JP5537431B2 - ウイルス融合のインヒビターのコレステロール誘導体 - Google Patents
ウイルス融合のインヒビターのコレステロール誘導体 Download PDFInfo
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- JP5537431B2 JP5537431B2 JP2010530421A JP2010530421A JP5537431B2 JP 5537431 B2 JP5537431 B2 JP 5537431B2 JP 2010530421 A JP2010530421 A JP 2010530421A JP 2010530421 A JP2010530421 A JP 2010530421A JP 5537431 B2 JP5537431 B2 JP 5537431B2
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- Prior art keywords
- inhibitor
- virus
- pharmaceutically acceptable
- cholesterol
- hiv
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 108091008578 transmembrane receptors Proteins 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 208000006961 tropical spastic paraparesis Diseases 0.000 description 1
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- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 230000007502 viral entry Effects 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 229940120938 zidovudine and lamivudine Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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Description
gp41の膜近位外部領域(MPER)に由来する脂質アンカーペプチド
モノクローナル抗体(MAb)2F5のエピトープELLELDKWASLWNWF(配列番号3)をも含む、gp41の膜近位外部領域(MPER)からのペプチドの抗ウイルス活性(IC50=30μM)は、最後の2つのC末端アミノ酸:ELLELDKWASLWN(配列番号4)の欠失により著しく減少し(IC50>100μM)、このことは、その抗ウイルス活性を発現するために該膜内に分配されるためには該ペプチドが必要であることと合致した。したがって、ペプチドELLELDKWASLW(配列番号2)(IC50>100μM)をC末端コレステロール基で誘導体化したところ、それは抗ウイルス効力を再獲得し(IC50=5.85μM)、該コレステロール基は、天然の3アミノ酸C末端NWF伸長と比べて活性を増強した。さらに、該脂質の性質が重要であった。なぜなら、ビス−Lys(Nε−パルミトイル)基は無効であったからである。これらの化合物の幾つかに関するHIV−1(HXB2)に対する抗ウイルス活性を図1に示す。用いたアッセイの詳細はJoyceら,J.Biol Chem.,2002,277,45811−45820において見出されうる。
C34へのコレステロールの付加は、その抗ウイルス効力を、C34および対照ペプチドC34−Aceta(この場合、該システイン残基はヨードアセトアミドでアルキル化されている)と比べて50倍増加させる。予想どおり、C末端ではなくN末端におけるコレステロールの付加は抗ウイルス活性にとって有害である(未誘導体化C34と比べて50倍の減少)。また、予想どおり、コレステロールはパルミチン酸より遥かに良好な脂質アンカーである。なぜなら、C34−Pamは、未誘導体化C34と比較されうる活性を有するからである。最後に、コレステロールの付加はT20に有害であり、これは恐らく、それ自身の親油性配列に対する阻害または異なるMOAによるものであろう。
種々のウイルス株に対する試験においては、C34−cholは、全ての株において、比較しうるIC50で、広範な応答を示した。全パネルにおいて、C34−cholは未誘導体化またはcys−アルキル化C34より〜50倍強力であった。
コレステロールでの誘導体化は、抗ウイルス効力の改善をもたらすことに加えて、該ペプチドのインビボでの半減期をも延長させる。マウスの腹腔内に3.5mg/kgの濃度で注射された場合、24時間後にC34−cholの〜60nMの血漿濃度が尚も検出可能であった。図3に示すとおり、この濃度は尚も、単一サイクル感染性アッセイにおける測定IC50(7pM)の>500倍である。得られた結果は、Cmax 3.1μM、Tmax 4時間、CI/F 0.60ml/分/kg、AUC(0−6時間) 11.5μM時間であった。
HIV−1感染性アッセイ(31)
