WO2016148437A1 - 흉선 기질 림프단백질 매개 신호전달을 제어하는 펩타이드 유도체 및 이를 포함하는 알러지 및 천식 질환 예방 및 치료용 약학 조성물 - Google Patents
흉선 기질 림프단백질 매개 신호전달을 제어하는 펩타이드 유도체 및 이를 포함하는 알러지 및 천식 질환 예방 및 치료용 약학 조성물 Download PDFInfo
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- WO2016148437A1 WO2016148437A1 PCT/KR2016/002388 KR2016002388W WO2016148437A1 WO 2016148437 A1 WO2016148437 A1 WO 2016148437A1 KR 2016002388 W KR2016002388 W KR 2016002388W WO 2016148437 A1 WO2016148437 A1 WO 2016148437A1
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- pharmaceutical composition
- peptide derivative
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- allergic
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- 0 *[C@@](Cc1c[n]c2ccccc12)C1OC1OC1CCCCC1 Chemical compound *[C@@](Cc1c[n]c2ccccc12)C1OC1OC1CCCCC1 0.000 description 5
- JMLIGWGNXHCPNW-BULBTXNYSA-N C[C@@H](C(N[C@@H](CCCNC(N)=N)C(N[C@@H](CCC(N)=O)C(N[C@@H](CCCNC(N)=N)C(N[C@@H](C)C(N[C@@H](CO)C(N[C@@H](C)C(O)=O)=O)=O)=O)=O)=O)=O)NC(C)=O Chemical compound C[C@@H](C(N[C@@H](CCCNC(N)=N)C(N[C@@H](CCC(N)=O)C(N[C@@H](CCCNC(N)=N)C(N[C@@H](C)C(N[C@@H](CO)C(N[C@@H](C)C(O)=O)=O)=O)=O)=O)=O)=O)NC(C)=O JMLIGWGNXHCPNW-BULBTXNYSA-N 0.000 description 1
- FIMXOQMJINQJKG-YQAXKJAASA-N C[C@@H](C(N[C@@H](CO)C(N[C@@H](C)C(O)=O)=O)=O)NC([C@H](CCCNC(N)=N)NC([C@H](CCC(N)=O)NC([C@H](CCCNC(N)=N)NC(C)=O)=O)=O)=O Chemical compound C[C@@H](C(N[C@@H](CO)C(N[C@@H](C)C(O)=O)=O)=O)NC([C@H](CCCNC(N)=N)NC([C@H](CCC(N)=O)NC([C@H](CCCNC(N)=N)NC(C)=O)=O)=O)=O FIMXOQMJINQJKG-YQAXKJAASA-N 0.000 description 1
- NVYUSSFNAWVFOR-JMXOTLKISA-N C[C@@H](C(N[C@@H](CO)C(N[C@H](C(N[C@@H](Cc1c[nH]c2ccccc12)C(O)=C1CC1)=O)O)=O)=O)NC1([C@H](CCCNC(N)=N)NC([C@H](CCC(N)=O)NC([C@H](CCCNC(N)=N)N)=O)=O)C2=CCC12 Chemical compound C[C@@H](C(N[C@@H](CO)C(N[C@H](C(N[C@@H](Cc1c[nH]c2ccccc12)C(O)=C1CC1)=O)O)=O)=O)NC1([C@H](CCCNC(N)=N)NC([C@H](CCC(N)=O)NC([C@H](CCCNC(N)=N)N)=O)=O)C2=CCC12 NVYUSSFNAWVFOR-JMXOTLKISA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- 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
Definitions
- the present invention relates to a peptide derivative compound that controls thymic stromal lymphoprotein-mediated signaling and a pharmaceutical composition for the prevention and treatment of allergic and asthma diseases containing the same as an active ingredient.
- Bronchodilators or anti-inflammatory drugs used in the treatment of allergic inflammatory diseases are performed mainly for symptomatic therapy, which can temporarily reduce the symptoms. However, they do not have fundamental control over allergic diseases. .
