JP2009511029A - Pf4とrantesとの相互作用に対するアンタゴニスト - Google Patents
Pf4とrantesとの相互作用に対するアンタゴニスト Download PDFInfo
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- JP2009511029A JP2009511029A JP2008534921A JP2008534921A JP2009511029A JP 2009511029 A JP2009511029 A JP 2009511029A JP 2008534921 A JP2008534921 A JP 2008534921A JP 2008534921 A JP2008534921 A JP 2008534921A JP 2009511029 A JP2009511029 A JP 2009511029A
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- 229960003009 clopidogrel Drugs 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
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- 238000003745 diagnosis Methods 0.000 description 1
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- 230000037213 diet Effects 0.000 description 1
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- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229960004198 guanidine Drugs 0.000 description 1
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 1
- 102000045341 human CCL5 Human genes 0.000 description 1
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- 229920001223 polyethylene glycol Polymers 0.000 description 1
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Classifications
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Abstract
Description
を有する:
式中、
X1は、リシン、グルタミン、アルギニン、ヒスチジン、および/もしくはアスパラギンを含む群より選択されるか、またはアミノ酸欠失であり;
X2は、グルタミン酸、アスパラギン酸、および/もしくはグルタミンを含む群より選択されるか、またはアミノ酸欠失であり;
X3は、グリシン、セリン、および/またはアラニンを含む群より選択され;
X4は、リシン、ロイシン、および/またはアルギニンを含む群より選択され;
X5は、セリン、システイン、グリシン、および/またはスレオニンを含む群より選択され;
X6は、セリン、グリシン、および/またはスレオニンを含む群より選択され;
X7は、アスパラギンおよび/またはグルタミンを含む群より選択され;
X8は、プロリン、チロシン、および/またはグリシンを含む群より選択され;
X9は、グリシン、アラニン、および/またはセリンを含む群より選択され;
X10は、イソロイシン、バリン、および/またはアスパラギンを含む群より選択され;
X11は、バリン、イソロイシン、および/またはアスパラギンを含む群より選択され;
X12は、フェニルアラニン、チロシン、イソロイシン、バリン、ロイシン、および/またはメチオニンを含む群より選択され;
X13は、イソロイシン、バリン、ロイシン、メチオニン、および/またはフェニルアラニンを含む群より選択され;
X14は、スレオニン、グリシン、アラニン、セリン、および/またはチロシンを含む群より選択され;
X15は、アルギニン、リシン、グルタミン、ヒスチジン、および/もしくはアスパラギンを含む群より選択されるか、またはアミノ酸欠失である。
を有し、かつ/または、式(2)に記載のSEQ ID NO: 2のポリペプチドが、式(2)に記載のアミノ酸配列SEQ ID NO: 2に対して少なくとも1つまたは複数のアミノ酸欠失、アミノ酸置換、および/またはアミノ酸挿入を有することが提供されうる。
心血管疾患および/もしくは炎症性疾患、特に、動脈硬化、アテローム性動脈硬化、不安定プラーク、狭窄、再狭窄、高血圧、関節炎、心筋炎、脳脊髄炎を含む自己免疫疾患、炎症性腸疾患、心筋梗塞や脳血管梗塞などの梗塞後の再灌流障害、移植拒絶反応、および/もしくは乾癬などの皮膚疾患などの、単球の漸増を伴う疾患;ならびに/または
特に喘息もしくは肺炎などのアレルギー疾患に対する好酸球増多症などの、その他の白血球集団のRANTES依存的漸増を伴う疾患。
細胞培養
ヒト臍帯由来の内皮細胞(ヒト臍静脈内皮細胞(HUVEC)、PromoCell、Heidelberg)を、内皮細胞増殖培地(PromoCell、Heidelberg)中で培養し、2〜4継代後に使用した。
