WO2023182185A1 - Peptide ayant une fonction d'affinité et/ou d'inhibition des gingipaïnes et son utilisation - Google Patents
Peptide ayant une fonction d'affinité et/ou d'inhibition des gingipaïnes et son utilisation Download PDFInfo
- Publication number
- WO2023182185A1 WO2023182185A1 PCT/JP2023/010461 JP2023010461W WO2023182185A1 WO 2023182185 A1 WO2023182185 A1 WO 2023182185A1 JP 2023010461 W JP2023010461 W JP 2023010461W WO 2023182185 A1 WO2023182185 A1 WO 2023182185A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- amino acid
- peptide
- acid sequence
- gingipain
- derivative
- Prior art date
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- 229940034610 toothpaste Drugs 0.000 description 1
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 1
- 229960000401 tranexamic acid Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- VXYADVIJALMOEQ-UHFFFAOYSA-K tris(lactato)aluminium Chemical compound CC(O)C(=O)O[Al](OC(=O)C(C)O)OC(=O)C(C)O VXYADVIJALMOEQ-UHFFFAOYSA-K 0.000 description 1
- WGIWBXUNRXCYRA-UHFFFAOYSA-H trizinc;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [Zn+2].[Zn+2].[Zn+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O WGIWBXUNRXCYRA-UHFFFAOYSA-H 0.000 description 1
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Classifications
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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
- A61K38/07—Tetrapeptides
-
- 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
- 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
-
- 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
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/99—Enzyme inactivation by chemical treatment
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
- C12Q1/37—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving peptidase or proteinase
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/531—Production of immunochemical test materials
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes
Definitions
- the present invention relates to peptides having affinity and/or inhibitory ability for gingipains and uses thereof. More specifically, the present invention provides a peptide having affinity and/or inhibitory ability for gingipain, a gingipain inhibitor, a gingivalis growth inhibitor, an oral composition, and a method for detecting gingipain using the peptide. Regarding.
- Porphyromonas gingivalis is a periodontal pathogen that is considered important in the onset and progression of periodontal disease, and gingipain, a type of protease produced by Porphyromonas gingivalis, is recognized as an important factor in periodontal disease. has been done.
- gingipains with different peptide cleavage site specificities, specifically, arginine-gingipain (Rgp), which cleaves the C-terminal side of arginine residues, and lysine-gingipains (Rgp), which cleaves the C-terminal side of lysine residues.
- arginine-gingipain Rgp
- lysine-gingipains Rgp
- Kgp lysine-gingipains
- gingipain inhibitors are expected to be an effective means for treating or preventing not only periodontal disease but also various diseases involving gingipain, and their development is progressing (Patent Documents 1 to 5). Furthermore, compounds that bind to gingipain with high affinity are expected to be applied to periodontal disease diagnostic techniques using gingipain as a marker.
- the object of the present invention is to provide a new substance that has specific affinity and/or inhibitory ability for gingipain.
- a peptide comprising the following amino acid sequence (I) or (II) and having a total number of amino acid residues of 4 to 15 [amino acid sequence (I): RX 1 X 2 RX 3 (amino acid sequence (I) [Amino acid sequence (II): RX 4 R ( In the amino acid sequence (II), X 4 is representing any natural amino acid residue); a peptide consisting of the amino acid sequence CRSVKWHHRVFGSC (SEQ ID NO: 11); and a peptide consisting of the amino acid sequence ITHTSRHC (SEQ ID NO: 12); and the following (a) to ( satisfies one or more of c); (a) the dissociation constant (K D ) for arginine-gingipain is 1.0 ⁇ 10 ⁇ 7 M or less; (b) the enzymatic activity of arginine-gingipain is 50% or more at 100 ⁇ M (c) provides a peptide, a derivative
- X 1 is selected from the group consisting of A, R, V, and E
- X 2 is selected from the group consisting of A, F, and K
- X 3 is selected from the group consisting of R and F.
- X 1 is selected from the group consisting of R and E
- X 2 is selected from the group consisting of A and K
- X 3 is R.
- X 1 is R, X 2 is K, and X 3 is R, or X 1 is R, and X 2 is A, X 3 is R, or X 1 is E, X 2 is K, and X 3 is R.
