TWI653980B - 治療及預防缺血性傷害之組成物與方法 - Google Patents
治療及預防缺血性傷害之組成物與方法Info
- Publication number
- TWI653980B TWI653980B TW103114403A TW103114403A TWI653980B TW I653980 B TWI653980 B TW I653980B TW 103114403 A TW103114403 A TW 103114403A TW 103114403 A TW103114403 A TW 103114403A TW I653980 B TWI653980 B TW I653980B
- Authority
- TW
- Taiwan
- Prior art keywords
- injury
- ischemic reperfusion
- peptide
- ischemic
- reperfusion injury
- Prior art date
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Abstract
本揭示案係關於一種用於治療及預防缺血性傷害的組成物。更特定言之,本揭示案係關於一種含有衍生自端粒酶之胜肽的組成物,該組成物對治療及預防缺血性傷害有效。
根據本揭示案的胜肽、具有與胜肽之胺基酸序列80%或以上之序列同源性的胜肽或係上述之片段的胜肽對治療及預防缺血性傷害具有優良效果。因此,含有胜肽的組成物可有效用於缺血性傷害,尤其是用於缺血性-再灌注傷害。
Description
本揭示案係關於一種用於治療及預防缺血性傷害的組成物。更特定言之,本揭示案係關於一種含有衍生自端粒酶之胜肽的組成物,該組成物對治療及預防缺血性傷害有效。
缺血性傷害係指由於對需要供血之器官(諸如心臟、腦部、腎臟等)限制供血所引發的組織傷害(心肌梗塞、腦梗塞、腎梗塞等),從而導致器官之功能障礙及死亡率上升。缺血性傷害引發心臟、腦部、腎臟等的致命性併發症,增加了器官移植的急性排異反應風險,且長期而言減小了移植器官之存活率。
由於缺血造成的實質供氧不足誘發一種稱為缺氧的病理狀況。延長的缺血及缺氧可導致組織之功能喪失及甚至細胞死亡。各種自發及醫原性病理狀況誘發缺血及缺氧。非限制性實例包括血管阻塞疾病、冠狀動脈血栓病、腦血管血栓形成、動脈瘤破裂、全身性出血、擠壓傷害、敗血症、重度皮膚灼傷、血管結紮術(例如,胸腹動脈瘤手術後的脊髓
缺血)、心肺分流術、器官移植、心肺衰竭(心源性猝死)、窒息等。
大體而言,藉由增加全身性供氧或移除血管閉塞之原因將供血及供氧恢復至正常水平來治療藉此引發的缺血及缺氧。當與缺血或缺氧延長之情境相比時,預計可藉由恢復供血獲得改良結果。然而,在恢復供血及供氧期間,除缺血或缺氧所引發之損傷外,可另外誘發細胞死亡或功能喪失。
恢復供血及供氧期間所誘發的額外損傷稱為再灌注傷害。由再灌注傷害所引發的反常組織傷害似乎與由炎性細胞至再灌注組織之黏合、炎性細胞之活化及自由基之後續產生所引起的急性發炎症狀類似[Granger等人,Ann.Rev.Physiol.,57,311-332,(1995)]。再灌注組織內的自由基及其他細胞毒性生物分子之產生可藉由活化壞死或凋亡路徑誘發細胞死亡。
