CN106466475A - Complex that antibacterial peptide and polymer are combined into, Preparation Method And The Use - Google Patents

Complex that antibacterial peptide and polymer are combined into, Preparation Method And The Use Download PDF

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CN106466475A
CN106466475A CN201510518175.6A CN201510518175A CN106466475A CN 106466475 A CN106466475 A CN 106466475A CN 201510518175 A CN201510518175 A CN 201510518175A CN 106466475 A CN106466475 A CN 106466475A
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poly
complex
copolymer
polymer
polyethylene glycol
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CN106466475B (en
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刘克良
王晨宏
郄建坤
冯思良
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Institute of Pharmacology and Toxicology of AMMS
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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
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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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  • Inorganic Chemistry (AREA)
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  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

The present invention relates to the complex that antibacterial peptide and polymer are combined into, the invention still further relates to the preparation method of described complex, and described complex be used for preparation prevention or treatment antibacterial peptide can prevent or the medicine of disease treated in purposes.While keeping antibacterial peptide activity, its hemolytic toxicity substantially reduces the complex of the present invention, has good application prospect.

Description

Complex that antibacterial peptide and polymer are combined into, Preparation Method And The Use
Technical field
The present invention relates to the complex that antibacterial peptide and polymer are combined into, the invention still further relates to institute State the preparation method of complex, and described complex is used for preparation prevention or treatment antibacterial peptide institute Purposes in the medicine of disease that can prevent or treat.
Background technology
Antibacterial peptide, because having the advantages that broad spectrum antibiotic activity and being not likely to produce drug resistance, is considered The antibiotic medicine of a new generation can be developed into.This has different from current antibiotic owing to them The sterilization mechanism of medicine：More basic amino acid is contained in most of antibacterial peptide sequences, thus rich Containing positive charge it is easy to there is electrostatic attraction, then cation with negatively charged phospholipid on cell membrane Polypeptide is inserted in the bilayer of cell membrane, forms hole, causes intracellular fluid seepage, thus Kill antibacterial.
Although having higher antibacterial activity, but find so far, also do not have from first antibacterial peptide Antimicrobial peptide medicaments get the Green Light list marketing.Maximum obstacle is that cationic antibacterial peptide is general except having Outside the difficulty that logical polypeptide runs in medicament research and development (as easy in vivo in polypeptide compounds and serum, Blood plasma combines and by proteolytic degradation, and Half-life in vivo is short, and stability is poor, and antigenicity is stronger Etc. defect), the also side effect such as very strong hemolytic.Therefore, antibacterial peptide needs relatively when using High dosage, and this leads to the generation of hemolytic toxicity.Thus, how to obtain stable, safe, Effectively antimicrobial peptide medicaments or preparation, it has also become one is rich in challenge and has grinding of practical value Study carefully focus.
Content of the invention
The present inventor, through untiringly making great efforts and substantial amounts of experiment, is surprised to find using cloudy The polyion complex of the electrostatic interaction preparation between ionomer and cationic antibacterial peptide (Polyionic complex), can substantially reduce its haemolysis while keeping antibacterial peptide activity Toxicity, this completes the present invention.
First aspect present invention is related to complex, and it comprises antibacterial peptide and polymer, wherein antibacterial Peptide is positively charged, polymer belt negative charge.
In embodiments of the invention, pass through electrostatic between described antibacterial peptide and polymer mutual Effect combines.
In embodiments of the invention, described antibacterial peptide is cationic antibacterial peptide.
In embodiments of the invention, described antibacterial peptide be selected from polypeptide, its derivant, its One of officinal salt and its D type isomer or two or more.
In embodiments of the invention, described cationic antibacterial peptide is with 5-20 positive charge Cationic antibacterial peptide, is selected from pexiganan, Omiganan, hLF1-11, P113, XMP629 In any one, or more several mixture.
Wherein, the peptide sequence of above several antibacterial peptide is respectively：
Pexiganan：GIGKF LKKAK KFGKA FVKIL KK-NH2
Omiganan：ILRWP WWPWR RK-NH2
LF1-11：GRRRR RSVQW CA
P113：AKRHH GYKRK FH-NH2
XMP629：KLFR-(3-(1-naphthyl)-A-QAK-(3-(1-naphthyl)-A-NH2
In one embodiment of the invention, described cationic antibacterial peptide is pexiganan.
In another embodiment of the present invention, described cationic antibacterial peptide is Omiganan.
In embodiments of the invention, wherein said polymer has good biocompatibility And biodegradable, can be used for internal as pharmaceutical carrier, auxiliary agent, excipient etc.；
In embodiments of the invention, described polymer contains hydrophilic segment or contains simultaneously There are hydrophilic segment and hydrophobic chain segment it is preferable that described hydrophilic segment is located at hydrophobic chain segment N-terminal,
The polymer of acidic amino acid or derivatives thereof is comprised in wherein said hydrophilic segment, or The hydrophilic amino acid such as acidic amino acid and serine, threonine is comprised in described hydrophilic segment Or derivatives thereof copolymer, for example comprise the copolymerization of acidic amino acid and serine or derivatives thereof Thing, or comprise the copolymer of acidic amino acid and threonine or derivatives thereof, optionally, described The N-terminal of acidic amino acid is also associated with causing the molecule of aminoacid polymerization, such as Polyethylene Glycol, Serine, threonine, C1-10Alkyl (such as C1-6Alkyl) or other can cause aminoacid be polymerized Small molecular weight compounds (molecular weight be less than 1000),
The polymer of hydrophobic amino acid or derivatives thereof is comprised in described hydrophobic chain segment.
In embodiments of the invention, described acidic amino acid includes glutamic acid, aspartic acid.
