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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
  • A61K38/10—Peptides having 12 to 20 amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K11/00—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K11/02—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof cyclic, e.g. valinomycins ; Derivatives thereof
• • 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

Definitions

• This disclosure relates to a composition.
• Vasoactive intestinal peptide a neuropeptide closely related to pituitary adenylate cyclase-activating polypeptide (PACAP), and its receptors, G protein-coupled receptors (GPCRs): VIPR1 and VIPR2 (also called VPAC1 receptor and VPAC2 receptor), are widely expressed in brain tissue and in many peripheral tissues such as the cardiovascular system, renal system, digestive system, immune system, endocrine system, and reproductive system. It has been reported that excessive activation of VIPR2 in brain tissue is involved in the onset of psychiatric disorders such as schizophrenia, including cognitive dysfunction (Non-Patent Document 1).
• Non-Patent Documents 2 and 3 It has also been reported that activation of VIPR2 is involved in the proliferation of colon cancer cells by suppressing cancer immunity, which is intractable, in colon cancer.
• Vasoactive intestinal peptide receptor 2 signaling promotes breast cancer cell proli feration by enhancing the ERK pathway.”
• Peptides vol. 161 (2023): 170940. doi:10.1016/j.peptides.2023.170940 Kittikulsuth, Wararat et al. “Vasoactive intestinal peptide blockade suppresses tumor growth by regulating macrophage polariz ation and function in CT26 tumor-bearing mice.” Scientific reports vol. 13,1 927. 17 Jan. 2023, doi:10.1038/s41598-023-28073-6
• the addition of an alkyl chain to the peptide of the formula (2) can be carried out, for example, by an addition reaction of a fatty acid to the peptide.
• the method of adding the dipalmitoyl group includes, for example, a method of mixing DBCO (Dibenzocyclooctyne)-KS-487 described in Japanese Patent Application No. 2022-125238 (International Application No.
• the linker may include, for example, PEG.
• the average molecular weight of the PEG is preferably, for example, 2000 or less, and more preferably, 1000 or less, 600 or less.
• the PEG may be, for example, a single substance with no distribution in degree of polymerization, or a mixture with a distribution.
• the linker may be represented by, for example, XN .
• the XN is, for example, any amino acid residue of 1 to 22.
• the XN is not particularly limited as long as it is a sequence that does not inhibit binding to LRP1, and examples thereof include sequences that can be substituted for PEG linkers, such as a glycine linker and a GS linker that combines glycine and serine.
• Examples of the formula (2) include the following peptides: c(Cys23- Thr24 - Tyr25 - Lys26 - Tyr27 - Nle28 - Leu29 - Ala30 - Glu31 - Nle32 - Cys34 )-OH (forming an S-S bond between the side chains of Cys23 and Cys34 ) (SEQ ID NO: 14)
• Examples of the formula (2) include the following peptides: Gly 1 -Thr 2 -Pro 3 -c(Cys 23 -Thr 24 -Tyr 25 -Lys 26 -Tyr 27 -Nle 28 -Leu 29 -Ala 30 -Glu 31 -Nle 32 -Cys 34 )-OH (forming an S-S bond between the side chains of Cys 23 and Cys 34 ) (SEQ ID NO: 15)
• Examples of the formula (2) include the following peptides: (C15) 2 -DBCO-PEG5-DBCO-PEG4-Gly 1 -Thr 2 -Pro 3 -c(Cys 23 -Thr 24 -Tyr 25 -Lys 26 -Tyr 27 -Nle 28 -Leu 29 -Ala 30 -Glu 31 -Nle 32 -Cys 34 )-OH (forming an S-S bond between the side chains of Cys 23 and Cys 34 ) (SEQ ID NO: 15)
• Examples of the formula (2) include the following peptides: (C17) 2 -PEG(MW600)-Gly 1 -Gly 2 -Gly 3 -Gly 4 -Gly 5 -Gly 6 -Thr 7 -Pro 8 -c(Cys 23 -Thr 24 -Tyr 25 -Lys 26 -Tyr 27 -Nle 28 -Leu 29 -Ala 30 -Glu 31 -Nle 32 -Cys 34 )-OH (forming an S-S bond between the side chains of Cys 23 and Cys 34 ) (SEQ ID NO: 16)
• Examples of the formula (2) include the following peptides: (C17) 2 -PEG(MW600)-Gly 1 -Gly 2 -Gly 3 -Gly 4 -Gly 5 -Gly 6 -Gly 7 -Thr 8 -Pro 9 -c(Cys 23 -Thr 24 -Tyr 25 -Lys 26 -Tyr 27 -Nle 28 -Leu 29 -Ala 30 -Glu 31 -Nle 32 -Cys 34 )-OH (forming an S-S bond between the side chains of Cys 23 and Cys 34 ) (SEQ ID NO: 17)
• the peptide may be, for example, a peptide consisting of an amino acid sequence having 80% or more identity to the amino acid sequence of the formula (2) and having the activity of the peptide.