器官移植期間發生之缺血性再灌注(Ischemic-reperfusion;IR)組織傷害導致在器官移植後器官功能之延緩恢復且此情況通常係長期維護移植器官之功能中由於炎性組織反應的非所欲預後標誌。伴隨器官(尤其是腎臟)移植偶發之初期缺血性再灌注傷害可導致後續器官衰竭及移植排異反應。
最近,已將腎缺血性再灌注傷害(ischemic-reperfusion injury;IRI)新辨識為急性炎症反應之一,其中涉及先天性免疫系統及後天性免疫系統兩者之炎性細胞。
皮瓣係指自身體之一部位提起且移動至另一部位的皮膚或組織,該皮瓣包括允許組織存活的血管。皮瓣手術係用於不可用(例如)植皮治療的失去之軟組織、慢性創口等。此為一種最常用於整形與重建手術中的外科方法。詳言之,該方法的優點在於經由移植包括骨骼、腱、肌肉、神經等在內的各種複合組織使得一期重建(primary reconstruction)成為可能,從而允許快速恢復。在皮瓣手術中,皮瓣之存活率對於缺血性再灌注傷害之治療至關重要。因此,穩定改良皮瓣存活率之方法將非常有用。
如所描述,用於治療經常發生之缺血性再灌注傷害之有效方法並不易於取得。因此,用於預防及治療缺血性再灌注傷害之有效方法將很有價值。
本揭示案之發明人已努力研製對治療及預防缺血性再灌注傷害有效之組成物並已完成本揭示案。
本揭示案之發明人已發現,衍生自端粒酶的胜肽對治療及預防缺血性再灌注傷害可具有優良效果。
本揭示案係針對提供一種對治療及預防缺血性再灌注傷害有效的組成物。
在一態樣中,本揭示案提供一種用於治療及預防缺血性傷害的組成物,該組成物含有包含序列編號1之胺基酸序列的胜肽、具有與胺基酸序列80%或以上之序列同源性的
胜肽或係上述之片段的胜肽。
在本揭示案之一示例性實施例中,片段可包括三個或更多個胺基酸。
在本揭示案之一示例性實施例中,缺血性傷害可由選自由以下組成之群組中的一或更多者引發:缺血性再灌注傷害、血管疾病、冠狀動脈血栓病、腦血管血栓形成、動脈瘤破裂、全身性出血、擠壓傷害、敗血症、皮膚灼傷、血管結紮手術、心肺分流術、器官移植、心肺衰竭(心源性猝死)及窒息。
在本揭示案之一示例性實施例中,缺血性傷害可由缺血性再灌注傷害引發。
在本揭示案之一示例性實施例中,缺血性再灌注傷害可選自由以下組成之群組:腦血管缺血性再灌注傷害、腎缺血性再灌注傷害、肝缺血性再灌注傷害、缺血性再灌注心肌症、缺血性再灌注皮膚傷害、腸胃缺血性再灌注傷害、腸道缺血性再灌注傷害、胃缺血性再灌注傷害、缺血性再灌注肺傷害、胰腺缺血性再灌注傷害、缺血性再灌注骨骼肌傷害、缺血性再灌注腹肌傷害、缺血性再灌注肢傷害、缺血性再灌注結腸炎、腸系膜缺血性再灌注傷害及無症狀缺血性再灌注傷害。
在本揭示案之一示例性實施例中,缺血性再灌注傷害可由器官移植引發。
在本揭示案之一示例性實施例中,缺血性再灌注傷害可發生在腎臟中。
在本揭示案之一示例性實施例中,缺血性再灌注傷害可發生在皮瓣中。
在本揭示案之一示例性實施例中,胜肽可衍生自人類端粒酶。
在本揭示案之一示例性實施例中,組成物可為醫藥組成物。
在本揭示案之一示例性實施例中,組成物可為食品組成物。
在另一態樣中,本揭示案提供一種用於治療及預防缺血性傷害之方法,該方法包括向需要該組成物之受試者施用上文所描述之組成物。
包含序列編號1之胺基酸序列的胜肽、具有與胺基酸序列80%或以上之序列同源性的胜肽或係上述之片段的胜肽對治療及預防缺血性傷害具有優良效果。因此,含有胜肽的組成物可有效用於缺血性傷害,尤其是用於由器官移植等引發的缺血性再灌注傷害。