In an enforcement of the present invention, described hydrophilic segment is polyglutamic acid.
In one embodiment of the invention, described hydrophilic segment is (glutamic acid-Radix Asparagi ammonia Acid) copolymer.
In one embodiment of the invention, described hydrophilic segment is polyethylene glycol paddy ammonia Acid.
In one embodiment of the invention, described hydrophilic segment is Polyethylene Glycol-(paddy ammonia Acid-aspartic acid) copolymer.
In one embodiment of the invention, described hydrophilic segment is (glutamic acid-Radix Asparagi ammonia Acid-serine) copolymer.
In one embodiment of the invention, described hydrophilic segment is Polyethylene Glycol-(paddy ammonia Acid-asparate-serine) copolymer.
In one embodiment of the invention, described hydrophobic chain segment is poly- isoleucine.
In one embodiment of the invention, described hydrophobic chain segment is poly- naphthylalanine.
In embodiments of the invention, described Polyethylene Glycol is PEG or mPEG.
In embodiments of the invention, the molecular weight of described Polyethylene Glycol is 600-20000.
In embodiments of the invention, described polymer is the compound shown in formula I：
Wherein R1Lack such as, or for the molecule of aminoacid polymerization can be caused, be selected from poly- second two Alcohol (poly glycol monomethyl ether or Polyethylene Glycol), serine, threonine, C1-10Alkyl is (for example C1-6Alkyl) or other can cause aminoacid polymerization small molecular weight compounds (molecular weight is little In 1000)；
R2Selected from-(CH2)xCOOH and its officinal salt, wherein x=0-5 (for example, 0,1, 2、3、4、5)；
R3It is selected from hydrophobic amino acid residues or derivatives thereof, described hydrophobic amino acid for example selects From Ile, Leu, Phe, Pro, Val, Trp；
M=5-100, and R2Can be identical or different；
N=0-100, and when n >=2, R3Can be identical or different.
In embodiments of the invention, the molecular weight of described Polyethylene Glycol is 600-20000.
In embodiments of the invention, described hydrophobic amino acid derivative is, for example, naphthylalanine, Benzyl glutamate or aspartic acid benzyl ester etc..
In embodiments of the invention, described m value is 15-51.
In embodiments of the invention, described n value is 5-19 for 0 or n.
The complex of any one according to a first aspect of the present invention, wherein said polymer is selected from hydrophilic In property anionic polymer, the amphiphilic pair of block anionic polymer, amphiphilic anionic polymer One or several；
Preferably, described polymer is selected from polyglutamic acid, poly-aspartate, (glutamic acid-Radix Asparagi Propylhomoserin) copolymer, polyethylene glycol glutamic acid, PEG-PASP, poly- second two Alcohol-(glutamate-aspartate) copolymer, polyglutamic acid-polyphenylalanine, polyglutamic acid- Poly- L-Valine, polyglutamic acid-poly- leucine, polyglutamic acid-poly- isoleucine, polyglutamic acid-poly- Naphthylalanine, poly-aspartate-polyphenylalanine, poly-aspartate-poly- L-Valine, poly- Radix Asparagi Propylhomoserin-poly- leucine, poly-aspartate-poly- isoleucine, poly-aspartate-poly- naphthylalanine, (glutamate-aspartate) copolymer-polyphenylalanine, (glutamate-aspartate) copolymerization Thing-poly- L-Valine, (glutamate-aspartate) copolymer-poly- leucine, (glutamic acid-Radix Asparagi Propylhomoserin) copolymer-poly- isoleucine, (glutamate-aspartate-serine) copolymer-poly- different Leucine, (glutamic acid -- aspartic acid) copolymer-poly- naphthylalanine, polyethylene glycol paddy ammonia Acid-poly- leucine, polyethylene glycol glutamic acid-poly- L-Valine, polyethylene glycol glutamic acid-poly- Isoleucine, polyethylene glycol glutamic acid-polyphenylalanine, polyethylene glycol glutamic acid-poly- naphthalene Alanine, PEG-PASP-poly- L-Valine, PEG-PASP-poly- bright Propylhomoserin, PEG-PASP-poly- isoleucine, PEG-PASP-polyphenyl Alanine, PEG-PASP-poly- naphthylalanine, Polyethylene Glycol-(glutamic acid-Radix Asparagi Propylhomoserin) copolymer-polyphenylalanine, Polyethylene Glycol-(glutamate-aspartate) copolymer- Poly- L-Valine, Polyethylene Glycol-(glutamate-aspartate) copolymer-poly- leucine, poly- second two Alcohol-(glutamate-aspartate) copolymer-poly- isoleucine, Polyethylene Glycol-(glutamic acid-sky Winter propylhomoserin-serine) copolymer-poly- isoleucine, Polyethylene Glycol-(glutamate-aspartate) One of copolymer-poly- naphthylalanine or several, wherein the aminoacid in hydrophilic segment can be pressed According to random order arrangement.Preferably, in hydrophilic segment, the number of aminoacid repetitives is 5-100, preferably 15-60.Preferably, the number of hydrophobic amino acid repetitives is 0-100, Preferably 5-19.
In embodiments of the invention, the molecular weight ranges of described Polyethylene Glycol are 1000-20000.
In one embodiment of the invention, described polymer is polyethylene glycol glutamic acid； In another embodiment of the present invention, described polymer is polyethylene glycol glutamic acid-poly- different Leucine.
The complex of any one according to a first aspect of the present invention, wherein polymer are rubbed with antibacterial peptide That ratio is 0.02:1～50:1, for example, 0.04:1～15:1, for example, 0.2:1～5:1.
In embodiments of the invention, wherein polymer and the mol ratio of antibacterial peptide are 0.04:1、 0.2:1、0.3:1、1:1、3:1、5:1.
