JP5802553B2 - ペプチジルジアシルグリセリド - Google Patents
ペプチジルジアシルグリセリド Download PDFInfo
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- JP5802553B2 JP5802553B2 JP2011506468A JP2011506468A JP5802553B2 JP 5802553 B2 JP5802553 B2 JP 5802553B2 JP 2011506468 A JP2011506468 A JP 2011506468A JP 2011506468 A JP2011506468 A JP 2011506468A JP 5802553 B2 JP5802553 B2 JP 5802553B2
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Classifications
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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
- A61K38/10—Peptides having 12 to 20 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Description
この出願は、2008年4月24日に出願され、名称を「ペプチジルジアシルグリセリド」とする米国仮出願第61/047,464号を基礎とする優先権を主張し、それは、出典明示して本明細書に組み込まれる。
適用なし。
適用なし。
適用なし。
当業者はそれらの既知の機能に対して適当な物質および濃度を決定するのに困難性はない。
鼻腔へのスプレーでのデリバリーはいかなる従来のスプレー技術または装置によってもよい。
この実施例は、本発明におけるPDAGの単離および構造解析を記載する。PDAGは、7〜10kDa分子量カットオフ透析カセット(Slide -A-Lyzer, Pierce Biotechnology, Inc.)越しで蒸留水に対して透析し、真空エバポレーションにより濃縮し、ついで、透析物を凍結乾燥することによって、調査規模の量で、凝血の血清フラクションから規定的に単離することができる。
この実施例は、本来のPDAGの構造解析を記載する。精製PDAGのエドマン分解配列解析は、(X1)LYDKGYTSKEQKDCVGI(X2)のアミノ酸配列を同定し、推定PDAGペプチドの分子量を1883.57amuと算出した。X1およびX2は、同定されない誘導アミノ酸または非アミノ酸補欠分子族であった。液体クロマトグラフィー/タンデム質量分析(LC/MSn)を用いて、精製PDAGを分析し、(a)N−末端およびC−末端補欠分子族を同定し、(b)ペプチドのアミノ酸配列を確認した。PDAG親ピーク(10.4分)のESI−MSは、3つの主要イオンフラグメントを明らかにした。最も豊富なもの(フラグメントA)は、トリプトファン(m/z)であると決定され、PDAG−トリプトファン付加体としてPDAGと共に溶出する。
pDAGペプチドは、標準固相合成プロトコルと、AAPPTEC 348 Sigma (Advanced Automated Peptide Protein Technologies, Inc., Louisville, KY)ペプチドシンセサイザーを用いるH−イソロイシン−2−クロロトリチル樹脂に結合する延長HGTUとで合成した。樹脂[Ala-Leu-Tyr(But)- Asp(OBut)-Lys(Boc)-Gly-Tyr(But)-Thr(But)-Ser(But)-Lys(Boc)-Glu(OBut)-Gln(Trt)- Lys(Boc)-Asp(OBut)-Cys(Trt)-Val-Gly-Ile-RESIN]に結合した完全保護ペプチド配列を、ジクロロメタンで洗浄して得た。ペプチド結合樹脂を、N,N−ジイソプロピルエチルアミン(20%)およびN,N−ジメチルアセトアミド(70%)中の10%無水酢酸の添加によって、ペプチドのN−末端アラニンにてアセチル化した。室温にて2時間後、樹脂をろ過し、N,N−ジメチルアセトアミドとジクロロメタンとで連続して洗浄し、次いで、凍結乾燥した。アセチル化した完全保護ペプチドを、1,1,1,3,3,3−ヘキサフルオロ−2−プロパノールのジクロロメタン中の1:4溶液20mlを用いて、樹脂から切り離した。室温にて2時間後、樹脂をろ過し、前記切り離し溶液2mlで洗浄した。ろ液を、ロータリーエバポレーターを用いて真空で蒸発乾燥した。試料を質量分析で分析して、m/z3286に予測質量を確認した(データは示さず)。