第1圖圖示在缺血性再灌注24小時後量測血尿素氮(blood urea nitrogen;BUN)及肌酸水平之結果。
第2圖圖示在缺血性再灌注24小時後用過碘酸-希夫氏(periodic acid-Schiff;PAS)染色劑對腎組織染色之結果。
第3圖圖示在缺血性再灌注24小時後實施腎組織傷害計分之結果。
第4圖圖示在缺血性再灌注24小時後用TUNEL染色劑對腎組織染色之結果。
第5圖圖示在缺血性再灌注24小時後量測用TUNEL染色劑所染色之TUNEL陽性細胞之結果。
第6圖圖示在缺血性再灌注24小時後藉由用F4/80(巨噬細胞標記物)及Gr-1(嗜中性白細胞標記物)從免疫組織學上對腎組織染色評估先天性免疫細胞之浸潤之結果。
第7圖圖示在缺血性再灌注24小時後量測腎組織中的F4/80(巨噬細胞標記物)及Gr-1(嗜中性白細胞標記物)陽性細胞之結果。
第8圖至第10圖圖示在缺血性再灌注24小時後腎組織中炎性細胞因子之抑制性分泌。
第11圖圖示為評估皮瓣存活率誘發缺血性再灌注傷害之過程。
第12圖圖示在誘發缺血性再灌注7天後量測已用PEP1處理之群組及已用鹽水處理之群組之皮瓣存活率之結果。
第13圖圖示使用ImageJ程式所獲得之數位影像。
可以各種方式修改及體現本揭示案。在下文中,將經由示例性實施例更詳細描述本揭示案。然而,以下實例不欲限制本揭示案。確切而言,本揭示案可基於隨附申請專利範圍作出各種改變。應將理解,本揭示案包括屬於本揭示案
之技術觀念及範疇內的任何改變、等效物或取代。在描述中,可忽略熟知特徵及技術之細節以避免不必要地模糊所呈現之實施例。
端粒已知為染色體之末端處所發現的遺傳物質之重複序列,用於防止染色體遭受損壞或合併至其他染色體上。每次細胞***時端粒之長度縮短,且在若干次細胞***後,端粒長度極度縮短到細胞停止***及死亡的程度。另一方面,已知延長端粒以延伸細胞之壽命。舉例而言,癌細胞分泌一種稱為端粒酶的酶,端粒酶預防端粒縮短,從而導致癌細胞增生。本揭示案之發明人已辨識,衍生自端粒酶的胜肽對治療及預防缺血性再灌注傷害有效並已完成本揭示案。
在本揭示案之一示例性實施例中,序列編號1之胜肽、係序列編號1之胜肽之片段的胜肽或具有與該等胜肽80%或以上序列同源性的胜肽包括衍生自端粒酶(特定而言,人類(智人)端粒酶)的胜肽。
本文所揭示之胜肽可包括包含胺基酸序列的胜肽,該等胜肽與序列編號1之胜肽或序列編號1之胜肽之片段具有至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%之序列同源性。此外,本發明所揭示之胜肽可包括與序列編號1之胜肽或其片段在至少一個胺基酸、至少2個胺基酸、至少3個胺基酸、至少4個胺基酸、至少5個轉化胺基酸、至少6個轉化胺基酸或至少7個胺基酸中具有差異的胜肽。
在本發明之一個實施例中,胺基酸中的改變包括胜
肽物理及化學特性之修飾。舉例而言,可執行胺基酸修飾以便改良胜肽之熱穩定性、改變受質特異性及改變最佳pH。
本文中的術語「胺基酸」不僅包括天然整合至胜肽中的22種標準胺基酸,而且包括D-異構體及修飾胺基酸。因此,在本發明之一特定實施例中,本文中的胜肽包括具有D-胺基酸的胜肽。另一方面,胜肽可包括非標準胺基酸,諸如已經轉譯後修飾之彼等胺基酸。轉譯後修飾之實例包括磷酸化、糖基化、醯基化(包括乙醯基化、肉豆蔻醯基化、棕櫚醯基化)、烷基化、羧基化、羥基化、糖化、生物素化、泛素化、化學特性的修改(例如,β-移除脫醯亞胺基化、脫醯胺基化)及結構修飾(例如,形成二硫鍵)。又,胺基酸之改變包括在與交聯劑形成胜肽共軛物的組合過程期間因化學反應而發生的胺基酸之改變,諸如胺基、羧基或側鏈的改變。