In embodiments of the invention, described complex forms nano-micelle structure in the solution； For example when polymer is for triblock polymer, for example Polyethylene Glycol-acidic amino acid polymer-dredge Waterborne polymeric segment, hydrophobic amino acid polymer is located at the inside of micelle, and it is outer to be acid ammonia Base acid polymer and antibacterial peptide, outermost is the molecule that Polyethylene Glycol etc. can cause aminoacid polymerization.
In embodiments of the invention, described positively charged antibacterial peptide is negatively charged with polymer There is electrostatic interaction in the group of lotus, such as the amino in described antibacterial peptide is hydrophilic with polymer Property segment (such as acidic amino acid) carboxyl occur electrostatic interaction.
A second aspect of the present invention is related to pharmaceutical composition, and it is arbitrary that it contains first aspect present invention The complex of item, and pharmaceutically acceptable carrier or excipient.
Third aspect present invention is related to the complex of any one of first aspect present invention in preparation prevention Treatment antibacterial peptide can prevent or the medicine of disease treated in purposes.
The purposes of any one according to a third aspect of the present invention, wherein said antibacterial peptide can prevent or Treatment disease refer to antibacterial (such as gram positive bacteria or gram negative bacteria), funguses or Disease caused by virus；Preferably, described antibacterial, funguses or virus refer to that antibacterial peptide can Suppression or antibacterial, funguses or the virus killed.
Such as pexiganan can be used for preventing or treat gram positive bacteria or gram negative bacteria draws The infection rising, then the compound of the present invention can be used for preparation prevention or treatment gram positive bacteria or leather The medicine of the negative microbial infection of Lan Shi.
The complex that fourth aspect present invention is related to any one of first aspect present invention is used in vitro / suppress in vivo or kill antibacterial (such as gram positive bacteria or gram negative bacteria), funguses or The purposes of virus；Preferably, described antibacterial, funguses or virus refer to antibacterial peptide can suppress or Antibacterial, funguses or the virus killed.
Fifth aspect present invention is related to the preparation method of the complex of any one of first aspect present invention, It comprises the following steps：
Antibacterial peptide and polymer are dissolved in the water respectively by a certain percentage, stirring makes it fully mixed Close, be then peeled off (material that removing is not bound with), obtain final product described complex, optionally, The step also including lyophilizing after separating；
Preferably, wherein polymer and the mol ratio of antibacterial peptide are 0.02:1～50:1, for example, 0.04:1～15:1, for example, 0.2:1～5:1.
In embodiments of the invention, described antibacterial peptide is cationic antibacterial peptide.
In embodiments of the invention, described antibacterial peptide be selected from polypeptide, its derivant, its One of officinal salt and its D type isomer or two or more.
For example, described cationic antibacterial peptide is the cationic antibacterial peptide with 5-20 positive charge, example As selected from pexiganan, Omiganan, any one in hLF1-11, P113, XMP629 Kind, or more several mixture.
In embodiments of the invention, described cationic antibacterial peptide is pexiganan.
In another embodiment of the present invention, described cationic antibacterial peptide is Omiganan.
In embodiments of the invention, described polymer is anionic polymer.
In embodiments of the invention, wherein said polymer has good biocompatibility, Can be used for internal as pharmaceutical carrier, auxiliary agent, excipient etc.；
In embodiments of the invention, described polymer contains hydrophilic segment or contains simultaneously There are hydrophilic segment and hydrophobic chain segment it is preferable that described hydrophilic segment is located at hydrophobic chain segment N-terminal,
The polymer of acidic amino acid or derivatives thereof is comprised in wherein said hydrophilic segment, or The hydrophilic amino acid such as acidic amino acid and serine, threonine is comprised in described hydrophilic segment Or derivatives thereof copolymer, for example comprise the copolymerization of acidic amino acid and serine or derivatives thereof Thing, or comprise the copolymer of acidic amino acid and threonine or derivatives thereof, optionally, described The N-terminal of acidic amino acid is also associated with causing the molecule of aminoacid polymerization, such as Polyethylene Glycol, Serine, threonine, C1-10Alkyl (such as C1-6Alkyl) or other can cause aminoacid be polymerized Small molecular weight compounds (molecular weight be less than 1000),
The polymer of hydrophobic amino acid or derivatives thereof is comprised in described hydrophobic chain segment.
In embodiments of the invention, described acidic amino acid includes glutamic acid, aspartic acid.
In an enforcement of the present invention, described hydrophilic segment is polyglutamic acid.
In one embodiment of the invention, described hydrophilic segment is (glutamic acid-Radix Asparagi ammonia Acid) copolymer.
In one embodiment of the invention, described hydrophilic segment is polyethylene glycol paddy ammonia Acid.
In one embodiment of the invention, described hydrophilic segment is Polyethylene Glycol-(paddy ammonia Acid-aspartic acid) copolymer.
In one embodiment of the invention, described hydrophilic segment is (glutamic acid-Radix Asparagi ammonia Acid-serine) copolymer.
In one embodiment of the invention, described hydrophilic segment is Polyethylene Glycol-(paddy ammonia Acid-asparate-serine) copolymer.
In one embodiment of the invention, described hydrophobic chain segment is poly- isoleucine.
In one embodiment of the invention, described hydrophobic chain segment is poly- naphthylalanine.
In embodiments of the invention, the molecular weight of described Polyethylene Glycol is 600-20000.
