WO2015190849A1 - Conjugué mélittine-polyéthylèneglycol et composition pharmaceutique contenant ledit conjugué - Google Patents

Conjugué mélittine-polyéthylèneglycol et composition pharmaceutique contenant ledit conjugué Download PDF

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Publication number
WO2015190849A1
WO2015190849A1 PCT/KR2015/005892 KR2015005892W WO2015190849A1 WO 2015190849 A1 WO2015190849 A1 WO 2015190849A1 KR 2015005892 W KR2015005892 W KR 2015005892W WO 2015190849 A1 WO2015190849 A1 WO 2015190849A1
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Prior art keywords
melittin
polyethylene glycol
mel
formula
compound
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English (en)
Korean (ko)
Inventor
정봉열
배근원
하재석
김명숙
김재준
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Humedix Co Ltd
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Humedix Co Ltd
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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
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K17/00—Carrier-bound or immobilised peptides; Preparation thereof
    • C07K17/02—Peptides being immobilised on, or in, an organic carrier
    • C07K17/08—Peptides being immobilised on, or in, an organic carrier the carrier being a synthetic polymer

Definitions

  • the present invention relates to a melittin-polyethylene glycol combination having a low cytotoxicity and an excellent anti-inflammatory effect, a method for preparing the same, and a pharmaceutical composition for treating or preventing inflammation including the same as an active ingredient.
  • Melittin is a natural physiologically active substance contained in bee venom and is a major component of bee venom. Melittin consists of 26 amino acids and has a helical structure (T C Terwilliger and D Eisenberg, J Biol Chem 257: 6016-6022 (1982)). Based on the proline amino acid No. 14, it has a bipolar property with hydrophobicity of the N-terminal part and hydrophilicity of the C-terminal part.
  • Melitin is known to be able to inhibit the growth of 20-30 types of bacteria, and particularly shows stronger antimicrobial activity in gram positive than gram negative. In addition, it is known to have antifungal action. Reduces interfacial tension of cell membranes and increases cell permeability. In addition, melittin has anti-inflammatory action by increasing cortisol in plasma. In addition, the efficacy of anti-cancer, anti-inflammatory, anti-pain has been reported.
  • melittin is toxic and has a short in vivo half-life.
  • the present inventors have made diligent research efforts to reduce the toxicity of melittin, and found that the melittin-polyethylene glycol combination reduces the cytotoxicity of melittin and maintains various biological activities such as anti-inflammatory and anticancer of melittin.
  • the present invention has been completed.
  • an object of the present invention is to provide a melittin-polyethylene glycol combination having a low cytotoxicity and an excellent anti-inflammatory effect.
  • Another object of the present invention is to provide a method for preparing the melittin-polyethylene glycol blend.
  • Still another object of the present invention is to provide a pharmaceutical composition for treating or preventing inflammation including the melittin-polyethylene glycol combination.
  • One embodiment of the present invention relates to a melittin-polyethylene glycol combination in which polyethylene glycol is bonded to the N-terminal amino group of melittin.
  • the melittin-polyethylene glycol combination according to one embodiment of the present invention may be a compound represented by the following Chemical Formula 1.
  • R is hydrogen or an alkyl group of C 1 -C 6 ,
  • n is an integer from 10 to 1000
  • n is an integer from 0 to 10
  • the alkyl group of C 1 -C 6 means a straight or branched hydrocarbon having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, or the like. Include but are not limited to.
  • R is methyl
  • n is an integer from 100 to 500
  • n is an integer from 0 to 3
  • Mel is a compound of Formula 1, which is melittin.
  • One embodiment of the present invention relates to a method for producing the melittin-polyethylene glycol blend, the production method of the present invention as shown in Scheme 1 below,
  • R, n, m and Mel are as defined in the formula (1).
  • step (i) the melittin of Formula 2 and polyethylene glycol-alkylaldehyde of Formula 3 are combined to obtain a compound of Formula 4.