- Th2 cells are well known to play a pivotal role in inducing allergic reactions.
- CD4 T cells When CD4 T cells are stimulated by antigens in lymphocytes, they can be differentiated into several Th cells according to cytokines that are recognized at the same time, and the recognized cytokines are thymic stromal lymphoprotein (TSLP). Or in the case of type 2 cytokines such as IL-4, these cells differentiate into Th2 to induce an allergic reaction.
- TSLP thymic stromal lymphoprotein
- dendritic cells that provide antigens to CD4 T cells have also been shown to respond to stimulation of TSLP and to help differentiate Th2 cells.
- cytokines secreted from the tissue after the differentiated Th2 cells move to allergens such as lungs or skin also play an important role in activation.
- cytokines include TSLP, IL-25, IL-33, etc.
- TSLP is expected to play the most effective role.
- TSLP is an important cytokine that functions both in the differentiation and activation of Th2 cells, and it is recognized that controlling it is important for treating allergic diseases.
- Korean Patent Publication No. 2008-0099330 discloses antibodies that neutralize the activity of human TSLP, and asthma
- Korean Unexamined Patent Publication No. 2009-0088950 discloses antibodies specific for TSLP and the treatment of inflammation and allergic inflammatory diseases using the same
- Patent Publication No. 2015-0006639 discloses a pharmaceutical composition having a TSLP secretion inhibitory activity containing a compound having a predetermined formula and a pharmaceutically acceptable salt thereof as an active ingredient.
- TSLP intracellular signal transduction by TSLP to exert the effect of inhibiting the phosphorylation of intracellular STAT5, peptide derivatives having excellent efficacy in the prevention and treatment of allergies and asthma diseases and pharmaceutical compositions comprising the same To provide.
- the present invention in order to solve the above problems, provides a peptide derivative represented by the following formula (1):
- R 1 is an alkyl group having 1 to 4 carbon atoms substituted with guanidine
- R 2 is any one selected from an amine group and the following [Formula 1]
- R 3 is any one selected from a hydroxy group and the following [Formula 2]. :
- the peptide derivative of Chemical Formula 1 may be any one of the peptide derivatives represented by the following Chemical Formulas 2 to 9:
- the present invention provides a pharmaceutical composition for preventing and treating allergy and asthma disease, which comprises the peptide derivative represented by the formula (1) or a salt thereof as an active ingredient.
- the peptide derivative of Chemical Formula 1 may be any one of the peptide derivatives represented by the following Chemical Formulas 2 to 9:
- the allergic disease may be atopic dermatitis, urticaria or allergic rhinitis disease.
- the pharmaceutical composition may further comprise one or more components selected from the group consisting of drugs, carriers, diluents, adjuvants and stabilizers for the prevention and treatment of other allergic and asthmatic diseases.
- the stabilizer may be selected from the group consisting of proteins, sugars, buffers and mixtures thereof.
- a peptide derivative and a pharmaceutical composition comprising the same, which can effectively inhibit the formation of an inflammatory response in an allergic or asthmatic disease, and can fundamentally prevent or treat various allergic and asthmatic diseases.
- FIGS. 1A to 1J are flowcharts schematically illustrating a process of synthesizing a TSLP binding peptide derivative according to the present invention using a solid phase method.
- Figure 2 is a graph showing the change in phosphorylation of intracellular STAT5 molecules by treatment of the compound according to formula 2 of the TSLP binding peptide derivative according to the present invention.
- Figure 3 is a graph showing the change in phosphorylation of intracellular STAT5 molecules by treatment of the compound according to formula 3 of the TSLP binding peptide derivative according to the present invention.
- Figure 4 is a graph showing the phosphorylation changes of intracellular STAT5 molecules by treatment of the compound according to formula 4 of the TSLP binding peptide derivative according to the present invention.
- FIG. 5 is a graph showing the phosphorylation change of intracellular STAT5 molecules by treatment of the compound according to Formula 5 among TSLP binding peptide derivatives according to the present invention.