In embodiments of the invention, described polymer is the compound shown in formula I：
Wherein R1Lack such as, or for the molecule of aminoacid polymerization can be caused, be selected from poly- second two Alcohol (poly glycol monomethyl ether or Polyethylene Glycol), serine, threonine, C1-10Alkyl is (for example C1-6Alkyl) or other can cause aminoacid polymerization small molecular weight compounds (molecular weight is little In 1000)；
R2Selected from-(CH2)xCOOH and its officinal salt, wherein x=0-5 (for example, 0,1, 2、3、4、5)；
R3It is selected from hydrophobic amino acid residues or derivatives thereof, described hydrophobic amino acid for example selects From Ile, Leu, Phe, Pro, Val, Trp；
M=5-100, and R2Can be identical or different；
N=0-100, and when n >=2, R3Can be identical or different.
In embodiments of the invention, the molecular weight of described Polyethylene Glycol is 600-20000.
In embodiments of the invention, described hydrophobic amino acid derivative is, for example, naphthylalanine, Benzyl glutamate or aspartic acid benzyl ester etc..
In embodiments of the invention, described m value is 15-51.
In embodiments of the invention, described n value is 5-19 for 0 or n.
In embodiments of the invention, wherein said polymer is selected from hydrophilic anions and is polymerized Thing, one of amphiphilic pair of block anionic polymer, amphiphilic anionic polymer or several；
Preferably, described polymer is selected from polyglutamic acid, poly-aspartate, (glutamic acid-Radix Asparagi ammonia Acid) copolymer, polyethylene glycol glutamic acid, PEG-PASP, Polyethylene Glycol-(paddy Propylhomoserin-aspartic acid) copolymer, polyglutamic acid-polyphenylalanine, polyglutamic acid-poly- L-Valine, Polyglutamic acid-poly- leucine, polyglutamic acid-poly- isoleucine, polyglutamic acid-poly- naphthylalanine, poly- Aspartic acid-polyphenylalanine, poly-aspartate-poly- L-Valine, poly-aspartate-poly- leucine, Poly-aspartate-poly- isoleucine, poly-aspartate-poly- naphthylalanine, (glutamate-aspartate) Copolymer-polyphenylalanine, (glutamate-aspartate) copolymer-poly- L-Valine, (glutamic acid - aspartic acid) copolymer-poly- leucine, (glutamate-aspartate) copolymer-poly- isoleucine, (glutamic acid -- aspartic acid) copolymer-poly- naphthylalanine, (glutamate-aspartate-serine) Copolymer-poly- isoleucine, polyethylene glycol glutamic acid-poly- leucine, polyethylene glycol paddy ammonia Acid-poly- L-Valine, polyethylene glycol glutamic acid-poly- isoleucine, polyethylene glycol glutamic acid-poly- Phenylalanine, polyethylene glycol glutamic acid-poly- naphthylalanine, PEG-PASP-poly- figured silk fabrics Propylhomoserin, PEG-PASP-poly- leucine, PEG-PASP-gather different bright ammonia Acid, PEG-PASP-polyphenylalanine, PEG-PASP-poly- naphthalene third ammonia Acid, Polyethylene Glycol-(glutamate-aspartate) copolymer-polyphenylalanine, Polyethylene Glycol-(paddy Propylhomoserin-aspartic acid) copolymer-poly- L-Valine, Polyethylene Glycol-(glutamate-aspartate) copolymerization Thing-poly- leucine, Polyethylene Glycol-(glutamate-aspartate) copolymer-poly- isoleucine, poly- second Glycol-(glutamate-aspartate-serine) copolymer-poly- isoleucine and Polyethylene Glycol-(paddy Propylhomoserin-aspartic acid) one of copolymer-poly- naphthylalanine or several, wherein hydrophilic segment In aminoacid can arrange in any order.Preferably, in hydrophilic segment, aminoacid repeats The number of unit is 5-100, preferably 15-60.Preferably, hydrophobic amino acid repetitives Number is 0-100, preferably 5-19.
In embodiments of the invention, the molecular weight ranges of described Polyethylene Glycol are 1000-20000.
In one embodiment of the invention, described polymer is polyethylene glycol glutamic acid； In another embodiment of the present invention, described polymer is polyethylene glycol glutamic acid-poly- different Leucine.
The invention still further relates to polymer is used for preparing the purposes of antimicrobial peptide medicaments preparation, wherein said poly- Compound is negatively charged.
In the present invention, described antibacterial peptide (antibacterial peptides) refers in multiple lifes In thing natural immune system, there is the small molecule polypeptide of antibacterial activity, also include with natural Antibacterial peptide is the simulating peptide of template synthetic.
In the present invention, described cationic antibacterial peptide (cationic antibacterial peptides) Refer to the general amphipathic molecule being made up of 12-50 amino acid residue that plant and animal produces, It is present in, and biology is internal, has opposing external microbe infringement, the work(of elimination vivo mutations cell Can, also include the simulating peptide with natural cationic antibacterial peptide for template synthetic.
In the present invention, described polymer is anionic polymer, i.e. the polymerization containing negative charge Thing.
In the present invention, described electrostatic interaction refers to attracting each other between opposite charges and phase With mutually exclusive between electric charge.
In the present invention, described antibacterial peptide is combined by electrostatic interaction with polymer and refers to anion Electrostatic attraction between the amino ion of the carboxylic ions of polymer and cationic polypeptide.
In the present invention, the polymer of aminoacid is also referred to as polyamino acid.
In the present invention, described hydrophobic amino acid residues refer to that hydrophobic amino acid removes formation Remaining part after the group of peptide bond, such as leucine residue are isobutyl group, and Phenylalanine is residual Base is benzyl etc..
In the present invention, if especially not dated, aminoacid is L-type.