- X 4 is selected from the group consisting of A, P, and K. In one embodiment, X 4 in the above amino acid sequence (II) is P. In one embodiment, the peptide or derivative thereof or salt thereof does not inhibit the enzymatic activity of papain by more than 5% at 100 ⁇ M. In one embodiment, the peptide comprising the above amino acid sequence (I) or (II) is a peptide represented by SEQ ID NOs: 1 to 10. According to another aspect of the present invention, there is provided a gingipain inhibitor comprising the above-mentioned peptide, a derivative thereof, or a salt thereof. According to another aspect of the present invention, there is provided a growth inhibitor of P.
- gingivalis which comprises the above-mentioned peptide, a derivative thereof, or a salt thereof.
- an oral composition comprising the above-mentioned peptide, a derivative thereof, or a salt thereof.
- a method for detecting gingipain which comprises detecting gingipain by an immunoassay method using the above-mentioned peptide, a derivative thereof, or a salt thereof.
- the immunoassay is a sandwich immunoassay using two types of peptides selected from the peptides with different amino acid sequences, derivatives thereof, or salts thereof.
- the sandwich immunoassay method is an ELISA method or an immunochromatography assay method.
- a novel peptide having affinity and/or inhibitory ability for gingipain is provided.
- FIG. 2 is a diagram showing the selection process of gingipain-binding peptides.
- FIG. 2 is a diagram showing an alanine-substituted peptide of peptide “R3-1”. It is a schematic diagram explaining a competition experiment using QCM. It is a graph showing affinity changes of alanine-substituted peptides.
- FIG. 3 is a diagram showing the results of specificity evaluation of peptide “R3-1”.
- FIG. 3 is a diagram showing the results of specificity evaluation of peptides “K7294” and “R5-7”.
- FIG. 3 is a diagram showing the evaluation effect of the ability to inhibit the growth of P. gingivalis bacteria.
- ⁇ representing a numerical range includes the numerical value of the upper limit and the lower limit.
- natural amino acids include alanine (A), leucine (L), arginine (R), lysine (K), asparagine (N), methionine (M), aspartic acid (D), and phenylalanine (F).
- cysteine (C) proline (P), glutamine (Q), serine (S), glutamic acid (E), threonine (T), glycine (G), tryptophan (W), histidine (H), tyrosine (Y) , isoleucine (I), and valine (V).
- A. Peptide - A peptide containing the following amino acid sequence (I) or (II) and having a total number of amino acid residues of 4 to 15 [Amino acid sequence (I): RX 1 X 2 RX 3 (In the amino acid sequence (I), X 1 , X 2 , and X 3 each independently represent any natural amino acid residue)], [Amino acid sequence (II): RX 4 R (In the amino acid sequence (II), X 4 represents any natural amino acid residue)]; - A peptide (peptide "K7226") consisting of the amino acid sequence of CRSVKWHHRVFGSC (SEQ ID NO: 11); and - A peptide (peptide "R5-7”) consisting of the amino acid sequence of ITHTSRHC (SEQ ID NO: 12); selected from A peptide, a derivative thereof, or a salt thereof that satisfies one or more of the following (a) to (c), preferably two or more, is provided
- the dissociation constant (K D ) for Rgp is 1.0 ⁇ 10 ⁇ 7 M or less, preferably 1.0 ⁇ 10 ⁇ 8 M or less, more preferably 1.0 ⁇ 10 ⁇ 9 M or less It is.
- Kgp enzyme activity is inhibited by 50% or more at 500 ⁇ M. In other words, the IC 50 for Kgp is 500 ⁇ M or less, preferably 400 ⁇ M or less, more preferably 300 ⁇ M or less.
- the peptide does not inhibit the enzymatic activity of papain, which is classified as a cysteine protease like gingipain, by more than 5% at 100 ⁇ M.
- the peptide (peptide "K7226") consisting of the amino acid sequence of SEQ ID NO: 11 may have a cyclic form at both terminal Cs due to disulfide bonds.
- the number of R's in the amino acid sequence of the peptide is typically 1 or more, for example 1, 2, 3, or 4, and may be 5 or more.
- X1 is selected from the group consisting of, for example, an alanine residue (A), an arginine residue (R), a valine residue (V), and a glutamic acid residue (E), preferably R and E.
- X2 is selected from the group consisting of, for example, alanine residue (A), phenylalanine residue (F), and lysine residue (K), preferably selected from the group consisting of A and K. be done.
- X 3 is selected, for example, from the group consisting of arginine residue (R) and phenylalanine residue (F), and is preferably R.
- X 1 is R, X 2 is K, and X 3 is R. In one embodiment, in amino acid sequence (I), X 1 is R, X 2 is A, and X 3 is R. In one embodiment, in amino acid sequence (I), X 1 is E, X 2 is K, and X 3 is R.
