JP6205345B2 - ウイルス侵入の阻害に関する方法および組成物 - Google Patents
ウイルス侵入の阻害に関する方法および組成物 Download PDFInfo
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- A61K47/59—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 the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—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 the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- A61K47/51—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 the non-active ingredient being a modifying agent
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- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
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- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- 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
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Description
この研究は国立保健研究機構(the National Institutes of Health)(認可番号 AI RI 076168)による援助を一部受けたものである。合衆国政府は本開示に対する特定の権利を有する。
特に定義されていない限り、本明細書に使用される全ての技術用語および科学用語は、本明細書の文脈において、当業者によって一般的に理解される意味を有している。
開示された組成物の調製に使用される成分および本明細書に開示する方法において使用される組成物自体について開示する。
(1.多量体)
a)多量体骨格
b)ヘテロ四量体
c)多量体の結合活性
d)ペプチド変異体
2.医薬担体/医薬品の送達
a)薬学的に許容可能な担体
b)治療上の使用
3.チップおよびマイクロアレイ
4.コンピュータ読み取り可能な媒体
5.開示する組成物によるスクリーニングによって同定される組成物
a)コンビナトリアルケミストリー
b)コンピュータを使った薬物設計
6.キット
7.類似の機能を有する組成物
C.組成物の作製方法
1.ペプチド合成
D.組成物の使用方法
1.組成物を研究ツ−ルとして使用する方法
2.ウイルス侵入阻害方法
E.実施例
例1:阻害D−ペプチド
a)ペプチド合成
b)ウイルス感染性アッセイ:
c)結果と考察
HPCDYPEWQWLCELGK(配列ID番号:26)
HPCDYPEWQWLCKLGK(配列ID番号:27)
HPCDYPEWQWLCRLGK(配列ID番号:28)
HACDYPEWQWLCELGK(配列ID番号:29)
a)D−ペプチドのコレステロールカーゴとの合成
b)結果
例3: モジュラーホモ三量体骨格
a)ペプチド合成
b)三量体合成
c)ウイルス感染性アッセイ
d)結果
実施例5:膜局在化の耐性コンデンサへの影響
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Claims (34)
- ポリエチレングリコール(PEG)リンカーによって作用強度増強カーゴ分子に連結された、少なくとも1つのD−ペプチドを含み、
前記作用強度増強カーゴ分子が、コレステロール若しくはチオコレステロール、アルカン鎖、又は脂肪酸であり、
前記D−ペプチドが、配列ID番号31のアミノ酸配列を含む8アミノ酸のコアペプチドを含み、
前記PEGリンカーが少なくとも12のエチレングリコール反復単位を含む組成物。 - 前記少なくとも一つのD−ペプチドが、PIE7(配列ID番号:6)、PIE7−GK(配列ID番号:23)、PIE7−GKK(配列ID番号:24)、K−PIE7−GK(配列ID番号:25)、PIE12(配列ID番号:26)、PIE13(配列ID番号:27)、PIE14(配列ID番号:28)、又はPIE15(配列ID番号:29)の少なくとも1つを含む、請求項1に記載の組成物。
- 前記少なくとも1つのD−ペプチドがヒト免疫不全ウイルス(HIV) gp41タンパク質のN−三量体ポケットと結合可能である、請求項1又は2に記載の組成物。
- 前記PEGリンカーが、PEG12,PEG16,PEG24,PEG25,PEG26,PEG27,PEG28,PEG29,PEG30,PEG31,PEG32,PEG33,PEG34,PEG35またはPEG36のうちの1つである、請求項1〜3の何れか一項に記載の組成物。
- 前記作用強度増強カーゴ分子がコレステロールまたはチオコレステロールである、請求項1〜4の何れか一項に記載の組成物。
- 前記作用強度増強カーゴ分子が脂肪酸である、請求項1〜4の何れか一項に記載の組成物。
- 前記脂肪酸がC8脂肪酸、C16脂肪酸およびC18脂肪酸のうちの少なくとも1つである、請求項6に記載の組成物。
- 前記作用強度増強カーゴ分子がアルカン鎖である、請求項1〜4の何れか一項に記載の組成物。