Brief description
The gel exclusion chromatography figure of Fig. 1 polymer
Fig. 2 PEG-PBLG (A) and the nuclear-magnetism of polyethylene glycol glutamic acid (B) Spectrogram
The schematic diagram of Fig. 3 complex preparation
The grain size distribution (A) of Fig. 4 complex 1 and transmission electron microscope picture (B)
The gel electrophoresiss of Fig. 5 complex
Fig. 6 PEG-PBLG (A), PEG-PBLG-poly- different bright Propylhomoserin (B) and the nuclear magnetic spectrogram of polyethylene glycol glutamic acid-poly- isoleucine (C)
The agarose gel electrophoresis figure of Fig. 7 complex
Fig. 8～12 are the hemolytic activity test result of pexiganan and its each complex
Specific embodiment
Below in conjunction with embodiment, embodiment of the present invention is described in detail, but ability Field technique personnel will be understood that, the following example is merely to illustrate the present invention, and is not construed as limiting Determine the scope of the present invention.Unreceipted actual conditions person in embodiment, according to normal condition or manufacture The condition of business's suggestion is carried out.Agents useful for same or the unreceipted production firm person of instrument, are and can lead to Cross city available from conventional products.
Embodiment 1 anionic polymer Polyethylene Glycol5000- polyglutamic acid49 (mPEG5000-b-PGlu49) preparation
By mPEG5000-NH2(purchased from triumphant positive biology company limited) is dissolved in N, N- dimethyl formyl Glutamic acid -5- benzyl ester-N- carboxyanhydrides (the Glu of 50 times of molal quantitys is added in amine (DMF) (OBzl)-NCA, list of references N.Nishiyama, et al, Langmuir 15 (1999) 377 383 synthesis), it is heated to 50 DEG C, after stirring 24 hours, concentrate solution is poured in ether, Separate out white precipitate, filter, vacuum drying, obtain white powder mPEG5000- b-PGlu (OBzl), Gel exclusion chromatography (GPC) measures molecular weight Mn=12214, the PDI=1.25 of polymer, such as Shown in Fig. 1, mPEG5000-b-PGlu(OBzl)49Curve and mPEG5000It is clearly distinguished from, Show to obtain block polymer.It is then added to remove in the sodium hydrate aqueous solution of 0.5N and protect Shield base, lyophilizing obtains white powder.Pass through1H NMR, compares Polyethylene Glycol CH2CH2In O The numerical value of H and benzyl ester C in polyglutamic acid6H5The numerical value of middle H, calculates m=49, product For mPEG5000-b-PGlu49.
The syntheti c route of Scheme1 poly glycol monomethyl ether-b- polyglutamic acid
Embodiment 2 antibacterial peptide and the preparation of polymer complex 1 (abbreviation complex 1)
By mPEG5000-b-PGlu49Water with pexiganan (microwave Peptide synthesizer voluntarily synthesizes) Solution is according to 1:1 mixed in molar ratio, is stirred at room temperature 12 hours, and molecular cut off is 3500 Dialyse 24 hours in bag filter, then lyophilizing, obtain complex 1 (as shown in Figure 3).Use The particle diameter of laser particle analyzer (DLS) test compound thing 1 is 195.7 ± 5.6nm for solution, grain Footpath is distributed as 0.12 ± 0.03 (table 1).Transmission electron microscope (TEM) display as shown in Figure 4 simultaneously It is nucleocapsid structure.Show that complex 1 is stable nano-micelle.
The particle diameter of table 1 complex and its dispersion index (n=3).
The preparation of the complex of other proportionings of embodiment 3
Respectively by pexiganan and mPEG5000-b-PGlu49According to mol ratio 1:5、1:0.2、1:25 Ratio mixing, the method with reference to embodiment 2 prepares complex 2, complex 3, complex 4.
Embodiment 4 anionic polymer mPEG5000The preparation of-b-PGlu
By mPEG5000-NH2It is dissolved in Glu (the OBzl)-NCA adding different proportion in DMF, It is heated to 50 DEG C, after stirring 24 hours, concentrate solution pours precipitation white precipitate in ether into, filters, Vacuum drying, obtains white powder.It is then added to remove in the sodium hydrate aqueous solution of 0.5N Protection group, lyophilizing.Pass through1H NMR calculates and determines that the number of repeat unit of glutamic acid is respectively m=15 And m=31, i.e. mPEG5000-b-PGlu15And mPEG5000-b-PGlu31.
Embodiment 5 antibacterial peptide and polymer complex 5,6 (abbreviation complex 5 and complex 6) Preparation
By mPEG5000-b-PGlu15And mPEG5000-b-PGlu31Respectively with pexiganan according to rubbing You compare 1:1 ratio mixing, the method with reference to embodiment 2 prepares complex 5 and complex 6. Particle diameter and its particle diameter distribution are listed in Table 1.
The gel electrophoresis test of embodiment 6 complex
For the ease of observing the generation of complex, the present invention uses fluorescently-labeled pexiganan to substitute Pexiganan, it has identical positive changes, and the preparation on complex does not affect.To be combined Thing 1-6, fluorescently-labeled pexiganan, and fluorescently-labeled pexiganan and Polyethylene Glycol5000 Mixture be added in 1% agarose gel hole according to finite concentration, the both sides of gel slab lead to Electric 20mV, observes fluorescent material moving direction after 35 minutes.Fluorescently-labeled training west shown in Fig. 5 Plus south, fluorescently-labeled pexiganan and Polyethylene Glycol5000Mixture all to negative pole move, its He moves to positive pole complex.With the increasing of anion number in complex, fluorescence intensity increases, This shows that pexiganan and Polyethylene Glycol-b- polyglutamic acid define complex, and with anion The increase stability of number improves.