- the total number of amino acid residues of the peptide containing the amino acid sequence (I) is typically 5 to 15, preferably 5 to 14, and may be, for example, 5 to 12.
- the number of amino acid residues added to the N-terminus of the amino acid sequence (I) is equal to the number of amino acid residues added to the C-terminus. can be greater than or equal to the number of The number of amino acid residues added to the N-terminal side of the amino acid sequence (I) is typically 1 to 10, and may be 1 to 8, for example. The number of amino acid residues added to the C-terminal side of the amino acid sequence (I) is typically 1 to 6, and may be 1 to 5, for example.
- X 4 is selected from the group consisting of, for example, an alanine residue (A), a proline residue (P), and a lysine residue (K), and is preferably P.
- the total number of amino acid residues of the peptide containing the amino acid sequence (II) is typically 4 to 15, preferably 5 to 14, for example 5 to 10.
- the number of amino acid residues added to the N-terminal side of the amino acid sequence (II) is equal to the number of amino acid residues added to the C-terminal side.
- the number of amino acid residues added to the N-terminal side of the amino acid sequence (II) is typically 1 to 12, and may be 1 to 8, for example.
- the number of amino acid residues added to the C-terminal side of the amino acid sequence (II) is typically 1 to 4, and may be 1 to 3, for example.
- the peptide comprising the amino acid sequence (II) comprises the amino acid sequence represented by LRX 4 R, and may be a peptide comprising the amino acid sequence represented by KLRX 4 R or ILRX 4 R, for example.
- the above peptide can be synthesized by chemical synthesis methods such as solid phase synthesis, stepwise extension, and liquid phase synthesis. Among these, solid phase synthesis is preferred. Examples of the solid phase synthesis method include Fmoc synthesis method and Boc synthesis method.
- a therapeutic, prophylactic, or diagnostic agent for diseases associated with gingipain can be provided, which contains the above-mentioned peptide as an active ingredient.
- the amount of the peptide in the therapeutic, prophylactic, or diagnostic agent may be an effective amount capable of exerting its function, and may be appropriately set depending on the intended use, dosage form, and the like. Examples of diseases related to gingipains include periodontal disease, type 2 diabetes, cardiovascular disease, pneumonia, rheumatoid arthritis, Alzheimer's disease, premature birth, and low birth weight.
- a peptide may be in the form of a derivative or salt as long as the effects of the present invention can be obtained. Therefore, in this specification, unless otherwise specified, a peptide may be a derivative of the peptide or a salt of the peptide or its derivative.
- peptide derivatives include those in which functional groups such as the N-terminal amino group, C-terminal carboxyl group, side chain carboxyl group, amino group, guanidino group, hydroxyl group, and thiol group are substituted with various substituents. It will be done.
- Substituents are not particularly limited, and include, for example, alkyl groups, acyl groups, hydroxyl groups, amino groups, alkylamino groups, nitro groups, amide groups, sulfonyl groups, halogens, and various protective groups. These substituents may be further substituted with halogen such as fluorine. Further, the substitution may be the introduction of a label such as a fluorescent label or a biotin label.
- the peptide salt is preferably a pharmacologically acceptable salt.
- Pharmaceutically acceptable salts include acid addition salts and base addition salts.
- acid addition salts include inorganic acid salts and organic acid salts.
- inorganic acid salts include hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, phosphate, and the like.
- organic acid salts include citrate, oxalate, acetate, formate, propionate, benzoate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, Examples include paratoluenesulfonate.
- Examples of base addition salts include inorganic base salts and organic base salts.
- Examples of inorganic base salts include sodium salts, potassium salts, calcium salts, magnesium salts, and ammonium salts.
- Examples of the organic base salt include organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt, and diisopropylammonium salt.
- the peptide described in Section A can exhibit a gingipain inhibitory effect. Therefore, according to another aspect of the present invention, there is provided a gingipain inhibitor comprising the peptide described in Section A.
- the gingipain to be inhibited may be one or both of Rgp and Kgp.
- As the peptide a peptide having an IC 50 of, for example, 500 ⁇ M or less, preferably 300 ⁇ M or less, and more preferably 100 ⁇ M or less against the gingipain to be inhibited can be preferably used.
- the gingipain inhibitor may be composed only of the peptide, or may contain other components.
- Other ingredients include a pharmacologically acceptable carrier, gingipain inhibitors other than the peptide (for example, gabexate mesylate, leupeptin, antipain, KYT-01, E-64, KYT-36, KYT-41, hinokitiol). , copper chlorophyllin metal salt), etc.