線維芽細胞を合成PDAGで24時間刺激した。RNAをその線維芽細胞から抽出し、IL−6転写物をリアルタイムPCRで測定し、IL−6タンパク質をELISAによって培地中で測定した。本発明者らは、100pg/mlのPDAGが線維芽細胞を刺激して、対照(未処理細胞)と比較してIL−6mRNAレベルを増大させた、P=0.001.同様に、PDAG処理線維芽細胞の培地中で約2倍のIL−6タンパク質(P=0.0001)が測定された。これらの結果を図5に提示する。
mRNAを100pg/mlの合成PDAGと共に一晩インキュベートした初代ヒト線維芽細胞から抽出した。NALP3およびNFκB転写物を測定した。NALP3転写物は1.75倍(P=0.007)に増加することが見出されたが、NFκB転写物は増加しなかった(P=0.4)。これらの結果を図6に提示する。
THP−1単球(5×104/ウェル)を、24ウェルマイクロプレート中の10%FBS入りハンクス緩衝生理食塩水1(Hank's Buffered Saline 1)中で培養した。細胞を2.5×104のAR39クラミジア肺炎(AR39 Chlamydia pneumoniae (CPn))菌細胞で感染して、MOI=1を獲得し、感染細胞は、毎日培地を交換しながら感染後72時間維持した。細胞は、感染の24時間前または感染の24時間後に、PDAG媒体(DMSO中0.01%Tween-20)またはPDAG(25ng/mlおよび50ng/ml)でのいずれかで処理した。72時間のインキュベーション期間後、細胞を収穫し、Cytofix/Cytoperm (BD Pharmingen)で透過可能にし、マウスα−CPNモノクローナルIgG(clone 61C75)を添加し、ついで、透過化細胞を1時間培養した。インキュベーション後、細胞を洗浄し、FITC標識α−マウスIgGを添加し、1時間インキュベートした。細胞を再び収穫し、洗浄した。感染細胞の定量はフローサイトメトリーで測定した。細胞の生存率をトリパンブルー色素排除法(trypan blue exclusion)で決定した。これらの結果を図7に提示する。
テトラサイクリン誘発性HBV−安定細胞株、HepDES19細胞 (Guo, 2007)をペニシリンおよびストレプトマイシン(Invitrogen)、10%FBS、500μg/mlのG418 (Invitrogen) ならびに1μg/mlのテトラサイクリン (Sigma- Aldrich, St. Louis, MO)入りのDMEM/F-12培地中で維持した。HepDES19細胞中でのHBV複製を開始するため、テトラサイクリンを培地から取り出し、その細胞をウイルスDNA分析前4〜5日間培養した。細胞をpDAGで処理するため、ペプチドをテトラサイクリン無し培地に添加し、毎日細胞培養上に塗布した。溶媒DMSOの濃度は毎日の処理において、0.01%に調整した。
メスのニュージーランドシロウサギを、本来のPDAG入り(n=3)となし(n=3)のFCAで接種した。血液試料を接種の一日前(バックグラウンド)および、接種後に3、5、7、10、12、14および17日目にも採取した。血清を、結核菌(M. tuberculosis)IgM産生につき、ELISAで3回分析した。接種後の各日の抗体価から、1日目の抗体価を用いてバッククラウンドを差し引いた。接種後5日目までに、FCA+PDAGで接種したウサギのIgM力価は、FCAのみを受けたウサギの抗体価と比べて著しく増大した(P=0.0004)。これらの結果を図9に描写する。
スイスウェブスターマウスに致死量、5×103cfu/マウスのサルモネラ菌(Salmonella typhimurium)を与えた。それらのマウスのうち15匹が、致死量摂取の24時間前に5μg/mlのPDAGで処理された。マウスはそのまま10日間毎日観察された。対照群で4日目に死亡が確認されたが、PDAG処理群では7日目まで確認されなかった。10日目まで、PDAG処理群において12匹のマウスが生き続けたが、未処理群では全てが死亡した。P<0.0001。これらの結果を図10に描写する。