- 前記アルカン鎖はC8アルカン、C16アルカンおよびC18アルカンのうちの少なくとも1つである、請求項8に記載の組成物。
- 前記少なくとも1つのD−ペプチドは、PIE7(配列ID番号:6)およびPIE12(配列ID番号:26)のうちの少なくとも1つを含む、請求項1〜9の何れか一項に記載の組成物。
- C末端でPEG24 リンカーによってコレステロールに連結されたPIE12(配列ID番号:26)(chol−PEG24−PIE12)を含む、請求項1に記載の組成物。
- 少なくとも3つのD−ペプチドおよび少なくとも1つの作用強度増強カーゴ分子を含み、
前記少なくとも3つのD−ペプチド及び前記少なくとも1つの作用強度増強カーゴ分子がそれぞれ多量体骨格に連結し、
前記少なくとも3つのD−ペプチドが、配列ID番号31のアミノ酸配列を含む8アミノ酸のコアペプチドを含み、
前記作用強度増強カーゴ分子が、コレステロール若しくはチオコレステロール、アルカン鎖、又は脂肪酸であり、
前記作用強度増強カーゴ分子が、少なくとも12のエチレングリコール反復単位を含むPEGリンカーを介して前記多量体骨格に連結している組成物。 - 前記多量体骨格は、3つのNHSエステル基および第4直交基を含むヘテロ四量体骨格であり、
前記少なくとも3つのD−ペプチドが、前記3つのNHSエステル基を介して前記ヘテロ四量体骨格に連結し、前記作用強度増強カーゴ分子が前記第4直交基を介して前記ヘテロ四量体骨格に連結し、
前記第4直交基が少なくとも12のエチレングリコール反復単位を含むPEGリンカーを含む、請求項12に記載の組成物。 - 前記少なくとも3つのD−ペプチドのそれぞれが、PIE7(配列ID番号:6)、PIE7−GK(配列ID番号:23)、PIE7−GKK(配列ID番号:24)、K−PIE7−GK(配列ID番号:25)、PIE12(配列ID番号:26)、PIE13(配列ID番号:27)、PIE14(配列ID番号:28)、又はPIE15(配列ID番号:29)から選択されるアミノ酸配列を含む、請求項12又は13に記載の組成物。
- それぞれのD−ペプチドが同一である、請求項12〜14の何れか一項に記載の組成物。
- 少なくとも2つのD−ペプチドが異なる、請求項12〜14の何れか一項に記載の組成物。
- それぞれのD−ペプチドが配列ID番号26のアミノ酸配列を含む、請求項14に記載の組成物。
- 前記作用強度増強カーゴ分子がコレステロール又はチオコレステロールである、請求項12〜17の何れか一項に記載の組成物。
- 前記作用強度増強カーゴ分子が脂肪酸である、請求項12〜17の何れか一項に記載の組成物。
- 前記脂肪酸が、C8脂肪酸、C16脂肪酸およびC18脂肪酸のうちの少なくとも1つである、請求項19に記載の組成物。
- 前記作用強度増強カーゴ分子がアルカン鎖である、請求項12〜17の何れか一項に記載の組成物。
- 前記アルカン鎖が、C8アルカン、C16アルカンおよびC18アルカンのうちの少なくとも1つである、請求項21に記載の組成物。
- 前記PEGリンカーは、PEG12,PEG16,PEG24,PEG25,PEG26,PEG27,PEG28,PEG29,PEG30,PEG31,PEG32,PEG33,PEG34,PEG35,PEG36,PEG57,またはPEG 132 である、請求項12〜22の何れか一項に記載の組成物。
- 前記多量体骨格は、トリス、ジリシン、ベンゼン環、リン酸またはペプチドコアを含む、請求項12〜23の何れか一項に記載の組成物。
- 前記作用強度増強カーゴ分子は、反応性基を介して前記ヘテロ四量体骨格に連結される、請求項13〜24の何れか一項に記載の組成物。
- 前記作用強度増強カーゴ分子は、マレイミド反応基を介して前記ヘテロ四量体骨格に連結される、請求項25に記載の組成物。
- 前記ヘテロ四量体骨格が下記式で表される構造を含む、請求項13に記載の組成物。
- 3つのPIE12(配列ID番号:26)D−ペプチドおよび多量体骨格に連結したコレステロール又はチオコレステロール、ここで該コレステロール又はチオコレステロールはPEG12リンカーを介して該多量体骨格に連結されている;3つのPIE12(配列ID番号:26)D−ペプチドおよび多量体骨格に連結したコレステロール又はチオコレステロール、ここで該コレステロール又はチオコレステロールはPEG16リンカーを介して該多量体骨格に連結されている;3つのPIE12(配列ID番号:26)D−ペプチドおよび多量体骨格に連結したコレステロール又はチオコレステロール、ここで該コレステロール又はチオコレステロールはPEG24リンカーを介して該多量体骨格に連結されている;3つのPIE12(配列ID番号:26)D−ペプチドおよび多量体骨格に連結したコレステロール又はチオコレステロール、ここで該コレステロール又はチオコレステロールはPEG36リンカーを介して該多量体骨格に連結されている;3つのPIE12(配列ID番号:26)D−ペプチドおよび多量体骨格に連結したコレステロール又はチオコレステロール、ここで該コレステロール又はチオコレステロールはPEG57リンカーを介して該多量体骨格に連結されている;3つのPIE12(配列ID番号:26)D−ペプチドおよび多量体骨格に連結したコレステロール又はチオコレステロール、ここで該コレステロール又はチオコレステロールはPEG132リンカーを介して該多量体骨格に連結されている;3つのPIE12(配列ID番号:26)D−ペプチドおよび多量体骨格に連結したC8脂肪酸、ここで該C8脂肪酸はPEG24リンカーを介して該多量体骨格に連結されている;3つのPIE12(配列ID番号:26)D−ペプチドおよび多量体骨格に連結したC16脂肪酸、ここで該C16脂肪酸はPEG24リンカーを介して該多量体骨格に連結されている;3つのPIE12(配列ID番号:26)D−ペプチドおよび多量体骨格に連結したC18脂肪酸、ここで該C18脂肪酸はPEG24リンカーを介して該多量体骨格に連結されている;3つのPIE12(配列ID番号:26)D−ペプチドおよび多量体骨格に連結したC8アルカン、ここで該C8アルカンはPEG24リンカーを介して該多量体骨格に連結されている;3つのPIE12(配列ID番号:26)D−ペプチドおよび多量体骨格に連結したC16アルカン、ここで該C16アルカンはPEG24リンカーを介して該多量体骨格に連結されている;3つのPIE12(配列ID番号:26)D−ペプチドおよび多量体骨格に連結したC18アルカン、ここで該C18アルカンはPEG24リンカーを介して該多量体骨格に連結されている;のうちの少なくとも一つを含む、請求項12に記載の組成物。