- the content of the peptide in the gingipain inhibitor may be any effective amount that provides the gingipain inhibitory effect of the peptide, and may be, for example, 0.1% to 100% by weight, preferably 1% to 100% by weight.
- a gingipain inhibitor can be used as a therapeutic, preventive, or diagnostic agent for diseases related to gingipain. Diseases related to gingipain are as described in Section A.
- the peptide described in section A can exhibit the effect of inhibiting the growth of Gingivalis bacteria. Therefore, according to another aspect of the present invention, there is provided a growth inhibitor of P. gingivalis, which comprises the peptide described in Section A.
- the P. gingivalis growth inhibitor may be composed only of the peptide, or may contain other components. Other components include a pharmacologically acceptable carrier, a growth inhibitor of G. gingivalis bacteria other than the peptide (for example, an antibiotic such as minocycline), and the like.
- the content of the peptide in the P. gingivalis growth inhibitor may be any effective amount that provides the peptide with the effect of inhibiting the growth of P. gingivalis, for example, 0.1% to 100% by weight, preferably 1% to 100% by weight. It can be.
- an oral composition comprising the peptide described in Section A. Due to the inclusion of the peptide, the oral composition can exhibit an inhibitory effect on gingipain activity and/or an inhibitory effect on the growth of Gingivalis bacteria.
- the amount of peptide to be blended in the oral composition may be an effective amount that achieves the effect of inhibiting gingipain activity and/or the effect of inhibiting the growth of gingivalis bacteria.
- the amount of the peptide etc. blended in the oral composition may vary depending on the dosage form of the composition, but for example, 0.1% to 80% by weight, preferably 0.5% to 50% by weight, more preferably 1% by weight. % to 50% by weight.
- Oral compositions include, for example, dentifrices such as toothpastes, moisturizing dentifrices, powdered dentifrices, liquid dentifrices, and liquid dentifrices, mouthwashes, mouth fresheners, oral sprays, It may be an oral ointment, a gargle, or the like.
- the oral composition can be, for example, a tablet, gum, gummy, candy, or drink.
- dentifrices may contain abrasives, thickeners, binders, surfactants, fragrances, sweeteners, colorants, preservatives, active ingredients, and the like.
- abrasives examples include silica-based abrasives such as silica gel, precipitated silica, aluminosilicate, and zirconosilicate, dibasic calcium phosphate dihydrate and anhydrate, tribasic calcium phosphate, quaternary calcium phosphate, calcium pyrophosphate, calcium carbonate, and water.
- examples include aluminum oxide, alumina, magnesium carbonate, tertiary magnesium phosphate, zeolite, hydroxyapatite, and synthetic resin abrasives.
- the amount of abrasive is adjusted depending on the dosage form, and is, for example, 2% to 40% by weight, preferably 10% to 30% by weight in toothpaste, and may be 0% by weight in liquid dentifrice.
- thickening agent examples include sugar alcohols such as sorbitol, xylitol, maltitol, and lactitol, and polyhydric alcohols such as glycerin, propylene glycol, and polyethylene glycol.
- sugar alcohols such as sorbitol, xylitol, maltitol, and lactitol
- polyhydric alcohols such as glycerin, propylene glycol, and polyethylene glycol.
- the blending amount is usually 5% to 50% by weight, preferably 20% to 45% by weight.
- binders examples include cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, and hydroxyethylcellulose, gums such as xanthan gum and gum arabic, organic binders such as carrageenan, polyvinyl alcohol, and sodium polyacrylate, gelling silica, and gel. Inorganic binders such as oxidizable aluminum silica, vegum, and laponite can be mentioned.
- the blending amount is usually 0.1% to 5% by weight in toothpastes, and 0% to 5% by weight in liquid toothpastes and mouthwashes.
- anionic surfactants nonionic surfactants, cationic surfactants, and amphoteric surfactants can be blended.
- anionic surfactants include alkyl sulfates such as sodium lauryl sulfate, N-acyl sarcosinates such as sodium N-lauroyl sarcosine and sodium N-myristoyl sarcosine, N-acyl glutamates such as sodium N-palmitoyl glutamate, Examples include sodium N-methyl-N-acyl taurate, sodium N-methyl-N-acylalanine, and sodium ⁇ -olefin sulfonate.