本文所揭示之胜肽可為已從天然源中辨識及分離的野生型胜肽。另一方面,當與序列編號1的胜肽或其片段相比時,本文所揭示之胜肽可為人工變異體,該等人工變異體包括一或更多個胺基酸經取代、刪除及/或***。野生型多胜肽中的胺基酸變化(不僅在人工變異體中)包含蛋白質折疊及/或不明顯影響活性的胺基酸之保守取代。保守取代之實例可處於鹼性胺基酸(精胺酸、離胺酸及組胺酸)、酸性胺基酸(麩胺酸及天冬胺酸)、極性胺基酸(麩醯胺酸及天冬醯胺酸)、疏水胺基酸(白胺酸、異白胺酸、纈胺酸及甲硫胺酸)、芳香族胺基酸(***酸、色胺酸及酪胺酸)及小胺基酸(甘胺酸、丙胺酸、絲胺酸及蘇胺酸)之群組內。技術
中已知大體不改變特定活性的胺基酸取代。最常發生的變化為Ala/Ser、Val/Ile、Asp/Glu、Thr/Ser、Ala/Gly、Ala/Thr、Ser/Asn、Ala/Val、Ser/Gly、Tyr/Phe、Ala/Pro、Lys/Arg、Asp/Asn、Leu/Ile、Leu/Val、Ala/Glu、Asp/Gly及上述之相反變化。下表2中展示保守取代之其他實例。
藉由按以下功效選擇明顯不同的取代執行胜肽之生
物學特性之實質修改:(a)維護取代區域內的多胜肽主鏈之結構(諸如片層或螺旋三維結構)的功效,(b)維護目標區域內的分子之電荷或疏水性的功效,或(c)維護側鏈大小之功效。藉由一般側鏈特性將天然殘基分成如下群組:(1)疏水性:正白胺酸、met、ala、val、leu、ile;(2)中性親水性:cys、ser、thr;(3)酸性:asp、glu;(4)鹼性:asn、gln、his、lys、arg;(5)影響鏈定向的殘基:gly、pro;及(6)芳香性:trp、tyr、phe。
非保守取代可藉由將上述類別之成員與不同類別之成員互換來執行。通常可用絲胺酸取代無關維護胜肽之適當三維結構的任何半胱胺酸殘基,從而增加了分子之氧化穩定性及防止不適當的交聯。反之,可藉由向胜肽添加半胱胺酸鍵實現穩定性的改良。
另一種類型胜肽之胺基酸變異體係具有胜肽糖基化之改變模式的彼等胜肽。本文中的術語「改變」意謂刪除胜肽中所發現的至少一個碳水化合物殘基及/或添加胜肽內不存在的至少一種糖基化殘基。
胜肽中的糖基化通常為N-連接或O-連接。本文中的「N-連接」係指碳水化合物殘基附接於天冬醯胺酸殘基之側鏈。作為三胜肽序列,天冬醯胺酸-X-絲胺酸及天冬醯胺酸-X-蘇胺酸(其中X為除脯胺酸外的任何胺基酸)係將碳水化合物殘基酶性附接於天冬醯胺酸之側鏈的識別序列。因此,當
多胜肽中的該等三胜肽序列之一者存在時,產生潛在糖基化位點。「O-連接糖基化」意謂將糖N-乙醯半乳糖胺、半乳糖或木糖中之一者附接於羥基胺基酸。羥基胺基酸最典型為絲胺酸或蘇胺酸,但可使用5-羥基脯胺酸或5-羥基離胺酸。
藉由改變胺基酸序列以含有上文所論及之三胜肽序列方便地執行添加糖基化位點至胜肽(用於N-連接糖基化位點)。可藉由將至少一個絲胺酸或蘇胺酸殘基添加至第一胜肽序列或藉由用彼等殘基取代作出該等改變(用於O-連接糖基化位點)。
