WO2022163978A1 - 미생물의 세포질 용출 효과가 우수한 신규의 항균 펩타이드 - Google Patents
미생물의 세포질 용출 효과가 우수한 신규의 항균 펩타이드 Download PDFInfo
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
- A01N37/46—N-acyl derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N63/00—Biocides, pest repellants or attractants, or plant growth regulators containing microorganisms, viruses, microbial fungi, animals or substances produced by, or obtained from, microorganisms, viruses, microbial fungi or animals, e.g. enzymes or fermentates
- A01N63/50—Isolated enzymes; Isolated proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
- A61Q17/005—Antimicrobial preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/52—Stabilizers
- A61K2800/524—Preservatives
Definitions
- the present invention relates to an antimicrobial peptide, a derivative thereof, or a fragment thereof; a polynucleotide encoding the antibacterial peptide, a derivative thereof, or a fragment thereof; And it relates to a carrier for external application to the skin, a cosmetic composition, a quasi-drug composition, and a pharmaceutical composition comprising the antibacterial peptide, a derivative thereof, or a fragment thereof.
- natural product-derived antibiotics such as an antibacterial composition (Korean Patent Publication No. 10-2020-0017912) containing a plant extract as an active ingredient are known, but natural products such as extracts have large particle sizes, and only natural products are used. Since it is difficult to show a meaningful effect, the need to develop an antibacterial material is emerging.
- the present inventors have completed the present invention by confirming that the antibacterial peptide of the present invention has significantly superior antibacterial effect compared to other peptides.
- One object of the present invention is to provide an antimicrobial peptide, a derivative thereof, or a fragment thereof.
- Another object of the present invention is to provide a polynucleotide encoding the antibacterial peptide, a derivative thereof, or a fragment thereof.
- Another object of the present invention is to provide a carrier for external application to the skin comprising the antibacterial peptide, a derivative thereof, or a fragment thereof.
- Another object of the present invention is to provide a cosmetic composition comprising the antibacterial peptide, a derivative thereof, or a fragment thereof.
- Another object of the present invention is to provide a quasi-drug composition comprising the antibacterial peptide, a derivative thereof, or a fragment thereof.
- Another object of the present invention is to provide a pharmaceutical composition comprising the antibacterial peptide, derivative thereof, or fragment thereof.
- the present invention has significantly increased antibacterial activity and reduced toxicity compared to other peptides, industrial application can be expected in industries such as preservatives, pharmaceuticals, and cosmetics.
- 1 is a diagram showing the results of confirming the antibacterial activity and cytotoxicity of the peptide of SEQ ID NO: 1 in comparison with the known peptide.
- FIG. 2 is a diagram showing the results of confirming the antimicrobial activity and cytotoxicity of the peptide of SEQ ID NO: 2 compared to the peptide of SEQ ID NO: 1.
- FIG. 3 is a view showing the results of confirming the antimicrobial activity and cytotoxicity of the peptides of SEQ ID NO: 2 and SEQ ID NO: 5 to SEQ ID NO: 8.
- Figure 4 is a view showing the results of confirming the antimicrobial activity and cytotoxicity of the peptides of SEQ ID NO: 2 to SEQ ID NO: 4.
- FIG. 5 is a view showing the results of confirming the antibacterial effect of the antibacterial peptide of the present invention against Escherichia coli , Staphylococcus aureus , Pneumonia aeruginosa , and Candida albicans .
- FIG. 6 is a view showing the results of analyzing the antibacterial effect of the antimicrobial peptide of the present invention on E. coli using a scanning electron microscope (SEM).
- One aspect of the present invention provides an antimicrobial peptide, a derivative thereof, or a fragment thereof comprising the amino acid sequence of any one of SEQ ID NOs: 5 to 8.
- antibacterial peptide refers to a peptide having antimicrobial activity, and since the antimicrobial activity is not limited to the type of microorganism, the 'antibacterial' refers to antibacterial, antifungal, and It can be mixed with antibiotics.
- the antimicrobial peptide of the present invention may include the amino acid sequence of any one of SEQ ID NOs: 5 to 8, and as long as it has antimicrobial activity, any one of SEQ ID NOs: 5 to 8 derivatives, or A fragment thereof may also be included.
- the antibacterial peptide may be a substance expressed as an intrinsic immune system (first defense) to protect an individual in various species such as microorganisms such as bacteria, plants, insects, amphibians, mammals, and humans, and has excellent antimicrobial activity and resistance compared to existing antibiotics It may have a characteristic that there is little, but is not limited thereto if it functions as an antibacterial peptide.
- first defense an intrinsic immune system
- the antimicrobial peptide of the present invention is not limited to the structure, etc., as long as it has antimicrobial activity, and the microorganism is not limited as long as it is included in the category of microorganisms, bacteria, fungi, etc. It may include all of them, and is not limited to the type and origin thereof.
- the antibacterial peptide consisting of any one of the amino acid sequence of SEQ ID NO: 5 to SEQ ID NO: 8, a derivative thereof, or a fragment thereof is E. coli ( Escherichia coli ), Staphylococcus aureus ), Pseudomonas aeruginosa ( Pneumonia aeruginosa ), And Candida ( Candida albicans ) It may inhibit the growth of any one or more selected from the group consisting of, but is not limited thereto.
- the antibacterial peptide and derivatives thereof consisting of any one of the amino acid sequences of SEQ ID NOs: 5 to 8 are E. coli ( Escherichia coli ), Staphylococcus aureus ), Pseudomonas aeruginosa ( Pneumonia aeruginosa ), And / or Candida bacteria ( Candida albicans ) It was confirmed that it has an antibacterial activity (Example 2).
- derivative refers to a derivative of an antibacterial peptide consisting of the amino acid sequence of any one of SEQ ID NOs: 5 to 8, specifically, some functional groups are added to the amino acid sequences of SEQ ID NOs: 5 to 8, Some amino acid sequence may be a peptide having an amino acid sequence deleted, modified, substituted, or added, but is not limited thereto.
- the derivative in the present invention may be any one or more selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 4, and functions as an antibacterial peptide like the antibacterial peptide consisting of the amino acid sequence of SEQ ID NO: 5 to SEQ ID NO: 8 It may be the same as described above for the antibacterial peptide.