Embodiment 7 anionic polymer polymer poly ethylene glycol5000- polyglutamic acid49- poly- isoleucine (mPEG5000-b-PGlu49- b-PIle) preparation
By mPEG5000-b-PGlu49It is dissolved in the isoleucine-N- carboxylic adding different proportion in DMF Basic ring inner-acid anhydride (Ile-NCA, list of references N.Nishiyama, et al, Langmuir 15 (1999) 377 383 synthesis), it is heated to 50 DEG C, after stirring 24 hours, concentrate solution pours analysis in ether into Go out white precipitate, filter, vacuum drying, obtain white powder.It is then added to the hydrogen of 0.5N Protection group is removed, lyophilizing obtains white powder in aqueous solution of sodium oxide.1H NMR detects, compares Polyethylene Glycol CH2CH2The numerical value of hydrogen and CH in poly- isoleucine in O3CH2CH(CH3) in The numerical value of hydrogen, calculates n=5 and n=13.I.e. mPEG5000-b-PGlu49-b-PIle5With mPEG5000-b-PGlu49-b-PIle13, Fig. 6 is triblock polymer mPEG5000-b-PGlu49-b-PIle13Nuclear magnetic spectrogram.
Scheme 2 triblock polymer mPEG5000-b-PGlu49-b-PIle13Synthetic route
Embodiment 8 antibacterial peptide and polymer complex 7,8 (abbreviation complex 7 and complex 8) Preparation
By mPEG5000-b-PGlu49-b-PIle5And mPEG5000-b-PGlu49-b-PIle13Respectively with Pexiganan is according to 1:1 mixed in molar ratio, the method with reference to embodiment 2 prepares complex 7 He Complex 8.
Embodiment 9 antibacterial peptide and polymer complex 9,10 (abbreviation complex 9 and complex 10) Preparation
By mPEG5000-b-PGlu49-b-PIle13With pexiganan respectively according to 1:3,3:1 mole Ratio mixing, the method with reference to embodiment 2 prepares complex 9 and complex 10.
Embodiment 10 anionic polymer mPEG2000-b-PGlu51-b-PIle19Preparation
By mPEG2000-NH2It is dissolved in addition Glu (OBzl)-NCA in DMF, be heated to 50 DEG C, After stirring 24 hours, concentrate solution pours precipitation white precipitate in ether into, filters, vacuum drying, Obtain white powder,1H NMR detection calculates glutamic acid repeating units number m=51, that is, mPEG2000-b-PGlu(OBzl)51.It is dissolved in DMF, add Ile-NCA again, plus To 50 DEG C, after stirring 24 hours, concentrate solution pours precipitation white precipitate in ether into heat, filters, Vacuum drying, obtains white powder, passes through1H NMR calculates isoleucine number of repeat unit N=19, i.e. mPEG2000-b-PGlu(OBzl)51-b-PIle19.It is then added to the hydrogen of 0.5N Remove protection group, lyophilizing in aqueous solution of sodium oxide, obtain white powder mPEG2000-b-PGlu51-b-PIle19.
Embodiment 11 antibacterial peptide and the preparation of polymer complex 11 (abbreviation compound 11)
By mPEG2000-b-PGlu51-b-PIle19With pexiganan according to 1:1 mixed in molar ratio, Method with reference to embodiment 2 prepares compound 11.
Embodiment 12 antibacterial peptide and the preparation of polymer complex 12 (abbreviation complex 12)
By mPEG2000-b-PGlu51-b-PIle19With pexiganan according to 1:5 mixed in molar ratio, Method with reference to embodiment 2 prepares complex 12.
The gel electrophoresis test of embodiment 13 complex
For the ease of observing the generation of complex, the present invention uses fluorescently-labeled pexiganan to substitute Pexiganan, it has identical positive changes, and the preparation on complex does not affect.To be combined Thing 7-12, fluorescently-labeled pexiganan, and fluorescently-labeled pexiganan and Polyethylene Glycol5000 Mixture be added in 1% agarose gel hole according to finite concentration, the both sides of gel slab lead to Electric 20mV, observes fluorescent material moving direction after 35 minutes.Fluorescently-labeled training west shown in Fig. 7 Plus south, fluorescently-labeled pexiganan and Polyethylene Glycol5000Mixture all to negative pole move, its He moves to positive pole complex.With increasing of anion number, fluorescence intensity increases, and this shows Pexiganan and the poly- isoleucine of Polyethylene Glycol-b- polyglutamic acid-b- define complex, and with The increase stability of anion number improves.
Embodiment 14 pexiganan and its mensure of the complex bacteriostatic activity being formed with polymer
Experiment strain (gram positive bacteria：Staphylococcus aureuses and bacillus subtilis, gram Negative bacterium：Escherichia coli) it is inoculated in nutrient broth respectively, cultivate 18-24 hour in 37 DEG C, survey Examination OD490It is worth for 0.5 about, before use according to 1:105Dilution, takes 12 Bacteria Culture pipes simultaneously Numbering.It is 1mg/mL (all with pexiganan that pexiganan or its complex are configured to concentration Gauge) storing solution, dilute method dilution again, each concentration is repeated 3 times, after adding 100 μ L bacterium solution, Gently shake uniformly, put 37 DEG C of culture 18-24 hours, observe.After culture, culture tube clarification, shakes Still clarify it is believed that this pipe asepsis growth after shaking；Assume cloudy state and show there is bacteria growing, from aseptic The culture tube of minimum pexiganan concentration is found out, the concentration of this pipe is and suppresses thin in each pipe of growth The minimum inhibitory concentration (MIC) of bacteria growing.The anti-bacterial result is as shown in table 2 although anion is gathered Compound does not have antibacterial activity, but complex show three kinds of common bacterial strains are had significantly antibacterial Activity, and suitable with positive control pexiganan bacteriostatic activity.
