JP6430938B2 - 合成ポリペプチドPnTx(19)、医薬組成物及びその使用 - Google Patents
合成ポリペプチドPnTx(19)、医薬組成物及びその使用 Download PDFInfo
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- JP6430938B2 JP6430938B2 JP2015527740A JP2015527740A JP6430938B2 JP 6430938 B2 JP6430938 B2 JP 6430938B2 JP 2015527740 A JP2015527740 A JP 2015527740A JP 2015527740 A JP2015527740 A JP 2015527740A JP 6430938 B2 JP6430938 B2 JP 6430938B2
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Classifications
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/43504—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates
- C07K14/43513—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates from arachnidae
- C07K14/43518—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates from arachnidae from spiders
-
- A—HUMAN NECESSITIES
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- 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
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- 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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- A—HUMAN NECESSITIES
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Description
PnTx(19)と呼ばれる合成ペプチド (NH3−GlyGluArgArgGInTyrPheTrplleAlaTrpTyrLysLeuAlaAsnSerLysLys−COOH)は、バイオインフォマティクスプログラムPEPOPを使用して部分的に設計された。この方法において、毒素PnTx2−6の19アミノ酸を含む不連続エピトープが提案された(FLEURY, Cecile, Bioinformatics tools dedicated to the study of the structure−function−antigenicity relationship in animal peptide toxins. Doctoral thesis, Department of Biochemistry and Immunology of the Unviersidade Federal de Minas Gerais, Belo Horizonte, MG, 180 p., 2009)。
成体ラット(240〜300g)を断頭し、迅速に脳を取り出し、ホモジネート溶液(スクロース0.32M、EDTA1M及びジチオトレイトール(DTT)0.25mM、pH=7.4)に浸し、氷中で維持し、それらを、Dunkley et al 1988 (DUNKLEY, P.R.; Brain Research, 441, 59−71, 1988)に記載されているように、シナプトソーム調製に使用した。
マウスを断頭により殺し、陰茎を外科的に切り取り、Krebs Ringer重炭酸塩溶液(NaCl, 118.1; KCl, 4.7; KH2PO4, 1.0; MgSo4, 1.0: NaHCO3, 25.0; CaCl2, 2.55;及びGlucose, 11.1mM)を含むペトリ皿に置き、95%O2及び5%CO2の混合物で瀑気した。腺、海綿体及び尿道を除去し、海綿体を白膜を取り除いて乾燥させ(desiccate)、それらの間の線維性中隔を切ることにより分離した。測定用の海綿体切片1x1x7mmをチャンバー中に個別に盛り、その一端を電極に固定し、もう一端を変換器に繋げた。当該チャンバーはKrebs(pH7.4)を含み、37℃で、95%O2及び5%CO2で保たれた。
L−グルタミン酸塩の放出は、Nicholls et al. 1987 (NICHOLLS, D. et al. J. Neurochem. 49, 5057, 1987)の示唆に従い解析された。前記ペプチドが、元の毒素と同様に、ラット大脳皮質シナプトソームにおいてL−グルタミン酸塩の放出を誘導出来るか否かを評価するため、以下の濃度:10−5M; 3x10−5M; 10−6M; 3x10−6Mでのその効果を解析した(実施例5)。
ナトリウム電流に対する作用
心筋に存在するナトリウムチャンネルNav1.5に対する毒素PnTx2−6及びペプチドPnTx−19の効果を解析するために、パッチクランプ試験を実施した。記録されたデータから、毒素PnTx2−6はナトリウム電流のピークの低下を引き起こし、不活性化電流を遅延させることが示された。これらの効果は、PnTx−19においては認められなかった(図6A及びC)。図6Bにおいて、PnTx2−6がナトリウム電流の密度の低下を促進することが観察されたのに対して、斯かる現象は、前記ペプチドの存在下では確認されなかった(図6D)。