- Antibacterial peptides and derivatives thereof comprising the amino acid sequence of SEQ ID NO: 5 to SEQ ID NO: 8 of the present invention may have a sequence as shown in Formula 1 below, and may have antibacterial activity, but is not limited thereto.
- X 1 to X 6 may be selected from basic amino acids, and may be selected from arginine, lysine, leucine and phenylalanine.
- the antibacterial peptide and its derivative comprising the amino acid sequence of any one of SEQ ID NO: 5 to SEQ ID NO: 8 may have the sequence of Formula 1, and the derivative of the present invention is the amino acid sequence of SEQ ID NO: 1 to SEQ ID NO: 4 It may be composed of an amino acid sequence, but is not limited thereto.
- SEQ ID NO: 1 H 2 N-[Lys-Lys-Leu-Phe-Lys-Lys-Ile-Leu-Lys-Tyr-Leu-Lys]-CO 2 H,
- SEQ ID NO: 2 H 2 N-[Arg-Arg-Leu-Phe-Arg-Arg-Ile-Leu-Arg-Tyr-Leu-Arg]-CO 2 H,
- SEQ ID NO: 3 H 2 N-[Arg-Phe-Leu-Phe-Arg-Leu-Ile-Leu-Arg-Tyr-Leu-Arg]-CO 2 H,
- SEQ ID NO: 4 H 2 N-[Arg-Arg-Leu-Phe-Arg-Leu-Ile-Leu-Arg-Tyr-Leu-Phe]-CO 2 H,
- SEQ ID NO: 5 H 2 N-[Arg-Lys-Leu-Phe-Lys-Arg-Ile-Leu-Arg-Tyr-Leu-Lys]-CO 2 H,
- SEQ ID NO: 6 H 2 N-[Lys-Arg-Leu-Phe-Arg-Lys-Ile-Leu-Lys-Tyr-Leu-Arg]-CO 2 H,
- SEQ ID NO: 7 H 2 N-[Lys-Arg-Leu-Phe-Lys-Arg-Ile-Leu-Arg-Tyr-Leu-Lys]-CO 2 H, and
- SEQ ID NO: 8 H 2 N-[Arg-Lys-Leu-Phe-Arg-Lys-Ile-Leu-Lys-Tyr-Leu-Arg]-CO 2 H
- the derivative consists of the 1st, 2nd, 5th, 6th, 9th, and 12th positions from the N-terminus of the antibacterial peptide consisting of the amino acid sequence of any one of SEQ ID NOs: 5 to 8
- the amino acid corresponding to any one position selected from the group may be substituted with another basic amino acid.
- Amino acid substitutions may generally occur based on the polar, charge, solubility, hydrophobic, hydrophilic and/or amphipathic nature of the residue.
- positively charged (basic) amino acids among amino acids having an electrically charged amino acid are arginine (R), lysine (Lysine; K), and histidine (H)
- negatively charged (acidic) amino acids include Glutamate (E) and Aspartate (D);
- nonpolar amino acids are glycine (G), alanine (A), valine (V), leucine (L), Contains Isoleucine (I), Methionine (M), Phenylalanine (F), Tryptophan (W) and Proline (P), and polar or hydrophilic amino acids are serine (Serine; S), threonine (T), cysteine (C), tyrosine (Y), asparagine (Asparagine; N) and glutamine (Glutamine; Q).
- 'substitution with another basic amino acid' is not limited as long as the amino acid before the substitution is substituted with another basic amino acid. That is, selected from the group consisting of the 1st, 2nd, 5th, 6th, 9th, and 12th positions from the N-terminus of the antibacterial peptide consisting of the amino acid sequence of any one of SEQ ID NOs: 5 to 8 It may be substituted with another basic amino acid in the amino acid before substitution present at any one position, specifically, any one selected from the group consisting of positions X 1, X 2, X 3, X 4, X 5, and X 6 An amino acid present at one position may be substituted with another basic amino acid. Specifically, the basic amino acid may be selected from histidine, lysine, and arginine, and may be lysine or arginine, but is not limited thereto.
- the derivative of the antibacterial peptide consisting of the amino acid sequence of any one of SEQ ID NOs: 5 to 8 may be any one or more selected from the group consisting of SEQ ID NOs: 1 to SEQ ID NO: 4, not limited
- the peptides of SEQ ID NOs: 5 to SEQ ID NO: 8 and derivatives thereof, peptides of SEQ ID NOs: 1 to 4 have the structure of Formula 1, and were confirmed to have antibacterial activity (Example 2).
- the antibacterial peptide or derivative thereof composed of the amino acid sequence of Formula 1 has excellent antibacterial activity, and more specifically, SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 5 to SEQ ID NO: 8, more specifically, SEQ ID NO: 5 to SEQ ID NO: 8, in particular, it was confirmed that the antibacterial activity of SEQ ID NO: 6 is remarkably excellent (Examples 1 and 2).
- fragment refers to a partial sequence of a peptide having a specific sequence, and may be a partial sequence of an antibacterial peptide or a derivative thereof consisting of an amino acid sequence of any one of SEQ ID NOs: 5 to 8, and the antibacterial Like a peptide or a derivative thereof, it may have antimicrobial activity.
- the antibacterial peptide, derivative thereof, or fragment thereof comprising the amino acid sequence of any one of SEQ ID NOs: 5 to 8 may be derived from a natural product, but is not limited thereto and has the same activity as the antibacterial peptide, derivative thereof, or fragment thereof. Sequences with can be included without limitation.
- the antibacterial peptide in the present invention has been described as an antibacterial peptide consisting of any one of the amino acid sequences of SEQ ID NOs: 5 to 8, derivatives thereof, or fragments thereof, but with the amino acid sequence of any one of SEQ ID NOs: 5 to 8
- the amino acid sequence of any one of SEQ ID NO: 5 to SEQ ID NO: 8 is not excluded by adding meaningless sequences before and after the amino acid sequence of the constituting antibacterial peptide, derivative thereof, or fragment thereof, or for maintaining the same function as the antibacterial peptide It may be apparent to those skilled in the art that the antibacterial peptide of the present invention corresponds to the antibacterial peptide of the present invention if it has the same or corresponding activity to the antibacterial peptide, derivative thereof, or fragment thereof composed of the sequence.