- nonionic surfactants include sugar fatty acid esters such as sucrose fatty acid ester and maltose fatty acid ester, sugar alcohol fatty acid esters such as maltitol fatty acid ester and lactitol fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, hexaglyceryl monolaurate, Polyglycerin fatty acid esters such as hexaglyceryl monomyristate, decaglyceryl monolaurate, decaglyceryl monomyristate, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, polyoxyethylene Polyoxyethylene fatty acid esters such as hydrogenated castor oil, polyoxyethylene higher alcohol ethers such as polyoxyethylene lauryl ether, fatty acid alkanolamides such as lauric acid diethanolamide, polyoxyethylene polyoxypropylene copoly
- cationic surfactants include alkylammonium and alkylbenzylammonium salts
- amphoteric surfactants include betaine-based surfactants such as alkyl betaines, fatty acid amidopropyl betaines, and alkylimidazolinium betaines.
- the blending amount of the surfactant in the oral composition is, for example, 0.001% to 10% by weight, preferably 0.1% to 5% by weight.
- Fragrances include peppermint oil, spearmint oil, anise oil, eucalyptus oil, wintergreen oil, cassia oil, clove oil, thyme oil, sage oil, lemon oil, orange oil, peppermint oil, cardamom oil, coriander oil, mandarin oil, Lime oil, lavender oil, rosemary oil, laurel oil, chamomile oil, caraway oil, marjoram oil, bay oil, lemongrass oil, origanum oil, pine needle oil, neroli oil, rose oil, jasmine oil, grapefruit oil, sweetie oil
- Natural fragrances such as oil, yuzu oil, iris concrete, absolute peppermint, absolute rose, orange flower, etc., and processing of these natural fragrances (front distillation cut, rear distillation cut, fractional distillation, liquid-liquid extraction, essence formation, powdered fragrances, etc.), and menthol, carvone, anethole, cineole, methyl salicylate, cinnamic aldehyde
- the fragrance material is preferably used in an amount of 0.000001% to 1% by weight in the oral composition. Further, it is preferable that the perfume for flavoring using the above-mentioned perfume material is used in the oral composition in an amount of 0.1% to 2% by weight.
- sweeteners include saccharin sodium, stevioside, paramethoxycinnamic aldehyde, perilartine, and the like.
- coloring agent include Blue No. 1, Yellow No. 4, and titanium dioxide.
- preservative examples include benzoic acid or its salts such as paraoxybenzoic acid ester and sodium benzoate.
- the oral composition contains nonionic disinfectants such as isopropylmethylphenol, cationic disinfectants such as cetylpyridinium chloride, chlorhexidine hydrochloride, benzalkonium chloride, and benzethonium chloride, tranexamic acid, and epsilon aminocaprone.
- nonionic disinfectants such as isopropylmethylphenol
- cationic disinfectants such as cetylpyridinium chloride, chlorhexidine hydrochloride, benzalkonium chloride, and benzethonium chloride, tranexamic acid, and epsilon aminocaprone.
- Anti-inflammatory agents such as allantoin, glycyrrhetinic acid, glycyrrhizic acid, enzymes such as dextranase, mutanase, amylase, protease, fluoride such as sodium fluoride, sodium monofluorophosphate, potassium salt of orthophosphoric acid, sodium Water-soluble phosphoric acid compounds such as salts, copper compounds such as copper gluconate and sodium copper chlorophyllin, inorganic salts such as sodium chloride, potassium nitrate, aluminum lactate, zinc chloride, zinc citrate, and strontium chloride, vitamins such as tocopherol acetate, Zeolite, azulene, dihydrocholesterol, chlorophyll, Japanese angelica soft extract, plant extracts such as thyme, scutellariae, clove, and hamamelis, anti-tartar agents, anti-plaque agents, etc. may be blended. These components can be blended in an effective amount within a range that
- a method for detecting gingipains which comprises detecting gingipains by an immunoassay using the peptide described in Section A.
- the gingipain to be detected may be one or both of Rgp and Kgp.
- the dissociation constant of the peptide for gingipain to be detected is preferably 1.0 ⁇ 10 ⁇ 8 M or less, more preferably 1.0 ⁇ 10 ⁇ 9 M or less.
- immunoassay methods include immunoblotting, enzyme-linked immunosorbent assay (EIA, ELISA), radiation immunoassay (RIA), fluorescent antibody method, and immunochromatography.
- EIA enzyme-linked immunosorbent assay
- ELISA enzyme-linked immunosorbent assay
- RIA radiation immunoassay
- fluorescent antibody method fluorescent antibody method
- immunochromatography immunochromatography
- the immunoassay method is preferably a sandwich immunoassay method, and can be, for example, a sandwich ELISA or a sandwich immunochromatography method.