フェノールレッド非含有ダルベッコ変法イーグル培地、10% ウシ胎児血清、1% ペニシリン/ストレプトマイシン中に維持されたP4−2/R5細胞(組込まれたβ−ガラクトシダーゼレポーター遺伝子をもHIV LTRプロモーターの制御下に含有する、CD4およびCCR5を発現するよう安定にトランスフェクトされた、内因性CXCR4を発現するHeLa細胞)を2.5×103 細胞/ウェルで96ウェルプレート内に播き、翌日、幾つかの力価の試験抑制性ペプチドの存在下、HIV−1のHXB株(そして幾つかの場合には種々の他の株)(Advanced Biotechnology Inc.,Bethesda,MD)に37℃で感染させた。ウイルスおよび抑制性ペプチドの両方と共に48時間インキュベートした後、細胞を細胞溶解し、Gal ScreenTM化学発光基質(Applied Biosystems,Foster City,CA)を該製造業者の説明に従い使用して、β−ガラクトシダーゼを検出した。Dynexルミノメーターを使用してデータを得、IC50値をKaleidaGraphにより計算した。侵入、逆転写、組込み及びtat媒介転写を含む初期HIV生活環のいずれかの段階を遮断する物質は全て、β−ガラクトシダーゼの産生を抑制しうるが、C34由来ペプチドは、細胞外でHIV−1エンベロープに結合して宿主細胞内へのウイルス侵入を抑制することにより侵入前段階において特異的に作用するとみなされている。
該コレステロール部分は一般に、gp41配列のC末端に付加された追加的システイン残基のチオール基を用いて、チオエーテル結合を介して該ペプチドに結合させる。
ブロモアセチル−コレステロールの合成
PEP2667の合成
Ac−WMEWDREINNYTSLIHSLIEESQNQQEKNEQELLGSGC−NH2(配列番号1)
Pioneer Peptide Synthesizer(Applied Biosystems)上でFmoc/t−Bu化学を用いる標準的な固相ペプチド合成により、ペプチドPEP2667を製造した。該ペプチドC末端アミドを得るために、DIPCDI/HOBtを活性化物質として使用してFmoc−Rinkリンカーで予め誘導体化されたChampion PEG−PS樹脂(Biosearch Technologies,Inc.,Novato,CA)上で該ペプチドを合成した。全てのアシル化反応は、樹脂遊離アミノ基上、4倍過剰の活性化アミノ酸を使用して、60分間にわたって行った。アミノ酸を等モル量のHBTU(2−(1H−ベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルウロニウムヘキサフルオロホスファート)および2倍モル過剰のDIEA(N,N−ジイソプロピル−エチルアミン)で活性化した。側鎖保護基は以下のとおりであった:Asp、Glu、Ser、ThrおよびTyrにはtert−ブチル;Asn、Cys、GlnおよびHisにはトリチル;Lys、Trpにはtert−ブトキシ−カルボニル;Argには2,2,4,6,7−ペンタメチルジヒドロベンゾフラン−5−スルホニル。
40mLのCH2Cl2中のコレステロール(0.99g,2.7mmol)の溶液にN−t−boc−アミド−dPEG4(商標)酸(1g,2.7mmol,Product N°10220,Quanta BioDesign,Ltd.)を加え、ついでN,N’−ジイソプロピルカルボジイミド(0.43mL,3.2mmol)および4−ジメチルアミノ−ピリジン(16mg,5%)を加えた。該混合物を室温で一晩攪拌し、溶媒を真空中で蒸発させた。該粗製物をEtOAcに溶解し、1N HCl、飽和NH4Clおよびブラインで洗浄し、Na2SO4で乾燥させ、濾過し、濃縮した。石油エーテル中の25〜50% EtOAc勾配を用いるシリカゲル上のフラッシュカラムクロマトグラフィー(BIOTAGE)により該粗製物を精製して、1.48gの所望の化合物を無色油として得た(収率75%)。
トリフルオロ酢酸(2mL,26mmol)を10mlのCH2Cl2中の1(1.48g,2mmol)の溶液に加え、該混合物を室温で3時間攪拌した。全ての揮発性物質を真空下で除去し、該粗製物を凍結乾燥させて、無色油を得、これを60mLのCH2Cl2に溶解した。ブロモ酢酸無水物(0.62g,2.4mmol)を加え、ついでN,N−ジイソプロピルエチルアミン(0.65mL,3.7mmol)を加え、該混合物を室温で3時間攪拌した。該溶媒を真空下で除去し、該粗製物を、石油エーテル中の50〜90%のEtOAcの勾配を用いるシリカゲル(BIOTAGE)上のフラッシュカラムクロマトグラフィーにより精製して、1.1gの所望の化合物を無色油として、2工程で74%の収率で得た。
(C34−コレステロール):コレステロイル化
Ac−WMEWDREINNYTSLIHSLIEESQNQQEKNEQELLGSGC(コレステリル)−NH2(配列番号1)
溶液中の参考例1および2の生成物の間の化学選択的チオエーテル結合により、C34−コレステロールを製造した。12mgの精製された参考例2の生成物(2.61μmol)を600μLのDMSOに溶解し、100μLのTHFに溶解された1.59mgの参考例1の生成物(3.13μmol,1.2当量)を加えた。ついで7μL(1容量%)のDIEA(N,N−ジイソプロピル−エチルアミン)を該混合物に加え、これを室温で攪拌した。溶離液として(A)水中の0.1% TFAおよび(B)アセトニトリル中の0.1% TFA、および直線勾配[30%(B)〜70%(B)で20’ − 80%(B)で3’ − 80%(B)で3’]を用い、1ml/分の流速を用いて、Phenomenex,Jupiter C4カラム(150×4.6mm,5μm)と共にWaters−Micromass LCZ Platformを使用する液体クロマトグラフィー−質量分析により、該反応をモニターした。
C34−(オキサ4)−コレステロールの合成