- the antibacterial peptide of the present invention is an antibacterial peptide, a derivative thereof, a fragment thereof, or 80%, 90%, 95%, 96% thereof consisting of the amino acid sequence of any one of SEQ ID NOs: 5 to 8; It may be a peptide consisting of an amino acid sequence having at least 97%, 98%, or 99% homology or identity.
- peptides having an amino acid sequence in which some sequences are deleted, modified, substituted, conservatively substituted or added may also be used in the present invention, provided they have the same or corresponding activity as a peptide consisting of an amino acid sequence of
- the amino acid sequence N-terminus and/or C-terminus is a case of adding a sequence that does not alter the function of the peptide, a naturally occurring mutation, a silent mutation or a conservative substitution thereof.
- conservative substitution means substituting an amino acid for another amino acid having similar structural and/or chemical properties. Such amino acid substitutions may generally occur based on similarity in the polarity, charge, solubility, hydrophobicity, hydrophilicity and/or amphipathic nature of the residues. Typically, conservative substitutions may have little or no effect on the activity of the peptide.
- the peptide of the present invention may be prepared by continuously forming amide bonds with one or more amino acids or suitably protected amino acids in an amino acid backbone that is constantly bound to a solid phase, but is not limited thereto.
- the peptide can insert, substitute, or delete other amino acids within a range that does not significantly reduce stability, and this also falls within the scope of the present invention.
- the peptide of the present invention may be prepared as a form in which a cell permeable peptide that promotes intracellular migration is bound to the C-terminus or the N-terminus.
- the cell-penetrating peptide includes a TAT peptide (Arg-Lys-Lys-Arg-Arg-Tyr-Arg-Arg-Arg) and a Tat-PTD peptide (Gly-Arg-Lys-Lys-Arg-Arg-Gln- Arg-Arg-Arg: Tat PTD), but the present invention is not limited thereto. Any cell-penetrating peptide known in the art may be used as long as it does not inhibit the activity of the peptide according to the present invention. do.
- the peptides and compounds of the present invention may be prepared in the form of a metal complex, and the metal may be selected from copper, magnesium, calcium, iron, zinc, nickel, silver, germanium, and gallium, but is not limited thereto. , but preferably copper may be used, but is not limited thereto.
- the peptide of the present invention may exist in the form of a salt.
- the salt form usable in the present invention may be one prepared during the final isolation and purification of the compound or by reacting an amino group with an appropriate acid.
- acid addition salts acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemi Sulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, mesitylenesulfonate, methanesulfonate, Naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamo
- the peptide of the present invention may be prepared in the form of a trifluoroacetate salt or an acetate salt.
- An amino group or a carboxyl group of an amino acid used for preparing a peptide included in the composition of the present invention may be protected by a suitable protecting group.
- the protected amino acid can be attached to a solid support or reacted in solution by adding the following amino acids under conditions suitable for forming an amide bond.
- the protecting group may be completely removed prior to addition of the amino acid protected with a suitable protecting group. After all amino acids have been linked as desired, the final desired peptide can be obtained by sequential or simultaneous separation from the free residual protecting group and the free solid support.
- a solid-phase peptide synthesis method synthesized using a solid-phase polymer member may be used.
- the protecting group of the amino acid must have a property of being stable under the conditions of the peptide condensation reaction, and must have the property of being easily removable without breaking the extended peptide chain or without racemization of any chiral center contained therein.
- suitable protecting groups include 9-fluorenylmethyloxycarbonyl (Fmoc), t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), biphenylisopropyl-oxycarbonyl, t-amyloxycarbonyl nyl, isobornyloxycarbonyl, ( ⁇ , ⁇ )-dimethyl-3,5-dimethoxybenzyloxycarbonyl, O-nitrophenylsulfenyl, 2-cyano-t-butyloxycarbonyl, and the like;
- Other suitable protecting groups known in the art for this purpose may also be used within the scope of the present invention.
- a 9-fluorenylmethyloxycarbonyl (Fmoc) protecting group may be used as the most preferred protecting group for the amino acid used in the peptide synthesis of the present invention.
- the protecting group of the amino acid residue used in the peptide synthesis of the present invention is t-butyl (t-Bu); for lysine, t-butoxycarbonyl (Boc); for serine, 7t-butyl (t-Bu); for threonine and allothreonine, t-butyl (t-Bu);
- trityl Trt is preferable, but the present invention is not limited thereto.
- the C-terminal amino acid may be attached to a suitable solid support or resin.
- a suitable solid support useful for the above synthesis is preferably a material inert to the reagents and reaction conditions of the stepwise condensation-deprotection reaction and insoluble in the medium used, for example, 2-chlorotrityl chloride resin (2-chlorotrityl chloride resin), link amid (rink amid) or link amide 4-methylbenzylhydrylamine resin (rink amid MBHA resin).
- a preferred solid support for the C-terminal peptide may be 2-chlorotrityl chloride, rink amid or link amide 4-methylbenzylhydrylamine resin (rink amid MBHA resin) commercially available from Novabiochem Corporation. .
- amide C-terminal amide (amide) in a solvent such as dichloromethane, N-methylpyridone (NMP) or DMF at a temperature of 10 °C to 50 °C, preferably at a temperature of 30 °C, for 1 to 24 hours 4 -Dimethylaminopyridine (DMAP), 1-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium-hexafluorophosphate ( N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcar in the presence or absence of BOP) or bis(2-oxo-3-oxazolidinyl)phosphine chloride (BOPCI) Bodiimi (DIC), [O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluor
- the Fmoc functional group as a preferred protecting group can be treated with an excess of a secondary amine solution, preferably a 20% piperidine DMF solution, prior to condensation with the C-terminal amino acid.
- cut Preferred reagents used to condense the desired amino acid to the deprotected 4-(2',4'-dimethoxyphenyl-Fmoc-aminomethyl)phenoxyacetamidoethyl resin include a DMF solvent for the suitably protected amino acid.
- N-methylmorpholine NMM
- 1-hydroxybenzotriazole HOBt
- O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluoro Rophosphate] HATU
- O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate HBTU
- N,N'-dicyclohexylcarbodiimide condensation reaction reagents such as (DCC) or N,N'-diisopropylcarbodiimide (DIC).