式(3)に記載の配列SEQ ID NO: 3のポリペプチド、式(15)に記載の配列SEQ ID NO: 15に記載のそのオルソログ、および、式(14)に記載の配列SEQ ID NO: 14の対照ペプチドを、4-メチルベンズヒドリルアミン樹脂を使用するt-Bocベースの固相ペプチド合成によって化学合成し、逆相HPLCによって精製し、6MグアニジンHCl/Tris(pH8)中でできる限り環を形成させた。エレクトロスプレー質量分析法によって分子量を測定した(Dawson PE, Kent SB. (2000) Annu Rev Biochem. 69: 923-960;Hackeng TM, Griffin JH, Dawson PE. (1999) Proc Natl Acad Sci U.S.A., Vol 96, p. 10068-10073)。
式(3)に記載の配列SEQ ID NO: 3のポリペプチドがRANTESとPF4とのヘテロ凝集体(heteroaggregate)の形成に与える阻害効果を解析するためのプラズモン共鳴分析
プラズモン共鳴分析は、HBS-EP緩衝液(10 mM HEPES、150 mM NaCl、0.005% Tween 20、pH 7.4)を用いて実施した。
式(3)に記載の配列SEQ ID NO: 3のポリペプチド、式(2)に記載のSEQ ID NO: 2のポリペプチド、および対照ペプチドがRANTESとPF4とのヘテロ凝集体の形成に与える阻害効果を解析するためのプラズモン共鳴分析
別の実験において、実施例1に記載の条件下で、RANTES(0.5μM)、または、0μM、10μM、50μM、および100μMの、式(3)に記載の配列SEQ ID NO: 3のポリペプチド、式(2)に記載のSEQ ID NO: 2のポリペプチド、および以下に示す式(14)に記載のSEQ ID NO: 14の対照ペプチドと共に予めインキュベーションされたRANTES(0.5μM)の結合を調べた。
活性化内皮における単球停止の阻害
活性化内皮細胞におけるMono Mac 6単球細胞の相互作用を調べた。
アテローム性動脈硬化のマウスモデルにおけるインビボ調査
9〜12週齢の雌性ApoE-/-同腹仔マウス(The Jackson Lab、Bar Harbor、Maine、USA)を、アテローム性動脈硬化のモデルとして使用した。これらに、脂肪に富む飼料(21%脂肪;Altromin C1061)を12週間与えた。この期間に、2つのマウス群に、以下に示す式(15)に記載の配列SEQ ID NO: 15
のペプチド(n=マウス12匹)、または、以下に示す式(14)に記載の配列SEQ ID NO: 14
の対照ペプチド(n=マウス7匹)を50μg含む生理食塩溶液を、週3回腹膜内注射した。非処置群のマウス(n=12)を、さらなる対照として使用した。
Claims (25)
- 以下に示す式(1)に記載のアミノ酸配列SEQ ID NO: 1
を有することを特徴とするポリペプチド、その薬学的に許容される塩、誘導体、および/または結合体:
式中、
X1は、リシン、グルタミン、アルギニン、ヒスチジン、および/もしくはアスパラギンを含む群より選択されるか、またはアミノ酸欠失であり;
X2は、グルタミン酸、アスパラギン酸、および/もしくはグルタミンを含む群より選択されるか、またはアミノ酸欠失であり;
X3は、グリシン、セリン、および/またはアラニンを含む群より選択され;
X4は、リシン、ロイシン、および/またはアルギニンを含む群より選択され;
X5は、セリン、システイン、グリシン、および/またはスレオニンを含む群より選択され;
X6は、セリン、グリシン、および/またはスレオニンを含む群より選択され;
X7は、アスパラギンおよび/またはグルタミンを含む群より選択され;
X8は、プロリン、チロシン、および/またはグリシンを含む群より選択され;
X9は、グリシン、アラニン、および/またはセリンを含む群より選択され;
X10は、イソロイシン、バリン、および/またはアスパラギンを含む群より選択され;
X11は、バリン、イソロイシン、および/またはアスパラギンを含む群より選択され;
X12は、フェニルアラニン、チロシン、イソロイシン、バリン、ロイシン、および/またはメチオニンを含む群より選択され;
X13は、イソロイシン、バリン、ロイシン、メチオニン、および/またはフェニルアラニンを含む群より選択され;
X14は、スレオニン、グリシン、アラニン、セリン、および/またはチロシンを含む群より選択され;
X15は、アルギニン、リシン、グルタミン、ヒスチジン、および/もしくはアスパラギンを含む群より選択されるか、またはアミノ酸欠失である。 - 19アミノ酸以上〜22アミノ酸以下の範囲内のいくつかのアミノ酸を有することを特徴とする、請求項1記載のポリペプチド。
- X1がリシンまたはアミノ酸欠失であることを特徴とする、請求項1または2記載のポリペプチド。
- X2がグルタミン酸またはアミノ酸欠失であることを特徴とする、前記請求項のいずれか一項記載のポリペプチド。
- X3がグリシンおよび/またはセリンを含む群より選択されることを特徴とする、前記請求項のいずれか一項記載のポリペプチド。
- X5がセリンであることを特徴とする、前記請求項のいずれか一項記載のポリペプチド。
- X8がプロリンおよび/またはチロシンを含む群より選択されることを特徴とする、前記請求項のいずれか一項記載のポリペプチド。
- X9がグリシンであることを特徴とする、前記請求項のいずれか一項記載のポリペプチド。
- X10がイソロイシンであることを特徴とする、前記請求項のいずれか一項記載のポリペプチド。