Table 2 pexiganan and its minimum inhibitory concentration (MIC) of the complex being formed with polymer
Embodiment 15 pexiganan and its mensure of the complex hemolytic activity being formed with polymer
Human red cell is configured to red blood cell suspension (10 times of preparations of dilution), west will be trained Plus south or complex are configured to the storing solution that concentration is 1mg/mL (all with the gauge of pexiganan), Dilute method dilution again, each sample in triplicate, shakes in agitator after adding red blood cell suspension, Centrifugation, takes supernatant to measure the OD value that wavelength is at 414nm in microplate reader, with blood red thin Born of the same parents are 0 (negative control) in PBS solution, and erythrocyte is 100% in Triton X-100 Haemolysis (positive control).Percentage of hemolysis is calculated by following formula：
In formula, A is the OD value at 414nm.
Fig. 8-Figure 12 compares for the hemolytic activity of pexiganan and complex, and result shows that each is multiple Compound all significantly reduces the hemolytic activity to human red cell.
Table 2 is the therapeutic index (HC of pexiganan and its complex10/ MIC) compare【Chen Y, Mant CT,Farmer SW,Hancock REW,Vasil ML,Hodges RS.J Biol Chem 2005；280:12316–29.】【Zhu WL,Nan YH,Hahm KS,Shin SY.J Biochem Mol Biol 2007；40:1090–4.】, therapeutic index is to evaluate drug safety Important indicator, the bigger medication of its numerical value is safer.Table 3 is visible, and the therapeutic index of complex all has Improve, the more therapeutic index of negative charge number are higher.
Therapeutic index (the HC of table 3 pexiganan and its complex10/ MIC) compare
Embodiment 16 antibacterial peptide and the preparation of polymer complex 13 (abbreviation complex 13)
By mPEG5000-b-PGlu15With Omiganan (microwave Peptide synthesizer voluntarily synthesizes) Aqueous solution is according to 1:1 mixed in molar ratio, the method with reference to embodiment 2 prepares complex 13.
Embodiment 17 antibacterial peptide and the preparation of polymer complex 14 (abbreviation complex 14)
By mPEG5000-b-PGlu31With Omiganan (microwave Peptide synthesizer voluntarily synthesizes) Aqueous solution is according to 1:1 mixed in molar ratio, the method with reference to embodiment 2 prepares complex 14.
Embodiment 18 antibacterial peptide and the preparation of polymer complex 15 (abbreviation complex 15)
By mPEG5000-b-PGlu49With Omiganan (microwave Peptide synthesizer voluntarily synthesizes) Aqueous solution is according to 1:1 mixed in molar ratio, the method with reference to embodiment 2 prepares complex 15.
Embodiment 19 Omiganan and its mensure of the complex bacteriostatic activity being formed with polymer
Method with reference to embodiment 14 measures the MIC of each complex, and result is as shown in table 4, multiple Compound shows there is obvious bacteriostatic activity to three kinds of common bacterial strains, and trains west with positive control Rice bacteriostatic activity difficult to understand is suitable.
Table 4 pexiganan and its minimum inhibitory concentration (MIC) of the complex being formed with polymer
The anxious poison experiment of the mice of the complex that embodiment 20 antibacterial peptide is combined into polymer
With 18～22g health balb/c male mice as experimental subject.According to the principle of random packet, Mice is pressed body weight random packet.Every group sets 8-10 mice.With lumbar injection, single-dose Mode to various dose medicine (pexiganan group, 25,30,35,40,45 and 50mg/kg；Multiple 1 group of compound, 600,800,1000,1100,1200,1300, and 1400mg/kg, wherein containing about 20% pexiganan), daily observed and recorded death condition after administration, observe one week altogether.Using OriginPro 8 software carries out data analysiss, calculates positive drug respective with test medicine LD50.
Pexiganan group：Different with dosage, mice typically upon administration half an hour little to 48 When interior death, substantially can survive afterwards.After lumbar injection, high dose group mice shows pole immediately The uncomfortable state of degree, rolls up, perpendicular hair, the equal pastiness of eyeball, extremity, tail, until dead.If little Mus can recover to rubescent state originally from pastiness, then will not be dead.Low dose group animal is acted normally.
The packet of table 5 pexiganan group mouse dose and death condition：
Using OriginPro 8 software analysis data, calculate median lethal dose(LD 50) LD50=38.86 mg/kg.
1 group of complex：
Acute toxic reaction phenomenon：Same positive control drug.
The 1 group of mouse dose packet of table 6 complex and death condition：
Using OriginPro 8 software analysis data, calculate median lethal dose(LD 50) LD50= 986.6mg/kg.Calculate according to pexiganan actual amount, LD50 improves 5 times.
Although the specific embodiment of the present invention has obtained detailed description, people in the art Member will be understood that.According to disclosed all teachings, various repairing can be carried out to those details Change and replace, these change all within protection scope of the present invention.The four corner of the present invention Be given by claims and its any equivalent.

Claims (12)

1. complex, it comprises antibacterial peptide and polymer, and wherein antibacterial peptide is positively charged, polymerization Thing is negatively charged；
Preferably, described antibacterial peptide is cationic antibacterial peptide, for example, with 5-20 positive charge Cationic antibacterial peptide；
Preferably, described antibacterial peptide is selected from polypeptide, its derivant, its officinal salt and its D One of type isomer or two or more.
2. the complex of claim 1, wherein said cationic antibacterial peptide is selected from pexiganan, Omiganan, any one in hLF1-11, P113, XMP629, or more several mixed Compound.