- Condensation of consecutive amino acids performed in the present invention may be performed manually or manually using an automatic peptide synthesizer widely known in the art.
- Preferred conditions for the synthesis reaction include deprotection of the ⁇ -amino acid protected with the Fmoc group by treatment with a secondary amine solution, preferably piperidine, followed by washing with a sufficient excess of solvent and another each protected ⁇ -amino acid desired for condensation.
- the reaction can be carried out, preferably in a DMF solvent, by adding the amino acid in a 3- to 7-fold molar excess.
- the peptide to be obtained from the resin can be removed from the resin by continuously or one-time manipulation of the peptide, and the protecting groups protecting the amino acid residues can be deprotected.
- Conditions for removal of the peptide from the resin and deprotection of the protecting groups present on the residue include a cocktail of cleavage reagents that generally cleave the resin-peptide bond, e.g., trifluoroacetic acid (TFA), triisopropylsilane (TIS) It can be obtained by treating a dichloromethane mixed cocktail solution composed of , thioanisole, water or ethanedithiol (EDT).
- the mixed solution thus obtained may form a precipitate by excessive treatment of the diethyl ether solvent stored in the refrigerator.
- the precipitate obtained as described above was completely precipitated by centrifugation, and excess trifluoroacetic acid, triisopropylsilane, thioanisole, water and ethanedithiol were first removed, and the above procedure was repeated twice or more to obtain a solidified precipitate.
- the completely deprotected peptide salt can be separated and purified using a mixed solvent composed of water and an acetonitrile solvent and reverse phase high performance liquid chromatography (HPLC).
- HPLC high performance liquid chromatography
- Another aspect of the present invention provides a polynucleotide encoding an antimicrobial peptide, a derivative thereof, or a fragment thereof consisting of an amino acid sequence of any one of SEQ ID NOs: 5 to 8.
- amino acid sequence, antibacterial peptide, derivative, and fragment of any one of SEQ ID NOs: 5 to 8 are as described above.
- the antibacterial peptide consisting of the amino acid sequence of any one of SEQ ID NOs: 5 to 8 may be composed of the sequence of Formula 1, and the derivative is selected from the group consisting of SEQ ID NOs: 1 to SEQ ID NO: 4 It may be composed of any one sequence, but is not limited thereto.
- antibacterial peptide, derivative thereof, or fragment thereof may be encoded by any one sequence selected from the group consisting of SEQ ID NOs: 9 to 16, but is not limited thereto.
- amino acid sequence of SEQ ID NO: 5 to SEQ ID NO: 8 or a derivative thereof is, for example, encoded by a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 9 to SEQ ID NO: 16 can
- polynucleotide refers to a DNA or RNA strand of a certain length or more as a polymer of nucleotides in which nucleotide monomers are connected in a long chain form by covalent bonds.
- the polynucleotide may encode an antibacterial peptide having the amino acid sequence of SEQ ID NO: 5 to SEQ ID NO: 8, a derivative thereof, or a peptide exhibiting the activity of a fragment thereof, but is not limited thereto.
- the polynucleotide may be included without limitation as long as it is a polynucleotide encoding a peptide having the activity of the antibacterial peptide, derivative thereof, or fragment thereof according to the present invention.
- the polynucleotide encoding the peptide exhibiting the activity of the antibacterial peptide, its derivative, or its fragment may include a nucleotide sequence encoding an amino acid described in Formula 1, the antibacterial peptide, its derivative, or its fragment.
- various modifications can be made to the coding region within the range that does not change the amino acid sequence of the peptide due to the degeneracy of the codon or in consideration of the codon preferred in the organism in which the peptide is to be expressed. .
- the polynucleotide may include, for example, the nucleotide sequence of SEQ ID NO: 9 to SEQ ID NO: 16, and the homology or identity thereof is 80%, specifically 90% or more, more specifically 95% or more, 96% or more, 97 % or more, 98% or more, or more specifically, 99% or more of the base sequence, but is not limited thereto.
- polynucleotide of the present invention is hybridized with a probe, for example, a sequence complementary to all or part of the nucleotide sequence under stringent conditions, and amino acids of SEQ ID NOs: 5 to 8, derivatives thereof, or fragments thereof Any sequence encoding the sequence may be included without limitation.
- stringent condition refers to a condition that enables specific hybridization between polynucleotides. These conditions are specifically described in the literature (eg, J. Sambrook et al.). For example, polynucleotides with high homology or identity are 40% or more, specifically 90% or more, more specifically 95% or more, 96% or more, 97% or more, 98% or more, and more specifically 99% or more.
- Hybridization requires that two nucleic acids have complementary sequences, although mismatch between bases is possible depending on the stringency of hybridization.
- the term “complementary” is used to describe the relationship between nucleotide bases capable of hybridizing to each other.
- adenine is complementary to thymine
- cytosine is complementary to guanine.
- the polynucleotides of the present invention may also comprise substantially similar nucleic acid sequences as well as isolated nucleic acid fragments complementary to the overall sequence.
- polynucleotides having homology or identity can be detected using hybridization conditions including a hybridization step at a Tm value of 55° C. and using the above-described conditions.
- the Tm value may be 60 °C, 63 °C, or 65 °C, but is not limited thereto and may be appropriately adjusted by those skilled in the art according to the purpose.
- the term 'homology' or 'identity' refers to a degree related to two given amino acid sequences or nucleotide sequences and may be expressed as a percentage.
- the terms homology and identity can often be used interchangeably.
- Sequence homology or identity of a conserved polynucleotide or peptide is determined by standard alignment algorithms, with default gap penalties established by the program used may be used.
- Substantially homologous or homologous sequences generally have moderate or high stringency conditions along at least about 50%, 60%, 70%, 80% or 90% of the entire or full-length sequence. It can hybridize under stringent conditions. It is obvious that hybridization also includes polynucleotides containing common codons in polynucleotides or codons taking codon degeneracy into account.
- a GAP program can be defined as the total number of symbols in the shorter of the two sequences divided by the number of similarly aligned symbols (ie, nucleotides or amino acids).