在本揭示案中,「缺血性傷害」係指由於限制供血且因此對需要供血的器官(諸如心臟、腦部、腎臟等)供氧不足而發生的損傷,該缺血性傷害可導致組織之功能障礙及細胞死亡。缺血性傷害之原因包括血管症、冠狀動脈血栓病、腦血管血栓形成、動脈瘤破裂、全身性出血、擠壓傷害、敗血症、重度皮膚灼傷、血管結紮術(例如,胸腹動脈瘤手術期間的脊髓缺血)、心肺分流術、器官移植、心肺衰竭(心源性猝死)、窒息等,但並不受限於此。
在本揭示案中,「缺血性傷害」亦包括在(例如)器官移植期間可發生的缺血性再灌注傷害。缺血性再灌注傷害包括腦血管缺血性再灌注傷害、腎缺血性再灌注傷害、肝缺血性再灌注傷害、缺血性再灌注心肌症、缺血性再灌注皮膚傷害、腸胃缺血性再灌注傷害、腸道缺血性再灌注傷害、胃缺血性再灌注傷害、缺血性再灌注肺傷害、胰腺缺血性再灌注傷害、缺血性再灌注骨骼肌傷害、缺血性再灌注腹肌傷
害、缺血性再灌注肢傷害、缺血性再灌注結腸炎、腸系膜缺血性再灌注傷害、無症狀缺血性再灌注傷害等,但並不受限於此。
在器官移植期間可經常發生缺血性再灌注傷害。舉例而言,眾所週知,移植腎臟之逐漸功能喪失及功能障礙與缺血性再灌注傷害關聯及由缺血性再灌注組織傷害活化先天性免疫系統係重要原因之一。
具有序列編號1之序列的胜肽、具有序列編號1之序列的胜肽之片段的胜肽或具有與根據本揭示案之胜肽80%或以上之序列同源性的胜肽為有利的,因為該等胜肽因低毒性展現出高活體內穩定性。序列編號1之胜肽衍生自端粒酶且由16個胺基酸組成。
序列編號1中所描述之胜肽與下表1中相同。下文表1中的「名稱」係用於區分胜肽。在一個態樣中,序列編號1之胜肽係人類端粒酶之整個胜肽。在本發明之不同特定實施例中,具有序列編號1之序列的胜肽、具有序列編號1之序列的胜肽之片段的胜肽或具有與根據本揭示案之胜肽80%或以上之序列同源性的胜肽包括藉由選擇及合成對應於端粒酶內的相關位置的胜肽而合成之「合成胜肽」。序列編號2係整個端粒酶之胺基酸序列。
在一態樣中,本揭示案提供一種用於治療及預防缺血性傷害的組成物,該組成物含有包含序列編號1之胺基酸序列的胜肽、具有與胺基酸序列80%或以上之序列同源性的胜肽或上述之片段的胜肽作為活性成分。
在本發明之一個實施例中,組成物可含有0.1μg/mg至1mg/mg,特定而言1μg/mg至0.5mg/mg,更特定言之10μg/mg至0.1mg/mg之包含序列編號1之至少一者之胺基酸序列的胜肽、包含與上文所論及之序列至少80%之序列同源性之胺基酸序列的胜肽或上文所論及之胜肽之片段。當含有在上文所論及之範圍內的胜肽時,可滿足組成物之安全性及穩定性兩者且該等範圍在成本效益方面適宜。
在本發明之一個實施例中,組成物可應用於包括人、犬、雞、豬、奶牛、羊、豚鼠及猴在內的所有動物。
在一示例性實施例中,本揭示案提供一種用於治療及預防缺血性再灌注傷害的醫藥組成物,該組成物含有包含序列編號1之胺基酸序列的胜肽、具有與胺基酸序列80%或以上之序列同源性的胜肽或係上述之片段的胜肽作為活性成分。
在本發明之一個實施例中,可經由口服、直腸、經皮、靜脈內、肌內、腹膜內、骨髓內、硬膜外或皮下路徑施用醫藥組合物。
口服給藥之形式可為(但不限於)錠劑、丸劑、軟膠囊或硬膠囊、顆粒劑、粉末劑、溶液或乳液。非口服給藥之形式可為(但不限於)注射、點滴、洗液、軟膏劑、凝膠
劑、乳膏劑、懸浮液、乳液、栓劑、貼片或噴霧。