- X12がフェニルアラニンおよび/またはチロシンを含む群より選択されることを特徴とする、前記請求項のいずれか一項記載のポリペプチド。
- X13がイソロイシンであることを特徴とする、前記請求項のいずれか一項記載のポリペプチド。
- X15がアルギニンを含む群より選択されるかまたは欠失であることを特徴とする、前記請求項のいずれか一項記載のポリペプチド。
- RANTESと血小板第4因子との間の相互作用に対するアンタゴニストとしての、前記請求項のいずれか一項記載のポリペプチド、その薬学的に許容される塩、誘導体、および/または結合体の使用。
- 医薬を製造するための、前記請求項のいずれか一項記載のポリペプチド、その薬学的に許容される塩、誘導体、および/または結合体の使用。
- 心血管疾患および/もしくは炎症性疾患、特に、動脈硬化、アテローム性動脈硬化、不安定プラーク、狭窄、再狭窄、高血圧、関節炎、心筋炎、脳脊髄炎を含む自己免疫疾患、炎症性腸疾患、梗塞後の再灌流障害、移植拒絶反応、および/もしくは皮膚疾患などの、単球の漸増を伴う疾患;ならびに/または
特に喘息もしくは肺炎などのアレルギー疾患に対する好酸球増多症などの、その他の白血球集団のRANTES依存的漸増を伴う疾患
を含む群より選択される疾患の治療的および/または予防的な処置用の医薬を製造するための、前記請求項のいずれか一項記載のポリペプチド、その薬学的に許容される塩、誘導体、および/または結合体の使用。 - 前記請求項のいずれか一項記載のポリペプチド、その薬学的に許容される塩、誘導体、および/または結合体を含む、医薬。
- 前記請求項のいずれか一項記載のポリペプチド、その薬学的に許容される塩、誘導体、および/または結合体を含む、単球停止(monocyte arrest)に対する作用物質。
- 前記請求項のいずれか一項記載のポリペプチドをコードする核酸配列を含む、核酸。
- 前記請求項のいずれか一項記載のポリペプチドをコードする核酸を含む、医薬。
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DE102005049637A DE102005049637A1 (de) | 2005-10-14 | 2005-10-14 | Antagonisten gegen die Interaktion von PF4 und RANTES |
DE102005049637.7 | 2005-10-14 | ||
PCT/EP2006/009790 WO2007042263A1 (de) | 2005-10-14 | 2006-10-11 | Antagonisten gegen die interaktion von pf4 und rantes |
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JP2009511029A true JP2009511029A (ja) | 2009-03-19 |
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JP (1) | JP5385611B2 (ja) |
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CN (2) | CN101356190B (ja) |
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CA (1) | CA2648649A1 (ja) |
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EA (1) | EA013508B1 (ja) |
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HK (1) | HK1127069A1 (ja) |
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CA2737924A1 (en) * | 2008-10-06 | 2010-04-15 | Joshua Robert Schultz | Methods of treating inflammation |
WO2011116245A2 (en) * | 2010-03-19 | 2011-09-22 | Carolus Therapeutics, Inc. | Methods of treating inflammation |
US11629196B2 (en) | 2020-04-27 | 2023-04-18 | Incelldx, Inc. | Method of treating SARS-CoV-2-associated hypercytokinemia by administering a human monoclonal antibody (PRO-140) that inhibits CCR5/CCL5 binding interactions |
US11402391B2 (en) | 2020-12-21 | 2022-08-02 | Incelldx, Inc. | Methods of treating a long-hauler subject for chronic COVID-19 by administering a CCR5 or CCL5 antagonist |