- Default parameters for the GAP program are: (1) a binary comparison matrix (containing values of 1 for identity and 0 for non-identity) and Schwartz and Dayhoff, eds., Atlas Of Protein Sequence And Structure, National Biomedical Research Foundation , pp. 353-358 (1979), Gribskov et al (1986) Nucl. Acids Res. 14: weighted comparison matrix of 6745 (or EDNAFULL (EMBOSS version of NCBI NUC4.4) substitution matrix); (2) a penalty of 3.0 for each gap and an additional 0.10 penalty for each symbol in each gap (or a gap open penalty of 10, a gap extension penalty of 0.5); and (3) no penalty for end gaps.
- Another aspect of the present invention provides a carrier for external application to the skin comprising an antimicrobial peptide, a derivative thereof, or a fragment thereof consisting of an amino acid sequence of any one of SEQ ID NOs: 5 to 8.
- amino acid sequence, antibacterial peptide, derivative, and fragment of any one of SEQ ID NOs: 5 to 8 are as described above.
- carrier means that any material or component, for example, a composition, can be supported, and may be used interchangeably with a carrier, an impregnating agent, or a medium.
- the composition which is an example of the carrier, may be applied and delivered to the skin through an application means such as a hand, a puff, a tip, or a brush.
- the carrier may be included in a cosmetic composition, a pharmaceutical composition, or a quasi-drug composition, but is not limited thereto, and for the purpose of the present invention, the carrier is an antibacterial ( antimicrobial) peptides, derivatives thereof, or fragments thereof.
- external preparation for skin refers to a formulation applied to the skin.
- the external preparation is not limited in shape as long as it is a formulation applied to the skin, and the external preparation may be further classified into an ointment, a cream, a lotion, a gel, and the like, but is not limited thereto.
- the ointment may be a semi-solid external preparation in which a main ingredient applied to the skin is dissolved or dispersed in a base.
- the base can be divided into an oily ointment or a water-soluble ointment according to the ingredients.
- Ointments using an oily base can soften the skin, have excellent sealing properties, and are suitable for application to wounds, but have disadvantages in that they are not easy to remove.
- It may be an advantageous formulation for topically permeating ingredients that are difficult to penetrate into the skin due to skin-like oil-soluble properties and skin softening action.
- the ointment is mainly composed of an oily phase such as oil, so it has excellent moisturizing properties and good penetration of fat-soluble components, but has a sticky disadvantage.
- the cream may be a semi-solid external preparation emulsified in a water-in-oil type, It may be a formulation with improved stickiness. As an emulsification process, it may be mixed through a surfactant or a special process to mix the oil phase and the aqueous phase.
- a cream may be a formulation that is easier to apply and remove than an ointment
- a lotion is a formulation having properties more similar to water than a cream, and may be an external formulation in which the main ingredient is dissolved in an aqueous solution, or emulsified or finely dispersed. It may be a solution, suspension, or emulsion using the main component, additive, purified water, etc. to make the whole homogeneous.
- the gel may be a semi-solid external preparation composed of organic molecules having a large molecular weight permeated with a liquid.
- a gelling agent may be dispersed in aqueous solution, and a gelling agent such as carbomer or synthetic polymer may be used.
- the type of solvent may be used in various types depending on the active ingredient, purpose of use, method of use, etc., and the topical application of the present invention is not limited thereto.
- Another aspect of the present invention provides a cosmetic composition
- a cosmetic composition comprising an antimicrobial peptide, a derivative thereof, or a fragment thereof consisting of an amino acid sequence of any one of SEQ ID NOs: 5 to 8.
- amino acid sequence, antibacterial peptide, derivative, and fragment of any one of SEQ ID NOs: 5 to 8 are as described above.
- the cosmetic composition includes a solution, an external ointment, a cream, a foam, a nourishing lotion, a flexible lotion, a perfume, a pack, a soft water, an emulsion, a makeup base, an essence, a soap, a liquid detergent, a bath agent, a sunscreen cream, a sun oil, and a suspension.
- emulsion, paste, gel, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation, patch and spray but limited thereto doesn't happen
- the cosmetic composition of the present invention may further include one or more cosmetically acceptable carriers to be formulated in general skin cosmetics, and conventional ingredients include, for example, oil, water, surfactant, humectant, lower alcohol, thickener, A chelating agent, a colorant, a preservative, a fragrance, etc. may be appropriately blended, but the present invention is not limited thereto.
- the cosmetically acceptable carrier included in the cosmetic composition of the present invention varies depending on the formulation of the cosmetic composition.
- the formulation of the present invention is an ointment, paste, cream or gel
- a carrier component animal oil, vegetable oil, wax, paraffin, starch, tracanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, zinc oxide, etc. may be used, but is not limited thereto. These may be used alone or in combination of two or more.
- lactose, talc, silica, aluminum hydroxide, calcium silicate, polyamide powder, etc. may be used as a carrier component, and in particular, in the case of a spray, additional chlorofluorohydro propellants such as, but not limited to, carbon, propane/butane or dimethyl ether. These may be used alone or in combination of two or more.
- a solvent, solubilizer, or emulsifier may be used as a carrier component, for example, water, glycerin, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzo Eate, propylene glycol, 1,3-butyl glycol oil and the like can be used, and in particular, cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol aliphatic ester, polyethylene glycol or sorbitan.
- Fatty acid esters may be used, but are not limited thereto. These may be used alone or in combination of two or more.
- the formulation of the present invention is a suspension
- a liquid diluent such as water, glycerin, ethanol or propylene glycol
- a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol esters and polyoxyethylene sorbitan esters , microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or tracanth may be used, but is not limited thereto. These may be used alone or in combination of two or more.
- alkali metal salts of fatty acids fatty acid hemiester salts, fatty acid protein hydrolysates, isethionate, lanolin derivatives, aliphatic alcohols, vegetable oils, glycerol, sugar, etc. are used as carrier components. may be, but is not limited thereto. These may be used alone or in combination of two or more.
- Another aspect of the present invention provides a quasi-drug composition
- a quasi-drug composition comprising an antimicrobial peptide, a derivative thereof, or a fragment thereof consisting of an amino acid sequence of any one of SEQ ID NOs: 5 to 8.
- amino acid sequence, antibacterial peptide, derivative, and fragment of any one of SEQ ID NOs: 5 to 8 are as described above.