- Figure 6 is a graph showing the phosphorylation change of intracellular STAT5 molecules by treatment of the compound according to formula 6 in the TSLP binding peptide derivative according to the present invention.
- Figure 7 is a graph showing the phosphorylation changes of intracellular STAT5 molecules by treatment of the compound according to formula 7, among TSLP binding peptide derivatives according to the present invention.
- FIG. 8 is a graph showing the phosphorylation change of intracellular STAT5 molecules by treatment of a compound according to Formula 9 among TSLP binding peptide derivatives according to the present invention.
- the inventors have identified for the first time that peptide derivatives having the general formula of Formula 1 effectively inhibit the binding between TSLP, one of the key cytokines inducing asthma and allergic diseases, and the TSLP receptor that binds to such TSLP.
- the present invention has been completed based on the above.
- R 1 is an alkyl group having 1 to 4 carbon atoms substituted with guanidine
- R 2 is any one selected from an amine group and the following [Formula 1]
- R 3 is any one selected from a hydroxy group and the following [Formula 2]. :
- the peptide derivative represented by Chemical Formula 1 includes an amino acid sequence of H 2 N-Arg-Gln-Arg-Ala-Ser-Ala-COOH in common, and the N-terminus of the amino acid sequence is substituted with another substituent as necessary. Or other amino acid residues may be additionally added to the N-terminus.
- Peptide derivatives according to the present invention can be prepared by the solid phase method using the Fmoc-method, for example, Fmoc-Ala-Wang-resin or H 2 for synthesizing peptides of the C-terminally amidated form.
- Fmoc-method for example, Fmoc-Ala-Wang-resin or H 2 for synthesizing peptides of the C-terminally amidated form.
- N-Ala-Wang-resin may be used as a starting material to prepare peptide derivatives in various forms.
- any one of the peptide derivatives represented by the following Chemical Formulas 2 to 9 may be prepared:
- the present invention provides a pharmaceutical composition for preventing and treating allergy and asthma diseases containing the peptide derivative represented by Formula 1 or a salt thereof as an active ingredient.
- the term "comprising as an active ingredient” means that the component is included in an amount necessary or sufficient to realize a desired biological effect.
- the determination of the amount to be included as an active ingredient is an amount for treating a subject disease, and may be determined in consideration of matters that do not cause other toxicity, for example, the disease or condition being treated, the form of the composition to be administered, It may vary depending on various factors such as the size of the subject or the severity of the disease or condition.
- One of ordinary skill in the art can empirically determine the effective amount of an individual composition without undue experimentation.
- the peptide derivative of Formula 1 may be any one of peptide derivatives represented by Formulas 2 to 9.
- the pharmaceutical composition according to the present invention can be used for the prevention and treatment of a wide range of allergic and asthmatic diseases, but the allergic disease may be atopic dermatitis, urticaria or allergic rhinitis disease.
- composition according to the present invention may be administered in the form of a complex preparation together with other allergic and asthma disease preventing and treating drugs, or may include other ingredients such as carriers, diluents, adjuvants and stabilizers and the like.
- the form of the composition according to the present invention may be variously selected depending on the mode to be administered, but is not limited thereto, for example, tablets, pills, powders, capsules, gels, ointments, fluids or suspensions, and the like. It may be in solid, semi-solid or liquid dosage form, and may be administered in unit dosage forms suitable for single dose administration of precise dosages.
- the compositions may include, depending on the desired formulation, a pharmaceutically acceptable carrier, diluent, adjuvant, stabilizer, defined as an aqueous-based carrier commonly used in formulating pharmaceutical compositions for human administration.
- diluents may include distilled water, physiological saline, Ringer's solution, glucose solution, Hank's solution, and the like.
- the pharmaceutical composition according to the present invention may also be administered in the form of a complex preparation together with other allergic and asthma disease prevention and treatment drug preparations or pharmaceutical preparations, and those skilled in the art for the prevention and treatment of various types of allergy and asthma disease Drugs can be considered.