在本發明之一個實施例中,若需要,醫藥組成物可含有添加劑,諸如稀釋劑、賦形劑、潤滑劑、黏合劑、崩解劑、緩衝劑、分散劑、介面活性劑、著色劑、芳香劑或甜味劑。在本發明之一個實施例中,醫藥組成物可由技術中的習知工業方法製造。
在本發明之一個實施例中,醫藥組成物之活性成分之劑量可根據患者年齡、性別、體重、病理及狀態、給藥路徑或處方醫師之診斷而變化。基於該等因素的劑量可決定在熟習此項技術者之水平內,及每日劑量(例如)可為(但不限於)0.1μg/kg/日至1g/kg/日,特定而言1μg/kg/日至10mg/kg/日,更特定言之10μg/kg/日至1mg/kg/日,更特定言之50μg/kg/日至100μg/kg/日。在本發明之一個實施例中,每日可施用醫藥組成物1至3次,但不限於此。
在一示例性實施例中,本揭示案提供一種用於治療及預防缺血性再灌注傷害的食品組成物,該組成物含有包含序列編號1之胺基酸序列的胜肽、具有與胺基酸序列80%或以上之序列同源性的胜肽或上述之片段的胜肽作為活性成分。
在本發明之一個實施例中,食品組成物不受限於特定形式,但(例如)可為錠劑、顆粒劑、粉末劑、液體及固體形式。除活性成分外,可與由熟習此項技術者適當選擇之工業中常用的成分一起形成各個形式,且各個形式與其他成分組合可產生協同效應。
對於上文所論及之活性成分的劑量決定處於熟習此項技術者之水平內,且每日劑量(例如)可為1μg/kg/日至10mg/kg/日,更特定言之10μg/kg/日至1mg/kg/日,更特定言之50μg/kg/日至100μg/kg/日,但不限於該等數字及可根據年齡、健康狀態、併發症及其他各種因素而變化。
本文所使用之術語意欲用於描述實施例,但不欲限制本發明。前面沒有數字的術語並不限制數量,但展示可存在所使用術語之一個以上之事物。應開放式解讀術語「包含」、「具有」、「包括」及「含有」(亦即,「包括但不限於」)。
使用論及數值範圍,而不是陳述範圍內的單獨數字,因此除非明確陳述,該範圍應將視為本文單獨描述範圍內的所有數字。所有範圍之末端值包括於該範圍內且可獨立組合。
除非另作說明或在上下文中明顯矛盾,可以適當次序執行本文所論及之所有方法。除非包括於申請專利範圍內,否則任一實施例及所有實施例或示例性語言(例如,「諸如」、「類似」)之使用係用於更清楚地描述本發明,而非限制本發明之範疇。在本文中的申請專利範圍外的任何語言不應解讀為本發明之必需。除非另有定義,本文所使用之技術及科學術語具有為本發明所屬技術領域中熟習此項技術者通常所理解之含義。
本發明之較佳實施例包括發明人已知的執行本發明之最佳模式。較佳實施例中的變化可在閱讀上文陳述後對熟
習此項技術者變得清楚。本發明人希望熟習此項技術者可充分使用變化及可以與本文中所列出方式不同的其他方式實施本發明。因此,如專利法所允許,本發明包括隨附申請專利範圍中所陳述之本發明之關鍵點之等效物、修改及變化。另外,除非另有明確陳述或在上下文中矛盾,上文所論及之組份之任何組合內的所有可能變化皆包括於本發明中。儘管藉由示例性實施例描述及展示本發明,但是熟習此項技術者將較好地理解,在不脫離由下文申請專利範圍所界定之本發明之精神及範疇的情況下,在形式及細節中可存在各種改變。
在以下實例中,藉由向腎及腹直肌肌皮瓣所誘發的缺血性再灌注傷害部分施用胜肽及確認抑制腎傷害及改良皮瓣存活性之效果來調查具有序列編號1之序列的胜肽(PEP 1)對預防及治療缺血性傷害的效果。
在下文中,將經由實例及測試實例詳細描述本揭示案。然而,以下實例及測試實例僅出於說明性目的,且將對熟習此項技術者顯而易見的是本揭示案之範疇不受限於該等實例及測試實例。