- quasi-drug refers to items with a milder action than pharmaceuticals among items used for the purpose of diagnosing, treating, improving, alleviating, treating or preventing diseases of humans or animals.
- quasi-drugs It excludes products used for pharmaceutical purposes, and includes products used for the treatment or prevention of diseases in humans and animals, and products with minor or no direct action on the human body.
- the quasi-drug composition of the present invention may be prepared selected from the group consisting of body cleanser, foam, soap, mask, ointment, cream, lotion, essence and spray, but is not limited thereto.
- the antibacterial peptide, derivative thereof, or fragment thereof comprising the amino acid sequence of any one of SEQ ID NOs: 5 to 8 is 0.01 wt% to 100.0 wt%, 0.1 wt% of the total composition to 10% by weight.
- Another aspect of the present invention provides a pharmaceutical composition for external application to the skin comprising an antimicrobial peptide, a derivative thereof, or a fragment thereof consisting of an amino acid sequence of any one of SEQ ID NOs: 5 to 8.
- amino acid sequence of any one of SEQ ID NOs: 5 to 8, antibacterial peptides, derivatives, fragments, and external preparations for skin are as described above.
- composition of the present invention in addition to including an antimicrobial peptide, a derivative thereof, or a fragment thereof consisting of the amino acid sequence of SEQ ID NO: 5 to SEQ ID NO: 8, may further include a pharmaceutically acceptable carrier.
- the term "pharmaceutically acceptable” means that when administered, it does not stimulate an organism and does not inhibit the biological activity and properties of the administered compound, which means that it can be commonly used in the pharmaceutical field.
- the pharmaceutical composition of the present invention, formulated together with the carrier, can be utilized as food, medicine, feed additive, drinking water additive, and the like.
- the type of the carrier is not particularly limited, and any carrier commonly used in the art may be used.
- Non-limiting examples of the carrier include saline, sterile water, Ringer's solution, buffered saline, albumin, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, maltodextrin, glycerol, ethanol, and the like. . These may be used alone or in combination of two or more, but is not limited thereto.
- the pharmaceutical composition of the present invention can be used by adding other pharmaceutically acceptable additives such as excipients, diluents, antioxidants, buffers or bacteriostats, if necessary, and fillers, extenders, wetting agents, disintegrants, dispersants, and interfacial agents.
- An activator, a binder or a lubricant may be additionally added and used, but is not limited thereto.
- composition of the present invention may be formulated and used in various formulations suitable for external application to the skin.
- Non-limiting examples of the external preparation for skin include an aerosol, a spray, a detergent, an ointment, an application powder, an oil, a cream, and the like, but is not limited thereto, as long as it can function as an external preparation for the skin.
- sterile aqueous solutions In order to formulate the pharmaceutical composition of the present invention for external use on the skin, sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, external preparations, etc. may be used, and the non-aqueous solvents and suspensions include propylene glycol, polyethylene Glycol, vegetable oil such as olive oil, ester such as ethyl oleate may be used, but is not limited thereto.
- the pharmaceutical composition of the present invention when formulating the pharmaceutical composition of the present invention, is mixed with a stabilizer or buffer in water to prepare a solution or suspension, and it is formulated in units such as ampoules.
- a propellant or the like when the pharmaceutical composition of the present invention is formulated as an aerosol, a propellant or the like may be formulated with an additive to disperse the dispersed concentrate or wet powder, but is not limited thereto.
- composition of the present invention when formulated into an ointment, cream, etc., animal oil, vegetable oil, wax, paraffin, starch, tracanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, oxidized It may be formulated using zinc or the like as a carrier, but is not limited thereto.
- the pharmaceutical composition of the present invention may be formulated for external use on the skin, more preferably a gel, a patch, a spray, an ointment, a warning agent, a lotion, a liniment agent, a pasta agent, and a cataplasm agent selected from the group consisting of It may have a formulation, but is not limited thereto.
- the pharmaceutically effective amount of the pharmaceutical composition of the present invention and the effective dosage for external application may vary depending on the formulation method, administration method, administration time and/or route of administration of the pharmaceutical composition, and the administration of the pharmaceutical composition
- the type and degree of response to be achieved, the type of subject to be administered, age, weight, general health condition, symptoms or severity of disease, sex, diet, excretion, drugs or other compositions used simultaneously with or at the same time in the subject It may vary depending on several factors including the component of the pharmaceutical field and similar factors well known in the pharmaceutical field, and those skilled in the art can easily determine and prescribe an effective dosage for the desired treatment.
- Administration of the pharmaceutical composition of the present invention may be administered once a day, may be administered divided into several times. Therefore, the above dosage does not limit the scope of the present invention in any way.
- administration in the present invention may be administration as an external preparation, and a preferred dosage of the pharmaceutical composition of the present invention may be 1 mg/kg to 1,OOO mg/kg per day.
- the administration route and administration method of the pharmaceutical composition of the present invention may be each independent, and the method is not particularly limited, and any administration route and administration method as long as the pharmaceutical composition can reach the desired site. method can be followed.
- the pharmaceutical composition may be administered as an external preparation for skin. Specifically, a method of applying or spraying the composition to the diseased site may be used, but is not limited thereto.
- the pharmaceutical composition of the present invention may be preferably administered by application or spraying, and specifically, in a method of topical application to areas in need of improvement of skin condition or prevention, improvement or treatment of skin diseases. may be administered.
- Another aspect of the present invention provides an antibacterial use of the antimicrobial peptide, derivative thereof, or fragment thereof of the present invention.
- the antibacterial means antimicrobial activity, and since the antimicrobial activity is not limited to the type of microorganism, the 'antibacterial' may be used interchangeably with antibacterial, antifungal, and antibiotic. have.
- antibacterial peptides, derivatives, and fragments are as described above.
- Another aspect of the present invention provides an antibacterial method comprising treating a subject with an antimicrobial peptide, derivative thereof, or fragment thereof of the present invention.
- the subject is not limited as long as it is a subject to be treated with an antibacterial peptide, a derivative thereof, or a fragment thereof, which requires antibacterial, and the treatment may be performed by spraying or applying an antibacterial peptide, a derivative thereof, or a fragment thereof to contact the subject. You are not limited if you can.