3. the complex of claim 1 or 2, wherein said polymer contain hydrophilic segment or Person contains hydrophilic segment and hydrophobic chain segment simultaneously it is preferable that described hydrophilic segment is positioned at thin The N-terminal of aqueouss segment, wherein
The polymer of acidic amino acid or derivatives thereof is comprised in described hydrophilic segment, or described Comprise in hydrophilic segment the hydrophilic amino acid such as acidic amino acid and serine, threonine or its The copolymer of derivant, for example, comprise the copolymer of acidic amino acid and serine or derivatives thereof, Or comprise the copolymer of acidic amino acid and threonine or derivatives thereof, optionally, described acidity The N-terminal of aminoacid is also associated with causing the molecule of aminoacid polymerization, such as Polyethylene Glycol, silk ammonia Acid, threonine, C1-10Alkyl (such as C1-6Alkyl) or other can cause aminoacid polymerization little Compound molecular weight (molecular weight is less than 1000),
The polymer of hydrophobic amino acid or derivatives thereof is comprised in described hydrophobic chain segment.
4. the complex of any one of claim 1-3, wherein said polymer is shown in formula I Compound：
Wherein R1Lack such as, or for the molecule of aminoacid polymerization can be caused, be selected from poly- second two Alcohol (Polyethylene Glycol or poly glycol monomethyl ether), serine, threonine, C1-10Alkyl is (for example C1-6Alkyl) or other can cause aminoacid polymerization small molecular weight compounds (molecular weight is less than 1000)；
R2Selected from-(CH2)xCOOH and its officinal salt, wherein x=0-5 (for example, 0,1, 2、3、4、5)；
R3Selected from hydrophobic amino acid residues or derivatives thereof, described hydrophobic amino acid be selected from Ile, Leu, Phe, Pro, Val and Trp；
M=5-100, and R2Can be identical or different；
N=0-100, and when n >=2, R2Can be identical or different.
5. the complex of any one of claim 1-4, wherein said polymer be selected from polyglutamic acid, Poly-aspartate, (glutamate-aspartate) copolymer, polyethylene glycol glutamic acid, poly- second Glycol-poly-aspartate, Polyethylene Glycol-(glutamate-aspartate) copolymer, polyglutamic acid- Polyphenylalanine, polyglutamic acid-poly- L-Valine, polyglutamic acid-poly- leucine, polyglutamic acid-poly- different Leucine, polyglutamic acid-poly- naphthylalanine, poly-aspartate-polyphenylalanine, poly-aspartate- Poly- L-Valine, poly-aspartate-poly- leucine, poly-aspartate-poly- isoleucine, poly- Radix Asparagi ammonia Acid-poly- naphthylalanine, (glutamate-aspartate) copolymer-polyphenylalanine, (glutamic acid- Aspartic acid) copolymer-poly- L-Valine, (glutamate-aspartate) copolymer-poly- leucine, (glutamate-aspartate) copolymer-poly- isoleucine, (glutamic acid -- aspartic acid) copolymer - poly- naphthylalanine, (glutamate-aspartate-serine) copolymer-poly- isoleucine, poly- second Glycol-polyglutamic acid-poly- leucine, polyethylene glycol glutamic acid-poly- L-Valine, polyethylene glycol Glutamic acid-poly- isoleucine, polyethylene glycol glutamic acid-polyphenylalanine, polyethylene glycol paddy ammonia Acid-poly- naphthylalanine, PEG-PASP-poly- L-Valine, PEG-PASP - poly- leucine, PEG-PASP-poly- isoleucine, PEG-PASP- Polyphenylalanine, PEG-PASP-poly- naphthylalanine, Polyethylene Glycol-(glutamic acid- Aspartic acid) copolymer-polyphenylalanine, Polyethylene Glycol-(glutamate-aspartate) copolymer - poly- L-Valine, Polyethylene Glycol-(glutamate-aspartate) copolymer-poly- leucine, Polyethylene Glycol - (glutamate-aspartate) copolymer-poly- isoleucine, Polyethylene Glycol-(glutamic acid-Radix Asparagi ammonia Acid-serine) copolymer-poly- isoleucine and Polyethylene Glycol-(glutamate-aspartate) copolymerization One of thing-poly- naphthylalanine or several, wherein the aminoacid in hydrophilic segment can according to appoint Meaning order arranges.
6. the complex of any one of claim 1-5, wherein polymer and the mol ratio of antibacterial peptide For 0.02:1～50:1, for example, 0.04:1～15:1, for example, 0.2:1～5:1.
7. pharmaceutical composition, it contains the complex of any one of claim 1-6, and pharmacy Upper acceptable carrier or excipient.
8. the complex of any one of claim 1-6 can be pre- in preparation prevention or treatment antibacterial peptide institute Purposes in the medicine of disease prevented or treat.
9. the purposes of claim 8, wherein said antibacterial peptide can prevent or the disease treated is Refer to antibacterial, funguses or the disease caused by virus；Preferably, described antibacterial, funguses or virus Refer to antibacterial, funguses or virus that antibacterial peptide can suppress or kill.
10. the complex of any one of claim 1-6 be used in vitro/suppress in vivo or kill thin The purposes of bacterium (such as gram positive bacteria or gram negative bacteria), funguses or virus；Preferably Ground, described antibacterial, funguses or virus refer to the antibacterial, funguses that antibacterial peptide can suppress or kill Or virus.
The preparation method of the complex of 11. any one of claim 1-6, it comprises the following steps：
Antibacterial peptide and polymer are dissolved in the water respectively by a certain percentage, stirring makes it fully mixed Close, separate, obtain final product described complex, optionally, after separating, also include the step of lyophilizing；
Preferably, wherein polymer and the mol ratio of antibacterial peptide are 0.02:1～50:1, for example, 0.04:1～15:1, for example, 0.2:1～5:1.
12. polymer are used for preparing the purposes of antimicrobial peptide medicaments preparation, and wherein said polymer belt is born Electric charge.
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