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DE10014516A1 (de) * | 2000-03-23 | 2001-09-27 | Weber Christian | Antagonisten des RANTES Rezeptors CCR1 zur Prävention und Therapie der Atherosklerose und Restenose |
JP2003500334A (ja) * | 1998-11-11 | 2003-01-07 | フォンダジオーネ セントロ サン ラファエロ デル モンテ タボール | 抗hiv作用を有するrantes由来ペプチド |
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WO1998006751A1 (en) * | 1996-08-16 | 1998-02-19 | Research Corporation Technologies, Inc. | Mcp-3, rantes and mip-1alpha receptor antagonists |
US6168784B1 (en) * | 1997-09-03 | 2001-01-02 | Gryphon Sciences | N-terminal modifications of RANTES and methods of use |
EP0906954A1 (en) * | 1997-09-29 | 1999-04-07 | Applied Research Systems ARS Holding N.V. | Amino-terminal truncated c-c chemokines as chemokine antagonist |
US6534626B1 (en) * | 1997-12-01 | 2003-03-18 | The United States Of America As Represented By The Department Of Health & Human Services | Chemokine variants |
ITMI20030107A1 (it) * | 2003-01-24 | 2004-07-25 | Primm Srl | Peptidi derivati da rantes. |
DE102005049637A1 (de) | 2005-10-14 | 2007-04-26 | Rheinisch-Westfälische Technische Hochschule Aachen | Antagonisten gegen die Interaktion von PF4 und RANTES |
CA2737924A1 (en) * | 2008-10-06 | 2010-04-15 | Joshua Robert Schultz | Methods of treating inflammation |
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DE10014516A1 (de) * | 2000-03-23 | 2001-09-27 | Weber Christian | Antagonisten des RANTES Rezeptors CCR1 zur Prävention und Therapie der Atherosklerose und Restenose |
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KR20080080093A (ko) | 2008-09-02 |
HK1127069A1 (en) | 2009-09-18 |
JP5385611B2 (ja) | 2014-01-08 |
ZA200804081B (en) | 2009-11-25 |
CN101356190B (zh) | 2012-11-14 |
BRPI0617384A2 (pt) | 2011-07-26 |
US8501680B2 (en) | 2013-08-06 |
WO2007042263A1 (de) | 2007-04-19 |
EP1934249A1 (de) | 2008-06-25 |
DE102005049637A1 (de) | 2007-04-26 |
CA2648649A1 (en) | 2007-04-19 |
CN102911260A (zh) | 2013-02-06 |
EP2363412B1 (de) | 2015-06-10 |
US20120077733A1 (en) | 2012-03-29 |
MX2008004866A (es) | 2008-10-20 |
US20080287652A1 (en) | 2008-11-20 |
EA200801077A1 (ru) | 2008-12-30 |
EA013508B1 (ru) | 2010-06-30 |
AU2006301494A1 (en) | 2007-04-19 |
AU2006301494B2 (en) | 2011-01-06 |
NO20082127L (no) | 2008-07-08 |
ES2546094T3 (es) | 2015-09-18 |
KR101477767B1 (ko) | 2015-01-02 |
US8110552B2 (en) | 2012-02-07 |
CN101356190A (zh) | 2009-01-28 |
IL190820A0 (en) | 2008-11-03 |
EP2363412A1 (de) | 2011-09-07 |
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