  • melittin purified from bee venom or commercially available melittin can be used without limitation. Purified melittin can be sterilized over a 0.2 um filter, and for further purification, salt removal may be added through dialysis.
  • Polyethyleneglycol-alkylaldehyde of the formula (3) is commercially available, the molecular weight is preferably 2 kDa to 40 kDa, more preferably 5 kDa to 20 kDa.
  • the coupling reaction may be performed in an acidic buffer solution of pH 3.5 to 6, and the buffer solution may be used as acetate buffer, phosphate buffer and the like.
  • the molar ratio of polyethyleneglycol-alkylaldehyde to melittin in the coupling reaction is preferably 1 to 10.
  • 0.5 to 2 molar ratio of polyethylene glycol-alkylaldehyde may be additionally added.
  • step (ii) the compound of formula 4 is reduced to prepare a melittin-polyethylene glycol compound of formula 1.
  • the reduction reaction may be performed using a reducing agent such as sodium cyanoborohydride (NaCNBH 3 ).
  • a reducing agent such as sodium cyanoborohydride (NaCNBH 3 ).
  • the preparation method according to an embodiment of the present invention may further comprise the step of purifying the prepared melittin-polyethylene glycol formulation.
  • the purification may be performed using a pH 7 to 8 buffer containing a salt such as sodium chloride on the cation exchange resin as an elution buffer.
  • a salt such as sodium chloride
  • the 1: 1 melittin-polyethylene glycol blend can be isolated purely.
  • Polyethyleneglycol-alkylaldehyde that does not bind to melittin does not bind to the cation exchange resin, and the binding of the polyethyleneglycol-alkylaldehyde to the cation exchange resin becomes weaker.
  • a strong binding melittin-polyethylene glycol mixture can be fractionated from the weak binding melittin-polyethylene glycol mixture, and finally the melittin unreacted when the highest salt concentration or sodium hydroxide is flown. It is fractionated.
  • the cation exchange resin is a polymer into which a functional group having a cation exchange capacity is introduced, and as the polymer matrix, for example, polystyrene, polyphenolic resin, cellulose, polyacrylamide , Test column, Sepharose (Sepharose) and the like can be used, and as a functional group having a cation exchange capacity, for example, RCH 2 SO 3 - H + , C 6 H 5 SO 3 - H + , C 6 H 5 PO 3 2- (Na + ) 2 , RCOO - Na + , C 6 H 5 CH 2 N (CH 2 COO - H + ) 2 , carboxymethyl, phosphate, sulfoethyl, sulfopropyl ( sulfopropyl), diethyl (2-hydroxypropyl quaternary amino) (diethyl (2-hydroxylpropyl quaternary amino)) and the like can be used.
  • Fractions containing only the melittin-polyethylene glycol combination of Formula 1 can be taken separately and lyophilized. If the final desired buffer solution is lyophilized, the composition may be determined using diafiltration such as concentration and dialysis.
  • the melittin-polyethylene glycol combination of the present invention can reduce the toxicity possessed by melittin, and can increase the anti-inflammatory effect.
  • the present invention provides a pharmaceutical composition for the treatment or prevention of inflammation, specifically rheumatoid arthritis, lupus, psoriasis, enteritis or osteoarthritis, comprising the melittin-polyethylene glycol combination of Formula 1 together with a pharmaceutically acceptable carrier It is about.
  • the pharmaceutical composition according to the invention may be administered orally (eg, by taking or inhaling) or parenterally (eg by injection, deposition, transplantation, suppository), and the injection may for example be intravenous injection. , Intracutaneous injection, intramuscular injection or intraperitoneal injection.
  • the pharmaceutical composition according to the present invention may be used as tablets, capsules, granules, fine subtilae, powders, sublingual tablets, suppositories, ointments, injections, emulsions, suspensions, syrups, sprays and the like. Can be formulated.
  • the pharmaceutical compositions according to the present invention in various forms can be prepared by known techniques using pharmaceutically acceptable carriers commonly used in each formulation.
  • Examples of pharmaceutically acceptable carriers include excipients, binders, disintegrating agents, lubricants, preservatives, antioxidants, isotonic agents, buffers, coatings, sweeteners, solubilizers, bases, dispersants, wetting agents , Suspending agents, stabilizers, coloring agents and the like.