- An effective amount of other ingredients such as carriers, diluents, adjuvants and stabilizers and the like is an amount effective to obtain a pharmaceutically acceptable formulation in terms of solubility, biological activity, etc. of the ingredient.
- the stabilizer may be selected from the group consisting of proteins, sugars, buffers and mixtures thereof.
- Fmoc-Ala-Wang Resin was used as a starting material, and the extension of the peptide chain by the coupling of Fmoc-amino acids was achieved using N-hydroxybenzo-triazole (HOBt) and O- (benzotriazole). 1-yl) -N, N, N, N-tetramethyluronium hexafluorophosphate (HBTU) method was used. After coupling the Fmoc-amino acid at the amino terminus of each peptide, the Fmoc group was removed with 20% piperidine / N-methylpyrrolidone (NMP) solution, washed several times with NMP and dichloromethane (DCM) and then nitrogen. Dry with gas.
- NMP N-methylpyrrolidone
- FIGS. 1F-1J a schematic synthetic scheme for the peptide derivatives of Formulas 6-9 is shown in FIGS. 1F-1J, and the reactants and reaction conditions used in the reactions shown in FIGS. 1F-1J are as follows:
- Compound 7 amino acid sequence (CH 3 CONH-Arg-Gln-Arg-Ala-Ser-Ala-Trp-COOH)
- Compound 8 Amino Acid Sequence (H 2 N-Ala-Arg-Gln-Arg-Ala-Ser-Ala-Trp-COOH)
- TSLP signaling is also well known for the characteristic phosphorylation of STAT5 in STAT molecules. Therefore, in order to confirm whether the compounds according to the present invention effectively inhibit the binding between TSLP and TSLP receptor, the phosphorylation degree of the STAT5 molecule can be confirmed in the JAK / STAT pathway activated by such binding. If the compounds according to the invention effectively inhibit the binding between TSLP and TSLP receptors, the phosphorylation level of the STAT5 molecule may be inhibited.
- HMC-1 a human mast cell line
- TSLP 100 ng / mL
- peptides of appropriate concentrations 0.3, 3, 30 ⁇ M
- the cells were fixed with a cytofix.
- the cells were permeabilized with a permeabilization buffer, followed by intracellular staining with anti-pSTAT5 antibody at 4 ° C. for 30 minutes. Cells were washed three times with the same buffer and analyzed by flow cytometry.
- 2 to 8 show graphs showing phosphorylation changes of intracellular STAT5 molecules by treatment of Compounds 2 to 7, and 9, and also Tables 1 to 3 show concentrations of 0.3, 3, and 30 ⁇ M, respectively.
- the phosphorylation level of intracellular STAT5 molecules was shown compared to the control group. As a control, only the cytokine TSLP was treated, and the phosphorylation of intracellular STAT5 molecules was 100%.
- the peptide derivatives according to the present invention can effectively inhibit the binding between the cytokine TSLP and the TSLP receptor, which plays a key role in causing allergic and asthmatic diseases, and according to the present invention, therefore, TSLP-mediated signal transduction By suppressing, the fundamental prevention and treatment of allergic and asthmatic diseases is possible.
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- Proteomics, Peptides & Aminoacids (AREA)
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Abstract
Description
화합물 | 세포내 STAT5 분자의 인산화 정도 (%) | ||
0.3 μM | 3 μM | 30 μM | |
2 | 84.4 | 77.9 | 69.8 |
3 | 73.5 | 67.8 | 66.9 |
4 | 71.0 | 68.3 | 70.9 |
5 | 86.1 | 84.6 | 77.1 |
Claims (7)
- 제1항 또는 제2항에 따른 펩타이드 유도체 또는 그 염을 유효성분으로 함유하는 알러지 및 천식 질환 예방 및 치료용 약학 조성물.
- 제3항에 있어서, 상기 알러지 질환은 아토피성 피부염, 두드러기 또는 알러지성 비염 질환인 것을 특징으로 하는 알러지 및 천식 질환 예방 및 치료용 약학 조성물.