- Sandwich immunoassay is a method for qualitative or quantitative analysis of a test substance by immobilizing a capture antibody on a support and binding the labeled antibody and capture antibody to the test substance in a sandwich-like manner. be.
- peptides A and B which are the peptides described in Section A and have different amino acid sequences, are used (as a result, peptides A and B each target different sites of the gingipain to be detected).
- peptides A and B each target different sites of the gingipain to be detected).
- unlabeled peptide A is immobilized as a capture antibody (primary antibody) on a carrier such as a 96-well microtiter plate or polystyrene beads, or biotin-labeled peptide A is immobilized on a 96-well avidin-coated well.
- Peptide B is immobilized on a microtiter plate and labeled with an enzyme such as horseradish peroxidase (HRP) or alkaline phosphatase (ALP), a fluorescent substance such as FITC, or a labeling substance such as biotin as a labeled antibody (secondary antibody).
- HRP horseradish peroxidase
- ALP alkaline phosphatase
- FITC fluorescent substance
- secondary antibody a labeling substance
- the labeled antibody may be labeled with biotin, and the labeled avidin or streptavidin may be bound to the biotin to develop color.
- the binding of gingipain and the capture antibody or the labeled antibody is carried out under temperature conditions of, for example, 0°C to 37°C, preferably 4°C to 25°C, and for a reaction time of, for example, 30 minutes to 24 hours, preferably 60 minutes to 120 minutes. It can be carried out.
- a stand peptide is interposed between the support and the peptide to alleviate the influence of the support and improve the measurement accuracy of gingipain. can be improved.
- kits for detecting or measuring gingipains According to another aspect of the present invention, at least two types of peptides having different amino acid sequences among the peptides described in Section A (as a result, the two types of peptides each have A kit for detecting or measuring gingipain is provided.
- the gingipain to be detected or measured may be one or both of Rgp and Kgp.
- One of the two types of peptides may be immobilized on a support, and the other may be labeled with a labeling substance.
- the kit may contain reagents such as a specimen collection device, a specimen processing liquid, and a coloring substrate, and may further contain equipment necessary for the test.
- the peptides that non-specifically bound to the beads were removed, and the peptides that did not bind to the beads were mixed with beads immobilized with gingipain (Rgp) purified from the culture supernatant of B. gingivalis (ATCC strain 33277) ( Figure 1 (b). )).
- the supernatant was removed by centrifugation, and the peptide bound to gingipain was recovered by washing and elution (FIG. 1(c)).
- the same operation was repeated four more times while gradually tightening the washing conditions (total of five selections). Specifically, 10mM sodium phosphate (pH 7.5), 100mM sodium chloride, and 5mM magnesium chloride were used as the selection buffer.
- the obtained gingipain-binding peptide was cloned using a commercially available cloning kit (Zero Blunt TOPO PCR Cloning Kit, Invitrogen), and a sequence sample was prepared using the dideoxy method and the base sequence was determined using a sequencer. Based on this, the amino acid sequence of the gingipain-binding peptide was determined.
- Rgp in the supernatant of the B. gingivalis culture was purified as follows. 1. Approximately 10 liters of the culture supernatant of P.
- gingivalis (ATCC strain 33277) was collected, concentrated, dialyzed against 10 mM phosphate buffer (pH 7.0), and then subjected to DEAE Sepharose anion chromatography equilibrated with the same buffer. Ta. After thoroughly washing the column with the same buffer, active fractions eluted with the same buffer containing 0.1M sodium chloride were collected and concentrated. 2. The obtained active fraction was dialyzed against 10 mM acetate buffer (pH 5.5) and subjected to CM Sephadex cation chromatography equilibrated with the same buffer. Non-adsorbed fractions eluted with the same buffer were collected, concentrated, and dialyzed against 10 mM phosphate buffer (pH 7.0). 3.
- the active fraction was subjected to Mono Q anion chromatography equilibrated with the same buffer. Active fractions eluted with a sodium chloride concentration gradient were collected and subjected to concentration dialysis. 4. The obtained enzyme fraction was subjected to affinity chromatography using Arg Sepharose. The column adsorbed fractions were eluted with lysine and they were concentrated. 5. After gel filtration of the concentrated sample using a TSK-G2000SW column (Tosoh), the active fraction was concentrated. 6. Purification into a single band was confirmed by SDS gel electrophoresis. In addition, the gingipain concentration in the culture supernatant was determined by Kadowaki et al., J. Biol. Chem. 269; 21371-8 (1994).
