.，Mao，R.，Teng，D.,Wang，X.,Hao,Y.,Feng,X.,Wang,J.,2017.Design and pharmacodynamics of recombinant NZ2114 histidine mutants with improved activity against methicillin-resistant Staphylococcus aureus.AMB Express 7,46.
sequence listing
<110> institute of feed of Chinese academy of agricultural sciences
<120> lipopeptides Lin-Lf4NH2 and Lin-Lf5NH2 and application thereof
<130> KHP201110677.5
<160> 2
<170> SIPOSequenceListing 1.0
<210> 1
<211> 17
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 1
Phe Lys Ala Trp Arg Trp Ala Trp Arg Trp Lys Lys Leu Ala Ala Pro
1 5 10 15
Ser
<210> 2
<211> 17
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 2
Phe Lys Ala Phe Arg Trp Ala Trp Arg Trp Lys Lys Leu Ala Ala Pro
1 5 10 15
Ser
Claims (8)
1. Lipopeptide Lin-Lf4NH2Characterized in that the lipopeptide Lin-Lf4NH2Is obtained by coupling linoleic acid at the N end of antibacterial peptide LfcinB4 and amidating and modifying the C end; wherein, the amino acid sequence of the antibacterial peptide LfcinB4 is shown in SEQ ID NO. 1.
2. Lipopeptide Lin-Lf5NH2Characterized in that the lipopeptide Lin-Lf5NH2Is obtained by coupling linoleic acid at the N end of antibacterial peptide LfcinB5 and amidating and modifying the C end; wherein, the amino acid sequence of the antibacterial peptide LfcinB5 is shown in SEQ ID NO. 2.
3. A broad spectrum antibacterial medicament or composition comprising a lipopeptide according to claim 1 and/or claim 2.
4. A preservative, antiseptic or surfactant comprising a lipopeptide according to claim 1 and/or claim 2.
5. The lipopeptide Lin-Lf4NH of claim 12Or the lipopeptide Lin-Lf5NH of claim 22Any of the following uses:
1) for the preparation of an antibacterial medicament or composition;
2) for the preparation of preservatives;
3) is used for preparing bactericide;
4) is used for preparing the surfactant.
6. Use according to claim 5, wherein the bacteria comprise gram-positive and gram-negative bacteria.
7. Use according to claim 6, characterized in that said bacteria comprise bacteria of the genus Staphylococcus (Staphylococcus), Escherichia (Escherichia), Salmonella (Salmonella).
8. The use according to claim 7, wherein the bacteria comprise Staphylococcus suis (Staphylococcus hyicus), Staphylococcus aureus (Staphylococcus aureus), Escherichia coli (Escherichia coli), Salmonella pullorum (Salmonella pullorum), Salmonella enteritidis (Salmonella enteritidis).
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