• the "having the activity of the peptide” means, for example, having LRP1 binding activity.
• the "80% or more identity” means, for example, 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more to the amino acid sequence of the formula (1).
• the peptide of formula (1) or formula (2) may be, for example, a salt thereof.
• the salt is not limited as long as it is a salt with a physiologically acceptable base or acid, and examples thereof include addition salts of inorganic acids (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), addition salts of organic acids (p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carboxylic acid, succinic acid, citric acid, benzoic acid, acetic acid, etc.), addition salts of inorganic bases (ammonium hydroxide, or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, etc.), and addition salts of amino acids.
• inorganic acids hydroochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.
• organic acids p
• the peptide of formula (1) or formula (2) may be, for example, a prodrug.
• the prodrug may be, for example, a compound in which the amino group of the peptide is acylated, alkylated, or phosphorylated (for example, a compound in which the amino group of the peptide is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, or tert-butylated), a compound in which the hydroxy group of the peptide is acylated, alkylated, phosphorylated, or borated (for example, a compound in which the hydroxy group of the peptide is acetylated, palmitoylated, propanoylated,
• the prodrug may be, for example, one that changes into the peptide under physiological conditions.
• the change into the peptide under physiological conditions can be described, for example, in "Drug Development,” Vol. 7, Molecular Design, pp. 163-198, Hirokawa Publishing, 1990.
• the prodrug may, for example, form a salt.
• the salt include the salts exemplified as the salts of the peptide.
• the peptide may be, for example, a crystal.
• the crystal form may be, for example, a single crystal or a mixture.
• the crystal may be produced, for example, by a known crystallization method.
• the peptide may be, for example, a pharma- ceutically acceptable co-crystal or co-crystal salt.
• the crystal or the co-crystal salt is a crystalline material composed of two or more distinct solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, and stability, etc.).
• the co-crystal or the co-crystal salt can be prepared, for example, by known co-crystallization methods.
• the surfactant is preferably polyoxyethylene castor oil (including derivatives) such as polyoxyethylene-35-ricinoleate, or polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene sorbitan fatty acid ester.
• the surfactant may be a synthetic product or a commercially available product.
• the surfactant may be, for example, one type or a combination of multiple types.
• examples include CREMOPHOR(R) EL, CREMOPHOR(R) ELP, and CREMOPHOR(R) RH 40 manufactured by BASF.
• examples include TWEEN (registered trademark) 80 (polysorbate 80), polyoxyethylene 20 sorbitan monooleate, TWEEN (registered trademark) 85 (polysorbate 85), TWEEN (registered trademark) 20 (polysorbate 20), etc., all of which are manufactured by ICI Americas.
• the content of the surfactant is preferably, for example, 1% by mass to 30% by mass, 3% by mass to 20% by mass, 5% by mass to 15% by mass, or 10% by mass to 20% by mass, based on the total mass of the composition.
• the composition of the present disclosure may be, for example, a liquid or a solid.
• the solvent for the liquid include water, an aqueous solvent of an aqueous/organic mixture, and the like.
• Examples of the pH of the liquid include, for example, pH 5.5-7.5, pH 6-7, and pH 6-6.5.
• the liquid it may be stored at room temperature, refrigerated (e.g., 2-8°C), or frozen (e.g., -20°C or -80°C).
• the solid may be prepared in a suitable manner, for example, in the form of a cake or powder by adding a cryoprotectant.
• composition of the present disclosure may further contain a pharma- ceutically acceptable carrier.
• the carrier include a suspending agent, solubilizing agent, stabilizer, isotonicity agent, preservative, adsorption inhibitor, surfactant, diluent, medium, pH adjuster, soothing agent, buffer, sulfur-containing reducing agent, antioxidant, etc., for administering the active ingredient, and may be added appropriately within a range that does not interfere with the effects of the present disclosure.
• the solution adjuvant is not particularly limited, and examples thereof include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, macrogol, castor oil fatty acid ethyl ester, etc.
• the stabilizer is not particularly limited, and examples include dextran 40, methylcellulose, gelatin, sodium sulfite, sodium metasulfate, etc.
• the preservative is not particularly limited, and examples thereof include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, sorbic acid, phenol, cresol, and chlorocresol.
• the adsorption inhibitor is not particularly limited, and examples thereof include human serum albumin, lecithin, dextran, ethylene oxide propylene oxide copolymer, hydroxypropyl cellulose, methyl cellulose, hydrogenated castor oil, polyethylene glycol, etc.