- 제3항에 있어서, 상기 약학 조성물은 다른 알러지 및 천식 질환 예방 및 치료용 약물, 담체, 희석제, 보조제 및 안정화제로 이루어진 군으로부터 선택된 하나 이상의 성분을 더 포함하는 것을 특징으로 하는 알러지 및 천식 질환 예방 및 치료용 약학 조성물.
- 제6항에 있어서, 상기 안정화제는 단백질, 당질, 완충제 및 그 혼합물로 이루어진 군으로부터 선택되는 것을 특징으로 하는 알러지 및 천식 질환 예방 및 치료용 약학 조성물.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
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JP2018500255A JP2018511654A (ja) | 2015-03-17 | 2016-03-10 | 胸腺間質リンホポエチン媒介信号伝逹を制御するペプチド誘導体及びこれを含むアレルギー及び喘息疾患の予防及び治療用薬学組成物 |
US15/558,286 US10059743B2 (en) | 2015-03-17 | 2016-03-10 | Peptide derivative for regulating thymic stromal lymphoid protein-mediated signaling and pharmaceutical composition for preventing and treating allergy and asthma diseases comprising same |
EP16765193.4A EP3272765A4 (en) | 2015-03-17 | 2016-03-10 | Peptide derivative for regulating thymic stromal lymphoid protein-mediated signaling and pharmaceutical composition for preventing and treating allergy and asthma diseases comprising same |
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KR10-2015-0036723 | 2015-03-17 | ||
KR20150036723 | 2015-03-17 | ||
KR10-2016-0026865 | 2016-03-07 | ||
KR1020160026865A KR101843248B1 (ko) | 2015-03-17 | 2016-03-07 | 흉선 기질 림프단백질 매개 신호전달을 제어하는 펩타이드 유도체 및 이를 포함하는 알러지 및 천식 질환 예방 및 치료용 약학 조성물 |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070237787A1 (en) * | 2004-03-23 | 2007-10-11 | Government Of The Usa, Represented By The Secretary , Depa | Methods for use of tslp and agonists and antagonists thereof |
US20130225490A1 (en) * | 1998-11-13 | 2013-08-29 | Immunex Corporation | Antibodies That Inhibit TSLP Activity |
KR20150006639A (ko) * | 2013-07-09 | 2015-01-19 | 주식회사 엘지생활건강 | Tslp 분비 저해능 및 이에 의한 알러지성 질환의 개선능을 가지는 조성물 |
-
2016
- 2016-03-10 WO PCT/KR2016/002388 patent/WO2016148437A1/ko active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130225490A1 (en) * | 1998-11-13 | 2013-08-29 | Immunex Corporation | Antibodies That Inhibit TSLP Activity |
US20070237787A1 (en) * | 2004-03-23 | 2007-10-11 | Government Of The Usa, Represented By The Secretary , Depa | Methods for use of tslp and agonists and antagonists thereof |
KR20150006639A (ko) * | 2013-07-09 | 2015-01-19 | 주식회사 엘지생활건강 | Tslp 분비 저해능 및 이에 의한 알러지성 질환의 개선능을 가지는 조성물 |
Non-Patent Citations (5)
Title |
---|
BOSNJAK ET AL.: "Treatment of Allergic Asthma: Modulation of Th2 Cells and their Responses", RESPIRATORY RESEARCH, vol. 12, 2011, pages 1 - 17, XP021108634 * |
DATABASE Pubchem [O] 5 December 2007 (2007-12-05), XP055312029, Database accession no. 21279213 * |
DATABASE Pubchem [O] 5 December 2007 (2007-12-05), XP055312030, Database accession no. 20017944 * |
See also references of EP3272765A4 * |
ZHANG ET AL.: "Functions of Thymic Stromal Lymphopoietin in Immunity and Disease", IMMUNOLOGIC RESEARCH, vol. 52, no. 3, 25 January 2012 (2012-01-25), pages 1 - 20, XP035054105 * |
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