溶液中の参考例2の生成物と参考例3の生成物との間の化学選択的チオエーテル結合により、ペプチドC34−(オキサ4)コレステロールを製造した。10mgの精製された参考例2の生成物(2.26μmol)を600μLのDMSOに溶解し、188μLのTHFに溶解された1.88mgの参考例3の生成物(2.49μmol,1.1当量)を加えた。ついで7μLのDIEA(N,N−ジイソプロピル−エチルアミン)を該混合物に加え、これを室温で攪拌した。溶離液として(A)水中の0.1% TFAおよび(B)アセトニトリル中の0.1% TFA、および直線勾配[35%(B)〜80%(B)で20’ − 80%(B)で3’ − 80%(B)で3’]を用い、1ml/分の流速を用いて、Phenomenex,Jupiter C4カラム(150×4.6mm,5μm)と共にWaters−Micromass LCZ Platformを使用する液体クロマトグラフィー−質量分析により、該反応をモニターした。
Claims (15)
- コレステロールまたはその誘導体にC末端において結合した、HIV−1のgp41のアミノ酸628−661から成る、ウイルス融合のインヒビターであって、該gp41のアミノ酸628−661のC末端と該コレステロールまたはその誘導体との間にリンカーGlySerGlyまたはGlySerGlyCysを有する、前記ウイルス融合のインヒビターまたはその医薬上許容される塩。
- 該リンカーが部分−(OCH2CH2)m−(ここで、mは1〜15の整数である)を含む、請求項1記載のインヒビター。
- 該リンカーが、部分−CH2C(O)−または−CH2C(O)NHCH2CH2(OCH2CH2)4C(O)−により、該システイン残基の硫黄原子を介して該コレステロールまたはその誘導体の酸素に結合している、請求項1記載のインヒビター。
- コレステロールを含む、請求項1〜3のいずれか1項記載のインヒビター。
- 請求項1〜5のいずれか1項記載のインヒビターまたはその医薬上許容される塩と医薬上許容される賦形剤とを含んでなる医薬組成物。
- 膣坐剤、膣リング、クリーム剤またはゲル剤である、請求項6記載の医薬組成物。
- 療法または予防によるヒトまたは動物の身体の治療方法において使用するための、請求項1〜5のいずれか1項記載のインヒビターまたはその医薬上許容される塩。
- 該療法が包膜ウイルスによる感染の治療または予防である、請求項8記載のインヒビター。
- 該ウイルスがHIV−1である、請求項9記載のインヒビター。
- 包膜ウイルスによる感染を治療または予防するための医薬の製造のための、請求項1〜5のいずれか1項記載の化合物またはその医薬上許容される塩の使用。
- 該ウイルスがHIV−1である、請求項11記載の使用。
- 包膜ウイルスに感染している非ヒト対象を治療する方法であって、請求項1記載のインヒビターまたはその医薬上許容される塩の治療的有効量をその対象に投与することを含んでなる方法。
- 包膜ウイルスに感染しやすい非ヒト対象をそのウイルスによる感染から予防する方法であって、請求項1記載のインヒビターまたはその医薬上許容される塩の予防的有効量をその対象に投与することを含んでなる方法。
- 同時投与、連続投与または別々の投与のための、請求項1〜5のいずれか1項記載のインヒビターまたはその医薬上許容される塩と、包膜ウイルスによる感染を治療または予防する別の化合物との組合せ。
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US8912322B2 (en) | 2010-07-29 | 2014-12-16 | University Of Georgia Research Foundation, Inc. | Aza-dibenzocyclooctynes and methods of making and using same |
EP2603241A2 (en) * | 2010-08-11 | 2013-06-19 | Jv Bio Srl | Multimeric inhibitors of viral fusion and uses thereof |
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BR112014014917A2 (pt) * | 2011-12-19 | 2018-05-15 | Janssen R&D Ireland | inibidores de fusão da membrana do hiv |
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WO2006105201A2 (en) * | 2005-03-30 | 2006-10-05 | Trimeris, Inc. | Conjugates comprised of fatty acid and hiv gp41-derived peptide |
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US8629101B2 (en) | 2014-01-14 |
CN101951958A (zh) | 2011-01-19 |
GB0720503D0 (en) | 2007-11-28 |
JP2011500755A (ja) | 2011-01-06 |
CN101951958B (zh) | 2013-12-04 |
JP2014111628A (ja) | 2014-06-19 |
WO2009053339A3 (en) | 2010-06-17 |
EP2205283B1 (en) | 2019-03-20 |
US20140094405A1 (en) | 2014-04-03 |
EP2205283A2 (en) | 2010-07-14 |
CA2699894A1 (en) | 2009-04-30 |
WO2009053339A2 (en) | 2009-04-30 |
AU2008314668A1 (en) | 2009-04-30 |
CA2699894C (en) | 2013-09-24 |
US20100305028A1 (en) | 2010-12-02 |
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