• the sulfur-containing reducing agent is not particularly limited, and examples thereof include those having a sulfhydryl group, such as N-acetylcysteine, N-acetylhomocysteine, thioxanthate, thiodiglycol, thioethanolamine, thioglycerol, thiosorbitol, thioglycolic acid and its salts, sodium thiosulfate, glutathione, and thioalkanoic acids having 1 to 7 carbon atoms.
• a sulfhydryl group such as N-acetylcysteine, N-acetylhomocysteine, thioxanthate, thiodiglycol, thioethanolamine, thioglycerol, thiosorbitol, thioglycolic acid and its salts, sodium thiosulfate, glutathione, and thioalkanoic acids having 1 to 7 carbon
• composition of the present disclosure may further contain, as appropriate, commonly added components such as inorganic salts, such as sodium chloride, potassium chloride, calcium chloride, sodium phosphate, potassium phosphate, and sodium bicarbonate; organic salts, such as sodium citrate, potassium citrate, and sodium acetate; and sugars, such as glucose.
• inorganic salts such as sodium chloride, potassium chloride, calcium chloride, sodium phosphate, potassium phosphate, and sodium bicarbonate
• organic salts such as sodium citrate, potassium citrate, and sodium acetate
• sugars such as glucose.
• the subject of administration may be a healthy person who is not affected by a central nervous system disease and/or brain metastasis cancer, a person who may be affected by a central nervous system disease and/or brain metastasis cancer, or a patient who is affected by a central nervous system disease and/or brain metastasis cancer.
• the subject of administration is preferably a subject for whom prevention and/or treatment of central nervous system disease and/or brain metastasis cancer is desired.
• composition of the present disclosure may be administered once or multiple times.
• the multiple times may be, for example, two, three, four, five or more times.
• the number of administrations may be appropriately determined while checking the effect on the subject.
• the administration interval may be appropriately determined while checking the preventive effect on the subject, and may be, for example, once a day, once a week, once every two weeks, once a month, once every three months, once every six months, etc.
• the alleviation of the symptom may be evaluated subjectively or objectively, for example, and specific examples include self-evaluation by the subject to which the composition is administered; evaluation by a physician; quality of life (QOL) evaluation; evaluation of delay in progression of symptoms of central nervous system disease and/or brain metastatic cancer, or reduction in the severity of symptoms of central nervous system disease and/or brain metastatic cancer.
• the objective evaluation may be an evaluation by an animal or an evaluation by a human.
• 16:0 azidocaproyl PE (Cat No: 870126P-25 mg) was purchased from Sigma-Aldrich, Cremophor EL (Cat No: 09727-14) from Nacalai Tesque, Inc., and ICG (Cat No: I0535) from Tokyo Chemical Industry Co., Ltd.
• micelles were prepared using ICG, dipalmitoylated KS-487, and Cremophor EL. Specifically, 1.0 mg of ICG was added to and dissolved in a DMSO solution containing dipalmitoylated KS-487. Next, 100 ⁇ l of Cremophor EL and 350 ⁇ l of purified water were mixed to prepare a surfactant solution. After the preparation, the surfactant solution was added to the DMSO solution containing dipalmitoylated KS-487 and ICG. The sample after the addition was thoroughly mixed using a vortex and sonicated in hot water at approximately 50°C. After the sonication, 450 ⁇ l of purified water was added.
• composition D The composition was stored in a refrigerator until use.
• composition A containing ICG but not containing KS-487 or Cremophor EL.
• Figure 5 shows bioimaging images and graphs showing the brain migration of compositions A to D.
• Figure 5 (A) from left to right, a bright field, the front side of the brain observed with fluorescence, the back side of the brain observed with fluorescence, and a split section of the brain observed with fluorescence are shown.
• Figure 5 (B) the vertical axis shows fluorescence intensity, and the horizontal axis shows the type of composition.
• composition A consisting only of ICG was administered
• composition B which did not contain dipalmitoylated KS-487, was administered, slight fluorescence derived from ICG was detected in the brain.
• compositions C and D which contained dipalmitoylated KS-487
• fluorescence derived from ICG was detected in the brain in a manner dependent on the concentration of dipalmitoylated KS-487 added.
• composition E a composition containing KS-133, dipalmitoylated KS-487, and Cremophor EL (composition E) was prepared.
• the preparation was carried out by the same method as in Example 1 (2), except that KS-133 was used instead of ICG.
• the schizophrenia model mouse was prepared by the method described in Japanese Patent Application No. 2020-059721 (International Publication No. 2021/200259).
• Ro25-1553, a VIPR2 selective agonist was subcutaneously administered once a day for 14 days to mice on the first day of birth. After the subcutaneous administration, the composition E or physiological saline was subcutaneously administered once a day for 14 days to mice (6 weeks old) that had been continuously raised.