Claims (28)
- 有効量の請求項1の化合物を含む、抗原性ペプチドの免疫原性を促進する医薬組成物。
- 医薬上許容される緩衝剤または生理学上許容される担体を有する、請求項2の医薬組成物。
- 緩衝剤が、塩中酢酸、塩中クエン酸、塩中ホウ酸、塩中リン酸およびそれらの組合せよりなる群から選択される、請求項3の医薬組成物。
- 担体製剤が、口腔内、皮下、静脈内、筋肉内、腹腔内、頬側または眼内経路、経直腸、非経口、経全身、経膣、局所、口腔内または鼻内スプレーおよびそれらの組合せに適した群から選択される、請求項3の医薬組成物。
- ピル、錠剤、トローチ、被覆錠剤、顆粒剤、カプセル剤、硬または軟ゼラチンカプセル剤、水性液剤、アルコール性液剤、油性液剤、シロップ剤、乳液剤、懸濁液剤、香錠、坐剤、注射用液、軟膏、チンキ剤、クリーム、ローション、粉剤、スプレー剤、経皮治療システム、鼻内スプレー、エアロゾル混合物、マイクロカプセル、インプラント、ロッドまたは膏薬の形態である、請求項2の医薬組成物。
- 非経口製剤が、湿潤剤、懸濁化剤、希釈剤、溶剤またはそれらの組合せを含有する、請求項5の医薬組成物。
- 希釈剤が1,3−ブタンジオールである、請求項7の医薬組成物。
- 溶剤が、水、リンガー液、等張性塩化ナトリウム剤および滅菌不揮発性油よりなる群から選択される、請求項7の医薬組成物。
- 不揮発性油が合成のモノ−またはジグリセリドを含む、請求項9の医薬組成物。
- 注射用液が脂肪酸を含有する、請求項6の医薬組成物。
- 保存剤を有する、請求項2の医薬組成物。
- 保存剤が、塩化ベンズアルコニウム、クロロブタノール、パラベン類、チメロソールおよびそれらの組合せよりなる群から選択される、請求項12の医薬組成物。
- 担体が、鼻内スプレーにおいて、生理食塩水を与える、請求項5の医薬組成物。
- 生理食塩水が0.1%から2.0%である、請求項14の医薬組成物。
- 生理食塩水が0.65%である、請求項14の医薬組成物。
- スプレー製剤が、当該化合物の有効な分散のための粉砕粒子サイズを有する、請求項5の医薬組成物。
- 粒子サイズが0.1から20ミクロンである、請求項17の医薬組成物。
- 粒子サイズが0.2から10ミクロンである、請求項17の医薬組成物。
- 粒子サイズが0.2から5ミクロンである、請求項17の医薬組成物。
- 界面活性剤、ビタミン類、ビタミン誘導体、抗ヒスタミン、湿潤剤、保存剤、保湿剤、乳化剤、香料よりなる群から選択される添加物を含有する、請求項2の医薬組成物。
- 医薬デリバリーシステムであって、
a.請求項2の医薬組成物;ならびに
b.時限放出、遅延放出、徐放およびそれらの組合せよりなる群から選択される放出手段
を含む医薬デリバリーシステム。 - 請求項2の医薬組成物を調剤する方法であって、
a.化合物を得ること;および
b.前記化合物を担体と均一に合体すること、ここに、担体は液体または固体のいずれかであること
を含む方法。 - 合体が、前記化合物を4%ラクトン溶液に分散させることによって支援される、請求項23の方法。
- 1−ペプチジル−2,3−ジアシルグリセリドを合成する方法であって、
a.固相法によって請求項1の化合物を合成すること、ここに、合成は脱保護ステップを有さないこと;
b.C−末端カルボン酸を活性化すること;
c.ジアシルグリセリドおよび触媒剤とインキュベートすること、ここに、インキュベーションは1−ペプチジル−2,3−ジアシルグリセリドを生成すること;および
d.ペプチド側鎖保護基をリエージェントKで切断すること
を含む方法。 - ジシクロヘキシルカルボジイミドで活性化する、請求項25の方法。
- 触媒剤がジメチルアミノピリジンである、請求項25の方法。
- 1−ペプチジル−2,3−ジアシルグリセリドがクロマトグラフィーで精製される、請求項25の方法。
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EP2293809A2 (en) | 2011-03-16 |
RU2010147464A (ru) | 2012-05-27 |
AU2009240516A1 (en) | 2009-10-29 |
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