- 前記組成物はHIVの細胞内への侵入を阻害する、請求項1〜28の何れか一項に記載の組成物。
- 請求項1〜29の何れか一項に記載の組成物、及び薬学的に許容可能な担体を含む薬学的組成物。
- 請求項1〜29の何れか一項に記載の組成物又は請求項30に記載の薬学的組成物を含み、前記組成物又は前記薬学的組成物がHIVに接触することを特徴とする、HIVの細胞内への侵入の阻害に用いるための組成物。
- 請求項1〜20の何れか一項に記載の組成物又は請求項30に記載の薬学的組成物を含み、前記組成物又は前記薬学的組成物が被験者に投与されることを特徴とする、被験者へのHIV感染の阻害に用いるための組成物。
- 前記組成物又は前記薬学的組成物が、ウイルス複製阻害剤、ウイルスプロテアーゼ阻害剤、ウイルス逆転写酵素阻害剤、ウイルス侵入阻害剤、ウイルスインテグラーゼ阻害剤、ウイルスRev阻害剤、ウイルスTat阻害剤、ウイルスNef阻害剤、ウイルスVpr阻害剤、ウイルスVpu阻害剤およびウイルスVif阻害剤からなる群から選択した少なくとも1つの抗ウイルス剤と組み合わせて被験者に投与される、請求項32に記載の組成物。
- 前記少なくとも1つの抗ウイルス剤が、Combivir(登録商標)(ラミブジン/ジドブジン)、CRIXIVAN(登録商標)(インジナビル)、EMTRIVA(登録商標)(エムトリシタビン)、EPIVIR(登録商標)(ラミブジン)、FORTOVASE(登録商標)(サキナビル−sg)、HIVID(登録商標)(ザルシタビン)、INVIRASE(登録商標)(サキナビル−hg)、KALETRA(登録商標)(ロピナビル/リトナビル)、LEXIVA(商標)(ホスアンプレナビル)、NORVIR(登録商標)(リトナビル)、RITROVIR(登録商標)(ジドブジン)、SUSTIVA(登録商標)(エファビレンツ)、VEDEX EC(登録商標)(ジダノシン)、VIDEX(登録商標)(ジダノシン)、VIRACEPT(登録商標)(ネルファナビル)、VIRAMUNE(登録商標)(ネビラピン)、ZERIT(登録商標)(スタブジン)、ZIAGEN(登録商標)(アバカビル)、FUZEON(登録商標)(エンフビルチド)、RESCRIPTOR(登録商標)(デラビルジン)、REYATAZ(登録商標)(アタザナビル)、TRIZIVIR(登録商標)(アバカビル/ラミブジン/ジドブジン)、VIREAD(登録商標)(テノホビルジソプロキシルフマル酸塩)、ISENTRESS(登録商標)(ラルテグラビル)、SELZENTRY(登録商標)(マラビロク)又はAGENERASE(登録商標)(アンプレナビル)である、請求項33に記載の組成物。
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WO2005080418A2 (en) | 2004-02-23 | 2005-09-01 | Borean Pharma A/S | Multimerised hiv fusion inhibitors |
US9381226B2 (en) * | 2007-02-08 | 2016-07-05 | University Of Utah Research Foundation | Methods and compositions related to inhibition of viral entry |
WO2009092612A1 (en) * | 2008-01-25 | 2009-07-30 | Universitätsklinikum Heidelberg | Hydrophobic modified pres-derived peptides of hepatitis b virus (hbv) and their use as vehicles for the specific delivery of compounds to the liver |
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EP2691105A1 (en) | 2014-02-05 |
US20170239364A1 (en) | 2017-08-24 |
WO2012135385A1 (en) | 2012-10-04 |
EP2691105A4 (en) | 2014-12-03 |
EP2691105B1 (en) | 2018-07-11 |
US10406229B2 (en) | 2019-09-10 |
US20200215191A1 (en) | 2020-07-09 |
JP2014510754A (ja) | 2014-05-01 |
CA2868735C (en) | 2020-02-25 |
US20140323392A1 (en) | 2014-10-30 |
CA2868735A1 (en) | 2012-10-04 |
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