ラットを、12時間照明/暗黒の調製された周期下、一定温度、水及び餌を自由に摂取できる条件下で維持した。それらを、ヘパリン(200IU)の腹腔内注射後10〜15分以内に殺した。胸部を開き、心臓を注意深く乾燥させ、NaCl (118.4), KCl (4.7), KH2PO4 (1.2), MgSo4.7H2O (1.2), CaCl2.2H2O (1.25), グルコース (11.7)及び NaHCO3 (26.5)(mmol/L)を含有するKrebs−Ringer溶液(KRS)を用いて大動脈の切り口からかん流した。かん流の流れは、37℃、一定速度(10mL/分)で、一定の酸素化(5%CO2及び95%O2)下で維持された。圧力変換器に接続した風船を右心室に挿入し、心室圧、心拍数及び誘導±dP/dtをモニタリングした(図7)。風船の体積は、最終的な拡張期血圧が約10mmHgとなるように調整された。均衡に達するまでの時間(30〜40分)の経過後、100μmol/Lの担体(対照)、かん流緩衝剤中の37.8nmol/L〜3.78μmol/Lの濃度の毒素、又は7.8nmol/L〜3.78μmol/Lの濃度のペプチドを注入した。
20〜23gの雄のSwissマウスを2つの群に分け(対照−アジュバント:水酸化アルミニウム−図8A及びPnTx−19−10μG−図8B)、各群は4頭の動物を含む。マウスを皮下経路により免疫化した。最初の導入から21、35及び49日後、マウスは上記調製物の補強を受けた。PnTx−19に対する抗体の存在を評価するために、マウスの尾から回収した血清を、最初の導入から15、30、40及び60日後に、間接的免疫酵素アッセイ(ELISA)によって評価した。アッセイは他の文献の記載と同様に実施された(DEL PINO, F.A.B., BRANDELLI, A., GONZALES, J.C., HENRIQUES, J.A.P., DEWES, H., Effect of antibodies against _−N−acetylglucosaminidase on reproductive efficiency of the bovine tick Boophilus microplus. Vet. Parasitol. 79, 247−255, 1998)。
Claims (7)
- 配列GERRQYFWIAWYKLANSKK(配列番号1)で表され、***機能不全に対する治療効果、又は***機能に対する増強効果を有する、合成ペプチド。
- N末端部分にアセチル化、及びC末端にアミド化の修飾を呈することを特徴とする請求項1に記載の合成ペプチド。
- ***機能不全を呈する対象の治療、及び/又は***機能の増強のための医薬の製造のためであることを特徴とする、請求項1に記載の合成ペプチドの使用。
- 配列番号1で表される合成ペプチド、及び1つの賦形剤、又は医薬として許容される複数の賦形剤の混合物を含有することを特徴とする医薬組成物。
- 前記ペプチドが、リポソーム、シクロデキストリン、生分解性ポリマー、カプセル、マイクロカプセル、ナノカプセル、マイクロ粒子、ナノ粒子、ボーラス調製物、浸透圧ポンプ、分散デバイス、脂肪球、経皮投与系、及び/又は温度変化に応じて体内で固体又はゲルを形成する液体からなる群から選択される調整放出系と組み合わせて、又は組み合わせずに存在することを特徴とする、請求項4に記載の医薬組成物。
- 経口、局所、筋肉内、静脈内、皮下及び吸入経路のいずれかにより、又は移植デバイスにより投与されることを特徴とする、請求項4に記載の医薬組成物。
- ***機能不全を呈する対象の治療、及び/又は***機能の増強のための医薬の製造に使用されることを特徴とする、請求項4〜6のいずれか1項に記載の医薬組成物の使用。
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BRBR1020120208008 | 2012-08-20 | ||
BR102012020800A BR102012020800A2 (pt) | 2012-08-20 | 2012-08-20 | Peptídeo sintético pntx (19), composições farmacêuticas e uso |
BR102013020574-5A BR102013020574B1 (pt) | 2013-08-13 | 2013-08-13 | PEPTÍDEO SINTÉTICO PnTx(19), COMPOSIÇÕES FARMACÊUTICAS E USO |
BRBR1020130205745 | 2013-08-13 | ||
PCT/BR2013/000319 WO2014028997A1 (pt) | 2012-08-20 | 2013-08-20 | Peptídeo sintético pntx(19), composições farmacêuticas e uso |
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KR101636851B1 (ko) * | 2016-06-03 | 2016-07-06 | (주)넥스젠바이오텍 | 피부 세포 증식 효과가 증가한 열 안정성 인간 상피세포성장인자-거미독 융합단백질 및 이를 유효성분으로 함유하는 피부 주름 개선 및 탄력 유지용 화장료 조성물 |
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