  • the pharmaceutical composition according to the invention comprises from about 0.01 to 95% by weight of the compound of the invention or a pharmaceutically acceptable salt thereof.
  • the specific dosage of the pharmaceutical composition of the present invention may vary depending on the type of mammal including the person being treated, weight, sex, degree of disease, judgment of a doctor, and the like.
  • 0.01 to 50 mg of active ingredient per kg of body weight is administered per day
  • 0.01 to 10 mg of active ingredient per kg of body weight per day are administered.
  • the total daily dose may be administered at one time or divided into several times depending on the extent of the disease, the judgment of the doctor.
  • the melittin-polyethyleneglycol copolymer in which polyethyleneglycol is bonded to the N-terminal amino group of the melittin according to the present invention is lower in cytotoxicity and excellent in anti-inflammatory effect than melittin.
  • a melittin-polyethylene glycol compound in which polyethylene glycol is bonded to the N-terminal amino group of melittin can be prepared in high yield and high selectivity.
  • Example 1 is a diagram showing the results of Iodine staining and Coomassie staining after electrophoresis of the melittin-polyethylene glycol compound preparation product obtained in Example 1.
  • FIG. 2 is an LC chromatograph after treatment of melittin (MEL) and melittin-polyethylene glycol compound (PEG-MEL) with Lys-C.
  • MEL melittin
  • PEG-MEL melittin-polyethylene glycol compound
  • MEL melittin
  • PEG-MEL melittin-polyethylene glycol combination
  • MEL 4 is a graph showing cytotoxicity of melittin (MEL) and 1: 1 melittin-polyethylene glycol combination (mono-PEG (5k) -MEL, mono-PEG (20k) -MEL).
  • MEL melittin
  • 1 melittin-polyethylene glycol combination mono-PEG (5k) -MEL, mono-PEG (20k) -MEL.
  • MEL melittin
  • mono-PEG (5k) -MEL melittin-polyethylene glycol combination
  • melittin 2.5 mg was dissolved in 50 mM acetate buffer, pH 3.5, 4.0, 5.0, 6.0, respectively.
  • sodium cyanoborohydride (NaCNBH 3 ) was added to induce a reduction reaction of the compound. The reaction was carried out at room temperature for 6 hours. Then, 100 times more glycine (Glycine) than the molar ratio of methoxy polyethyleneglycol-propionaldehyde was added to stop the reaction.
  • PEG-MEL melittin-polyethylene glycol compound
  • a melittin-polyethyleneglycol blend was prepared in the same manner as in Example 1 except that the molar ratio of melittin and polyethylene glycol-propionaldehyde was 1: 7 or 1:10 at pH 3.5.
  • the product was analyzed using HPLC and the results are shown in Table 1 below.
  • melittin 2.5 mg was dissolved in 50 mM acetate buffer, pH 4.0.
  • linear methoxy polyethyleneglycol-propionaldehyde PEG, molecular weight 20 kDa
  • PEG linear methoxy polyethyleneglycol-propionaldehyde
  • NaCNBH 3 sodium cyanoborohydride
  • the obtained melittin-polyethylene glycol mixture preparation product was analyzed using HPLC, and the results are shown in Table 4 below.
  • the reaction solution obtained in Example 1 was prepared by 0.2um filter.
  • the cation exchange resin column SP capto TM Impres, GE
  • the filtered reaction solution was flowed out.
  • an additional buffer solution was sufficiently flowed. Only 1: 1 melittin-polyethyleneglycol blend (mono-PEG (5k) -MEL) was purified from the melittin and melittin-polyethyleneglycol blends bound to the cation exchange resin.
  • the eluted fractions were subjected to electrophoresis and purified purely 1: 1 melittin-polyethylene glycol compound (mono-PEG (5k) -MEL) through Coomassie staining and Iodine staining. The more polyethylene glycol bound to one molecule melittin, the weaker the binding force with the ion exchange resin was confirmed.
  • the reaction solution obtained in Example 4 was prepared by 0.2um filter.
  • the cation exchange resin column SP capto TM Impres, GE
  • the filtered reaction solution was flowed out.
  • an additional buffer solution was sufficiently flowed. Only 1: 1 melittin-polyethyleneglycol combination (mono-PEG (20k) -MEL) was purified in the melittin and melittin-polyethyleneglycol combinations bound to the cation exchange resin.
  • the eluted fractions were electrophoresed to purify 1: 1 melittin-polyethylene glycol compound (mono-PEG (20k) -MEL) through Coomassie staining and Iodine staining. The more polyethylene glycol bound to one molecule melittin, the weaker the binding force with the ion exchange resin was confirmed.