• the composition E was diluted with physiological saline so that the amount of KS-133 contained in the composition E was 3 mg/kg.
• object recognition training was performed.
• the mice were subjected to a recognition test for a novel object.
• the novel object recognition test was conducted during the light period (8:00-20:00) according to Non-Patent Document 1. First, in a soundproof laboratory set to an illuminance of 30 lux, the subject mice were habituated for 10 minutes a day for three consecutive days in a test cage (30 cm x 30 cm x 35 cm) made of acrylic modified polyvinyl chloride, covered only with sterilized wooden soft chips (Sankyo Labo Service Co., Ltd.).
• Figure 6 is a graph showing the results of the test trials.
• the vertical axis shows the exploratory time
• the horizontal axis shows the breakdown of the administered drugs.
• the vertical axis shows the discrimination index.
• the exploratory time for novel objects was significantly longer than the exploratory time for known objects (p value of Student's t-test less than 0.05).
• Figure 7 is a table showing the results of the pharmacokinetic study.
• the plasma KS-133 concentrations (nmol/ml) were 14.717, 22.465, 10.600, and 2.005 at 1, 3, 6, and 10 hours, respectively, or 19.112, 24.938, 13.369, and 1.008 at 1, 3, 6, and 10 hours, respectively.
• the plasma KS-133 concentration peaked 3 hours after administration.
• the hypothalamus KS-133 concentrations (nmol/g) were 0.074, 0.124, 0.027, and 0.015 at 1, 3, 6, and 10 hours, respectively, or 0.097, 0.137, 0.065, and 0.015 at 1, 3, 6, and 10 hours, respectively.
• the peak concentration of KS-133 in the hypothalamus was 3 hours after administration.
• the concentrations (nmol/g) of KS-133 in the cerebral cortex were 0.096, 0.121, 0.056, and 0.014 at 1, 3, 6, and 10 hours, respectively, or 0.105, 0.137, 0.068, and 0.011 at 1, 3, 6, and 10 hours, respectively.
• the peak concentration of KS-133 in the cerebral cortex was 3 hours after administration.
• the concentrations (nmol/g) of KS-133 in the liver were 3.642, 6.308, 3.796, and 0.941 at 1, 3, 6, and 10 hours, respectively, or 4.750, 8.292, 3.883, and 0.612 at 1, 3, 6, and 10 hours, respectively.
• the peak concentration of KS-133 in the liver was 3 hours after administration.
• the trends in KS-133 concentration in each tissue were well correlated.
• composition E caused KS-133 to migrate in a time-dependent manner to brain tissues such as the hypothalamus and cerebral cortex.
• composition> (Appendix 1) Drugs, A linear peptide and/or a cyclic peptide having an amino acid sequence represented by the following formula (2), a derivative or modification thereof, or a pharmacologically acceptable salt thereof; At least one surfactant; A composition comprising: Formula (2): X 23 -X 24 -X 25 -X 26 -X 27 -X 28 -X 29 -X 30 -X 31 -X 32 -X 33 -X 34
• X 23 and X 24 each independently represent serine, homoserine, threonine, cysteine, D-cysteine, allothreonine, 2,3-diaminopropionic acid, 2,4-diaminobutanoic acid, ornithine, lysine, arginine, proline, cis-4
• X23 represents serine, threonine, cysteine, D-cysteine, or proline
• X24 represents serine, homoserine, threonine, allothreonine, 2,3-diaminopropionic acid, 2,4-diaminobutanoic acid, ornithine, lysine, arginine, proline, cis-4-hydroxy-proline, or trans-4-hydroxy-proline;
• X23 represents serine, threonine, cysteine, D-cysteine, or proline
• X24 represents serine, homoserine, threonine, allothreonine, 2,3-diaminopropionic acid, 2,4-diaminobutanoic acid, ornithine, lysine, arginine, proline, cis-4-hydroxy-proline, or trans-4-hydroxy-proline
• composition according to any one of claims 1 to 4, wherein the drug is a cyclic peptide consisting of an amino acid sequence represented by the following formula (1), a derivative or modification thereof, or a pharmacologically acceptable salt thereof:
• Formula (1) c[X 1 -Pro 2 -X 3 -Tyr 4 -Leu 5 -Pro 6 -c(X 7 -X 8 -Leu 9 -Cys 10 ]-X 11 )-X 12 -X 13
• X1 represents cysteine, Mpa (3-mercaptopropionic acid) or D-cysteine
• X3 represents N-methylated glycine, N-methylated alanine, 2-azetidine-2-carboxylic acid, proline, hydroxyproline, 3,4-dehydroproline, pipecolic acid, serine, or lysine
• X8 represents tyrosine, proline, or arginine

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