- the antibacterial peptides, derivatives, and fragments are as described above.
- SEQ ID NO: 5 to SEQ ID NO: 8 and derivative peptides thereof were prepared.
- Phenylalanine / Ile Isoleucine / Lys: Lysine / Leu: Leucine / Arg: Arginine / Tyr: Tyrosine
- the peptide was cleaved from the resin by using a mixture of trifluoroacetic acid/triisopropylsilane/water (95:2.5:2.5) (10 ml) for the resin on which the peptide was condensed for 3 hours. .
- a precipitate was formed by treating 100 ml of a diethyl ether solvent refrigerated with the thus-obtained mixed solution. The resulting precipitate was completely precipitated by centrifugation, and trifluoroacetic acid was first removed. work) was repeated twice to obtain a solidified precipitate.
- the precipitate (peptide) was purified by HPLC using a gradient solvent system of 5% to 100% acetonitrile/water containing 0.001% trifluoroacetic acid over 50 minutes using a C-18 column.
- the purified pure fraction was freeze-dried to obtain 155 mg of the antibacterial peptide of SEQ ID NO: 1 as a white powdery trifluoroacetate salt.
- SEQ ID NO: 1 H 2 N-[Lys-Lys-Leu-Phe-Lys-Lys-Ile-Leu-Lys-Tyr-Leu-Lys]-CO 2 H
- SEQ ID NO: 2 to SEQ ID NO: 8 were prepared by using the same manufacturing process as in Preparation Example 1-1, but by changing the order of amino acids protected with Fmoc.
- SEQ ID NO: 2 H 2 N-[Arg-Arg-Leu-Phe-Arg-Arg-Ile-Leu-Arg-Tyr-Leu-Arg]-CO 2 H
- SEQ ID NO: 3 H 2 N-[Arg-Phe-Leu-Phe-Arg-Leu-Ile-Leu-Arg-Tyr-Leu-Arg]-CO 2 H
- SEQ ID NO: 4 H 2 N-[Arg-Arg-Leu-Phe-Arg-Leu-Ile-Leu-Arg-Tyr-Leu-Phe]-CO 2 H
- SEQ ID NO: 5 H 2 N-[Arg-Lys-Leu-Phe-Lys-Arg-Ile-Leu-Arg-Tyr-Leu-Lys]-CO 2 H
- SEQ ID NO: 6 H 2 N-[Lys-Arg-Leu-Phe-Arg-Lys-Ile-Leu-Lys-Tyr-Leu-Arg]-CO 2 H
- SEQ ID NO: 7 H 2 N-[Lys-Arg-Leu-Phe-Lys-Arg-Ile-Leu-Arg-Tyr-Leu-Lys]-CO 2 H
- SEQ ID NO: 8 H 2 N-[Arg-Lys-Leu-Phe-Arg-Lys-Ile-Leu-Lys-Tyr-Leu-Arg]-CO 2 H
- Example 1 Evaluation of antibacterial activity and cytotoxicity of SEQ ID NOs: 5 to 8 and derivatives thereof
- antibacterial activity and cytotoxicity were evaluated.
- Antimicrobial activity and cytotoxicity of SEQ ID NO: 1 to SEQ ID NO: 4, which are antibacterial peptides and derivatives thereof, consisting of any one amino acid sequence selected from SEQ ID NO: 5 to SEQ ID NO: 8 of the present invention were evaluated.
- the antibacterial activity against Escherichia coli was measured, and the cell viability was measured by treating E. coli with an antibacterial peptide and then compared.
- E. coli used in this experiment was purchased from the Korea Research Institute of Bioscience and Biotechnology Biological Resources Center (KTCC) and cultured using LB medium.
- Human keratinocytes (HaCaT) were purchased from ATCC (American Type Culture Collection, USA), and 10% Incubated in Dulbecco's modified Eagle's medium (DMEM, Gibco, USA) containing fetal bovine serum (FBS, Gibco, USA) and 1% antibiotic-antimycotic (Gibco, USA) in a 5% CO2 incubator at 37°C.
- DMEM Dulbecco's modified Eagle's medium
- FBS fetal bovine serum
- Gibco, USA antibiotic-antimycotic
- E. coli was cultured for about 8 hours using LB medium, and then the cultured bacteria were dispensed into 96 well plates.
- Antibacterial peptide samples by concentration were put into each well, and after incubation at 37 °C for 24 hours, absorbance was measured at 600 nm using a microplate reader, and the sample was expressed as a percentage (%) compared to the untreated group.
- MTT assay was performed to determine the survival rate of HaCaT cells against the antimicrobial peptide.
- HaCaT cells were cultured in a 96-well plate at 2 ⁇ 10 5 cells/ml for 24 hours, then samples were treated for each concentration and cultured again for 24 hours. The cultured medium was removed and treated with MTT solution (0.5 mg/ml in PBS). After 4 hours, the MTT solution was removed, DMSO was added to each well, formazan was dissolved at 37°C for 30 minutes, and absorbance was measured at 570 nm using a microplate reader (Molecular Devices Spectra MAX, Sunnyvale, CA, USA). . All experiments were statistically processed by taking the average value of 3 wells for each concentration, and it was expressed as a relative survival rate (%) compared to the sample untreated group.
- the antibacterial activity and cytotoxicity of the antibacterial peptide of SEQ ID NO: 1 were preferentially measured, and the antibacterial activity and cytotoxicity of SEQ ID NO: 1 and the known antibacterial peptide were compared and analyzed.
- the sequence of the antibacterial peptide used in this example is as follows.
- SEQ ID NO: 1 has a significant effect as an antibacterial peptide compared to the known peptide, despite the fact that one amino acid is added to the known peptide sequence.
- SEQ ID NO: 1 and SEQ ID NO: 2 were comparatively analyzed.
- SEQ ID NO: 2 has a significant effect as an antibacterial peptide.
- SEQ ID NO: 5 to SEQ ID NO: 8 The antibacterial activity and cytotoxicity of SEQ ID NO: 5 to SEQ ID NO: 8 were comparatively analyzed.
- the experimental method used an antibacterial activity experiment, and the MIC and IC 50 values for the experimental results were calculated by evaluating the minimum growth inhibitory concentration and 50% growth inhibition concentration as absorbance OD values, respectively.