  • Example 5 Peptide mapping was performed to determine whether the melittin-polyethylene glycol single compound (mono-PEG (5k) -MEL) obtained in Example 5 was specifically conjugated to the N-terminus. Melitin-polyethyleneglycol single combination was treated with endoproteinase Lys-C followed by LC-MS / MS analysis.
  • the melittin-polyethyleneglycol formulation obtained in Example 5 was further subjected to Superdex 200 gel filtration. Peptide mapping was performed by collecting only the fractions except the front and back fractions of the melittin-polyethylene glycol peak. The results are shown in FIG.
  • L1-PEG (5793 Da) was detected at retention time similar to L2. This is theoretically 137 Da that is greater than 5656 Da. This is the fraction of polyethylene glycol poly-dispersity (average molecular weight 4985 Da, molecular weight dispersibility: 4029 ⁇ 6041), except the long tailing portion of the melittin-polyethylene glycol peak in the tablet using Superdex 200 gel filtration The average molecular weight is expected to increase because it was obtained as a sample.
  • Absorbance A Absorbance of the sample at 415 nm wavelength
  • Absorbance B Absorbance of phosphate buffer at 415 nm
  • Absorbance C Absorbance of 1% Triton X-100 at 415 nm
  • the erythrocyte destructive capacity of 1: 1 melittin-polyethylene glycol copolymer (mono-PEG (5k) -MEL) was lower than that of melittin (MEL).
  • Cell growth inhibition activity was measured according to the XTT assay (Cell Proliferation Kit II (XTT) assay (Roche)) method.
  • XTT Cell Proliferation Kit II
  • XTT Cell Proliferation Kit II assay
  • RAW 264.7 cells were seeded in a 96-well plate at a concentration of 5 ⁇ 10 5 cells / ml at 200 ul per well, and then the melittin and 1: 1 melittin-polyethylene glycol blends were added at each concentration of lipopolysaccaride (LPS). After treatment with, incubated in 37 °C, 5% CO 2 incubator. As inflammation markers during inflammation, NO (nitrite oxide) and TNF- ⁇ produced by LPS were measured. JSH, Bay11-1272 anti-inflammatory reagent was used as a TNF- ⁇ inhibitor positive control.
  • the measurement of NO was performed at 37 ° C. after simultaneous treatment with melittin (MEL) or 1: 1 melittin-polyethylene glycol compound (mono-PEG (5k) -MEL, mono-PEG (20k) -MEL) and LPS. in 5% CO 2 incubator and cultured for 24 hours. 50 ul of the supernatant was mixed with the same amount of Griess reagent (1% Sulfarunilamide, 0.1% naphthyethylenediamine dihydrochloride, and 2% phosphoric acid), and the absorbance was measured at 540 nm after standing at room temperature for 10 minutes. The results are shown in FIG.
  • melittin (MEL) and 1: 1 melittin-polyethylene glycol combination inhibit NO production in a concentration-dependent manner. It was. However, in the case of melittin, a sharp decrease in NO at a concentration of 5 ug / ml or more is expected to be a cytotoxic effect.
  • the 1: 1 melittin-polyethylene glycol combination was shown to inhibit NO production in a concentration dependent manner even at concentrations that do not exhibit cytotoxicity.
  • TNF- ⁇ was performed after simultaneous treatment with melittin (MEL) or 1: 1 melittin-polyethylene glycol compound (mono-PEG (5k) -MEL, mono-PEG (20k) -MEL) and LPS, followed by 37 C was incubated for 6 hours in a 5% CO 2 incubator. Supernatant was taken and TNF- ⁇ ELISA was performed. The results are shown in FIG. 6 and Table 7.
  • melittin (MEL) and 1: 1 melittin-polyethylene glycol combination (mono-PEG (5k) -MEL) were shown to inhibit the production of TNF- ⁇ in a concentration dependent manner.
  • melittin (MEL) and 1: 1 melittin-polyethylene glycol combination (mono-PEG (5k) -MEL) were shown to inhibit the production of TNF- ⁇ in a concentration dependent manner.
  • the inhibitory effect of melittin appeared more urgent at the concentration showing cytotoxicity.
  • melittin inhibited the production of NO and TNF- ⁇ by 34% and 31%, respectively, at a concentration of 2.5 ug / ml, which showed no cytotoxicity
  • a 1: 1 melittin-polyethylene glycol compound (mono -PEG (5k) -MEL) showed inhibitory effects of 72% and 57% at 20 ug / ml concentrations without cytotoxicity, respectively.
  • the 1: 1 melittin-polyethylene glycol combination (mono-PEG (20k) -MEL) showed 45% and 42% inhibition at 20 ug / ml concentrations without cytotoxicity, respectively.