- a cDNA display library consisting of a peptide having cysteine at both ends and 12 random amino acids between them (total number of amino acid residues: 14) was created, and a recombinant gingipain (Abcam "Recombinant Gingipain R1 protein (His tag)" was prepared. ), a total of seven selections were performed in the same manner as above to obtain a gingipain-binding peptide. Specifically, the second elution was performed using dithiothreitol, the third to sixth elutions were performed using biotin, and the seventh elution was performed using KYT-1, an Rgp inhibitor. Competitive elution was performed using The amino acid sequence of the resulting gingipain-binding peptide was determined in the same manner as above.
- Candidate peptides were selected taking into consideration the characteristics of the amino acid sequence, ease of synthesis, etc., and peptide synthesis was performed by the Fmoc method (purity of the synthesized peptide by RP-HPLC ⁇ 90%).
- alanine-substituted peptides were examined for changes in affinity for gingipain using the quartz crystal microbalance (QCM) method. Specifically, gingipain is brought into contact with a substrate on which an alanine-substituted peptide has been immobilized in advance, and the alanine-substituted peptide and gingipain are added and bonded, and then peptide "R3-1" is added.
- the affinity of the alanine-substituted peptide for gingipain is lower than that of peptide "R3-1"
- gingipain is transferred to peptide "R3-1" by competitive reaction (FIG. 3, upper case).
- Figure 4 shows a summary of the results of measuring changes in affinity for seven types of alanine-substituted peptides. From the results in Figure 4, the 4 residues from the C-terminus of peptide "R3-1" play an important role in binding to gingipain, and the contribution of 1 to 4 residues from the N-terminus of the peptide to the binding activity is compared. You can see that it's not very accurate. This also suggested that the N-terminal 1 to 4 residues of peptide "R3-1" may be chemically modified without significantly affecting the interaction with gingipain.
- a peptide analog without the N-terminal 1 to 4 residues of peptide "R3-1” was considered to reduce the cost of peptide synthesis and improve binding specificity to proteins. Therefore, we designed a peptide in which the N-terminal three residues of peptide "R3-1" were removed, and a peptide derivative in which the N-terminal three residues were chemically modified.
- the affinity of peptides for gingipains was performed using the Biacore® system, which utilizes surface plasmon resonance (SPR) technology. Specifically, the synthesized peptide was immobilized on a sensor chip for the Biacore (R) system, and a purified culture supernatant of a wild-type strain of P. gingivalis was added thereto. In this system, when gingipain in the culture supernatant and the peptide on the chip combine, the mass of the immobilized peptide increases and the refractive index of the solvent on the sensor chip surface changes. By measuring this change, it becomes possible to monitor the state of binding in real time.
- SPR surface plasmon resonance
- peptide "R3-1" showed a very strong reaction to purified culture supernatant containing gingipain (Wild type, protein amount: 22 ⁇ g/mL), while The reaction to the purified culture supernatant that does not contain gingipain (-Kgp & -Rgp, protein amount: 22 ⁇ g/mL) is very weak, and the reaction to the 10 times concentrated solution (-Kgp & -Rgp, protein amount: 220 ⁇ g/mL) is somewhat weak. Although it showed a reaction, the reaction was lower than that of the culture supernatant containing gingipain. From this, it is considered that the specificity of peptide "R3-1" to gingipain is quite high.
- Peptide "R3-1" was dissolved in dimethyl sulfoxide, and the resulting solution was diluted with distilled water (Otsuka Pharmaceutical Factory Co., Ltd., Lot. 0D96N) so that the final concentration of the peptide was 1,280 ⁇ g/mL. did. Then, after diluting with ATCC2722 medium to 160 ⁇ g/mL, 20 ⁇ g/mL, and 2.5 ⁇ g/mL, the final concentrations were 0.06 ⁇ g/mL, 0.12 ⁇ g/mL, and 0.25 ⁇ g/mL using the same medium.
- mL 0.5 ⁇ g/mL, 1 ⁇ g/mL, 2 ⁇ g/mL, 4 ⁇ g/mL, 8 ⁇ g/mL, 16 ⁇ g/mL, 32 ⁇ g/mL, 64 ⁇ g/mL, and 128 ⁇ g/mL.