- the peptides of SEQ ID NO: 5 to SEQ ID NO: 8, in particular, SEQ ID NO: 6 and SEQ ID NO: 8, have significantly increased antibacterial activity and significantly reduced cytotoxicity compared to the peptide of SEQ ID NO: 1, resulting in a significant effect as an antibacterial peptide It was confirmed that there is
- SEQ ID NO: 3 and SEQ ID NO: 4 despite the similarity to the sequence of the peptide of SEQ ID NO: 2, the antibacterial activity of SEQ ID NO: 2 is significantly increased compared to SEQ ID NO: 3 and SEQ ID NO: 4 and the cytotoxicity is reduced Therefore, it was confirmed that the effect of SEQ ID NO: 2 as an antibacterial peptide is very excellent as compared to the peptides of SEQ ID NO: 3 and SEQ ID NO: 4, and not all peptides having a size and sequence similar to those of the present invention have excellent antibacterial activity.
- Example 2 Evaluation of antibacterial activity and cytotoxicity of antibacterial peptides against other bacteria
- the antibacterial peptide of the present invention has antibacterial activity in other bacteria other than E. coli, the Ministry of Food and Drug Safety official strain Escherichia coli , Staphylococcus aureus , Pneumonia aeruginosa , and Candida ( Candida albicans ) was confirmed for the antibacterial effect.
- Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa used LB medium, and Candida bacteria were cultured using YM medium, and the cultured bacteria were dispensed into 96 well plates.
- Antimicrobial peptide samples by concentration were put into each well, and after incubation at 37 °C for 24 hours, absorbance was measured at 600 nm using a microplate reader, and the sample was expressed as a percentage (%) compared to the untreated group.
- the IC 50 values showing the antibacterial activity of the peptides of SEQ ID NO: 1 to SEQ ID NO: 8 against four bacteria are as follows, and in all SEQ ID NOs except SEQ ID NOs: 3 and 4, Escherichia coli, Staphylococcus aureus, It showed strong antibacterial activity against Pseudomonas aeruginosa and Candida (Table 2).
- Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Candida were cultured in each medium, and then the cultured bacteria were treated with a certain amount of solid medium to harden. After 10 ul of antibacterial peptide sample was treated on the solid surface of the solid medium, a dry 3M paper disk was placed on it, and then incubated at 37°C for 16 hours to observe the size of the inhibition ring.
- the antibacterial peptides of SEQ ID NOs: 5 to 8 and derivatives thereof of the present invention exhibit remarkable antibacterial activity not only in E. coli, but also in Staphylococcus aureus, Pseudomonas aeruginosa, and Candida.
- Example 3 Antibacterial activity effect using the destruction of the microbial cell membrane of the antibacterial peptide
- E. coli was treated with the peptide of SEQ ID NO: 6 for 30 minutes, and then the antibacterial effect was analyzed using a scanning electron microscope (SEM). .
- the antimicrobial peptide, derivative thereof, or fragment thereof of the present invention has excellent antibacterial activity and reduced cytotoxicity, and thus has a significant effect as an antibacterial peptide.
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Abstract
Description
Claims (11)
- 서열번호 5 내지 서열번호 8 중 어느 하나의 아미노산 서열로 구성되는 항균(antimicrobial) 펩타이드, 이의 유도체, 또는 이의 단편.
- 제1항에 있어서, 상기 유도체는 상기 서열번호 5 내지 서열번호 8 중 어느 하나로 구성되는 항균 펩타이드의 N-말단으로부터 1번째, 2번째, 5번째, 6번째, 9번째, 및 12번째 위치로 구성되는 군에서 선택된 어느 하나의 위치에 상응하는 아미노산이 다른 염기성 아미노산으로 치환된, 항균 펩타이드, 이의 유도체, 또는 이의 단편.
- 제2항에 있어서, 상기 염기성 아미노산이 라이신(Lysine) 또는 아르기닌(Arginine)인 것인, 항균 펩타이드, 이의 유도체, 또는 이의 단편.
- 제1항에 있어서, 상기 유도체는 서열번호 1 내지 서열번호 4로 구성되는 군에서 선택되는 어느 하나 이상인 것인, 항균 펩타이드, 이의 유도체, 또는 이의 단편.
- 제1항에 있어서, 상기 항균 펩타이드, 이의 유도체, 또는 이의 단편은 대장균(Escherichia coli), 황색포도상구균(Staphylococcus aureus), 녹농균(Pneumonia aeruginosa), 및 칸디다균(Candida albicans)으로 구성되는 군에서 선택된 어느 하나 이상의 생장을 저해하는 것인, 항균 펩타이드, 이의 유도체, 또는 이의 단편.
- 제1항 내지 제5항 중 어느 한 항의 항균 펩타이드, 이의 유도체, 또는 이의 단편을 코딩하는 폴리뉴클레오티드.
- 제6항에 있어서, 상기 항균 펩타이드, 이의 유도체, 또는 이의 단편은 서열번호 9 내지 서열번호 16의 서열 중 어느 하나의 서열로 코딩되는 것인, 폴리뉴클레오티드.
- 제1항 내지 제5항 중 어느 한 항의 항균 펩타이드, 이의 유도체, 또는 이의 단편을 포함하는 피부 외용제용 담체.
- 제1항 내지 제5항 중 어느 한 항의 항균 펩타이드, 이의 유도체, 또는 이의 단편을 포함하는 화장료 조성물.
- 제1항 내지 제5항 중 어느 하나의 항균 펩타이드, 이의 유도체 또는 이의 단편을 포함하는 의약외품 조성물.
- 제1항 내지 제5항 중 어느 한 항의 항균 펩타이드, 이의 유도체, 또는 이의 단편을 포함하는 피부 외용제용 약학적 조성물.
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EP21923387.1A EP4289858A1 (en) | 2021-01-27 | 2021-11-05 | Novel antimicrobial peptide with excellent microbial cytoplasm elution effect |
CN202180091845.4A CN116745311A (zh) | 2021-01-27 | 2021-11-05 | 具有优异的微生物细胞质洗脱效果的新型抗微生物肽 |
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- 2021-11-05 WO PCT/KR2021/016051 patent/WO2022163978A1/ko active Application Filing
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