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Abstract

La présente invention concerne un conjugué mélittine-polyéthylèneglycol dans lequel le polyéthylèneglycol est couplé à un groupe amino N-terminal de la mélittine, un procédé de fabrication dudit conjugué et une composition pharmaceutique pour le traitement ou la prévention d'une inflammation contenant ce conjugué en tant que principe actif. Le conjugué mélittine-polyéthylèneglycol selon la présente invention est moins cytotoxique et présente un excellent effet anti-inflammatoire par rapport à la mélittine.
PCT/KR2015/005892 2014-06-13 2015-06-11 Conjugué mélittine-polyéthylèneglycol et composition pharmaceutique contenant ledit conjugué Ceased WO2015190849A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111110856A (zh) * 2020-02-28 2020-05-08 苏州大学 一种基于抗菌肽和亲水聚合物的抗菌药物及制备方法
CN113827703A (zh) * 2020-06-08 2021-12-24 沈阳药科大学 一种蜂毒肽-聚唾液酸静电复合物的制备及其用途
CN114437193A (zh) * 2022-01-29 2022-05-06 陕西未来多肽生物科技有限公司 一种金-蜂毒肽纳米杂化物及其应用

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KR101935095B1 (ko) * 2015-07-31 2019-01-04 이화여자대학교 산학협력단 신규한 세포투과성 펩타이드
KR102042059B1 (ko) * 2017-12-15 2019-11-07 주식회사 인스바이오팜 멜리틴 나노 입자를 포함하는 암 예방, 치료 및 개선용 조성물

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US5428128A (en) * 1993-06-21 1995-06-27 Mensi-Fattohi; Nahla Site specific synthesis of conjugated peptides
KR20020012278A (ko) * 1999-06-19 2002-02-15 추후기재 가수분해 가능한 친지체 성분의 양친매성 약제-올리고머접합체 및 이것의 제조 및 사용 방법
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KR20120125754A (ko) * 2011-05-09 2012-11-19 대한민국(농촌진흥청장) 멜리틴 성분을 포함하는 간질환 치료용 약학조성물
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111110856A (zh) * 2020-02-28 2020-05-08 苏州大学 一种基于抗菌肽和亲水聚合物的抗菌药物及制备方法
CN111821466A (zh) * 2020-02-28 2020-10-27 苏州大学 一种抗菌药物的制备方法
CN111888483A (zh) * 2020-02-28 2020-11-06 苏州大学 一种基于蜂毒肽和柔性聚乙二醇的抗菌药物
CN111821466B (zh) * 2020-02-28 2022-10-18 苏州大学 一种抗菌药物的制备方法
CN111888483B (zh) * 2020-02-28 2022-10-18 苏州大学 一种基于蜂毒肽和柔性聚乙二醇的抗菌药物
CN111110856B (zh) * 2020-02-28 2022-12-16 苏州大学 一种基于抗菌肽和亲水聚合物的抗菌药物及制备方法
CN113827703A (zh) * 2020-06-08 2021-12-24 沈阳药科大学 一种蜂毒肽-聚唾液酸静电复合物的制备及其用途
CN114437193A (zh) * 2022-01-29 2022-05-06 陕西未来多肽生物科技有限公司 一种金-蜂毒肽纳米杂化物及其应用

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