- Diluted solutions of various concentrations were similarly prepared for gabexate methylate (manufactured by Tokyo Kasei Co., Ltd.) and KYT-1 (Peptide Institute).
- test substance peptide, gabexate methylate (GM), or KYT-1
- ATCC2722 medium positive control; PC
- PC negative control
- an Rgp solution dissolved in HEPES buffer to a concentration of 0.1 nM, 1 nM, or 10 nM was used.
- a dimethyl sulfoxide solution (10 mM) of labeled peptide was diluted 2,000 times with HEPES buffer and added at a volume of 100 ⁇ L/well. 6) After over night reaction at 4°C, the reaction solution was discarded and each well was washed.
- Table 6 shows the combinations of peptides used as solid-phase peptides and labeled peptides, and the absorbance measurement results.
- the peptide according to the embodiment of the present invention is suitably used in the treatment, prevention, diagnosis, etc. of diseases related to gingipain such as periodontal disease.
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Abstract
Le but de la présente invention est de fournir un nouveau composé ayant une fonction d'affinité et/ou d'inhibition spécifique aux gingipaïnes. La présente invention concerne un peptide, ou un dérivé de celui-ci, ou un sel du peptide ou du dérivé, ledit peptide étant choisi parmi des peptides qui comprennent la séquence d'acides aminés (I) ou (II), le nombre total des résidus d'acides aminés étant de 4 à 15 [séquence d'acides aminés (I) : RX1X2RX3 (dans la séquence d'acides aminés (I), X1, X2 et X3 représentent chacun indépendamment un résidu d'acide aminé naturel arbitraire)], [séquence d'acides aminés (II) : RX4R (dans la séquence d'acides aminés (II), X4 représente un résidu d'acide aminé naturel arbitraire)], des peptides comprenant la séquence d'acides aminés CRSVKWHHRVFGSC (SEQ ID NO : 11), et des peptides comprenant la séquence d'acides aminés ITHTSRHC (SEQ ID NO : 12), une ou plusieurs des conditions (a) à (c) suivantes étant satisfaites. (a) la constante de dissociation (KD) par rapport à l'arginine-gingipaïne n'est pas supérieure à 1,0×10-7 M. (b) à 100 μΜ, l'activité enzymatique de l'arginine-gingipaïne est inhibée de pas moins de 50 %. (c) à 500 μΜ, l'activité enzymatique de la lysine-gingipaïne est inhibée de pas moins de 50 %.
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999055742A1 (fr) * | 1998-04-29 | 1999-11-04 | Marchant Roger E | Tensioactifs presentant un mimetisme par rapport au glycocalyx |
JP2012232923A (ja) * | 2011-04-28 | 2012-11-29 | Sunrise Kogyo Kk | 短鎖ペプチド |
JP2015529221A (ja) * | 2012-09-07 | 2015-10-05 | エージェンシー フォー サイエンス,テクノロジー アンド リサーチ | ペプチドおよびそれらの使用 |
JP2017520569A (ja) * | 2013-06-26 | 2017-07-27 | ザイジェン インフラメーション エルティーディー | 様々な疾患の処置のためのjnk阻害剤分子の新規使用 |
US20190209646A1 (en) * | 2016-09-29 | 2019-07-11 | Meharry Medical College | Bacterial inhibitors |
CN110305193A (zh) * | 2019-07-18 | 2019-10-08 | 河南科技大学 | 一种抗牙龈卟啉单胞菌多肽及应用 |
-
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- 2023-03-16 WO PCT/JP2023/010461 patent/WO2023182185A1/fr unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999055742A1 (fr) * | 1998-04-29 | 1999-11-04 | Marchant Roger E | Tensioactifs presentant un mimetisme par rapport au glycocalyx |
JP2012232923A (ja) * | 2011-04-28 | 2012-11-29 | Sunrise Kogyo Kk | 短鎖ペプチド |
JP2015529221A (ja) * | 2012-09-07 | 2015-10-05 | エージェンシー フォー サイエンス,テクノロジー アンド リサーチ | ペプチドおよびそれらの使用 |
JP2017520569A (ja) * | 2013-06-26 | 2017-07-27 | ザイジェン インフラメーション エルティーディー | 様々な疾患の処置のためのjnk阻害剤分子の新規使用 |
US20190209646A1 (en) * | 2016-09-29 | 2019-07-11 | Meharry Medical College | Bacterial inhibitors |
CN110305193A (zh) * | 2019-07-18 | 2019-10-08 | 河南科技大学 | 一种抗牙龈卟啉单胞菌多肽及应用 |
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