實例1:胜肽之合成
根據固相胜肽合成之習知方法合成序列編號1之胜肽。更特定言之,藉由使用ASP48S(Peptron,Inc.,Daejeon ROK)經由Fmoc固相胜肽合成(solid phase peptide synthesis;SPPS)自C末端耦接各種胺基酸來合成胜肽。使用具有第一胺基酸在C末端處附接於樹脂的彼等胜肽,如下所示:
NH2-Lys(Boc)-2-氯基-三苯甲基樹脂
NH2-Ala-2-氯基-三苯甲基樹脂
NH2-Arg(Pbf)-2-氯基-三苯甲基樹脂
在N末端處藉由Fmoc保護待合成胜肽之所有胺基酸,及藉由可溶解於酸的Trt、Boc、t-Bu(t-butylester;第三丁酯)、Pbf(2,2,4,6,7-五甲基二氫-苯并呋喃-5-磺醯基)保護胺基酸殘基。實例包括以下:Fmoc-Ala-OH、Fmoc-Arg(Pbf)-OH、Fmoc-Glu(OtBu)-OH、Fmoc-Pro-OH、Fmoc-Leu-OH、Fmoc-Ile-OH、Fmoc-Phe-OH、Fmoc-Ser(tBu)-OH、Fmoc-Thr(tBu)-OH、Fmoc-Lys(Boc)-OH、Fmoc-Gln(Trt)-OH、Fmoc-Trp(Boc)-OH、Fmoc-Met-OH、Fmoc-Asn(Trt)-OH、Fmoc-Tyr(tBu)-OH、Fmoc-Ahx-OH、Trt-巰基乙酸。
將HBTU[2-(1H-苯并***-1-基)-1,1,3,3-四甲基銨六氟磷酸鹽]/HOBt[N-羥基苯并***]/NMM[4-甲基嗎啉]用作偶合劑。使用20% DMF中的呱啶移除Fmoc。為了自殘基移除保護或為了自樹脂分離合成胜肽,使用分解混合液[TFA(trifluoroacetic acid;三氟乙酸)/TIS(triisopropylsilane;三異丙基矽烷)/EDT(ethanedithiol;乙二硫醇)/H2O=92.5/2.5/2.5/2.5]。
藉由使用固相支架及重複以下製程來執行胜肽合成:從胺基酸保護開始,各種胺基酸之單獨反應,用溶劑洗滌及脫保護。藉由使用組合至起始胺基酸之固相支架及胺基
酸保護,使相應胺基酸單獨反應,用溶劑洗滌及脫保護及重複該等製程來合成各個胜肽。在自樹脂釋放後,所合成胜肽藉由HPLC純化、藉由質譜分析法確認,及凍乾,且藉由MS針對合成驗證,及隨後凍乾。
所製備胜肽之純度經高效能液相層析發現為95%或更高。
基於具有序列編號1的PEP 1之合成製程描述特定胜肽合成製程,如下所示。
1)偶合
將用NH2-Lys(Boc)-2-氯基-三苯甲基樹脂保護的胺基酸(8當量)及DMF中所融化的偶合劑HBTU(8當量)/HOBt(8當量)/NMM(16當量)混合在一起,並在室溫(RT)下培育2小時。在培育後,反應混合物經歷DMF、MeOH及DMF之相繼洗滌。
2)Fmoc脫保護
20% DMF中的呱啶經添加及在RT下培育5分鐘,2次,隨後用DMF、MeOH及DMF相繼洗滌。
3)藉由重複上文所論及之反應1)及2)製作胜肽之基本構架
NH2-E(OtBu)-A-R(Pbf)-P-A-L-L-T(tBu)-S(tBu)-R(Pbf)L-R(Pbf)-F-I-P-K(Boc)-2-氯基-三苯甲基樹脂。
4)分解:將分解混合液添加至完全合成胜肽,由此自樹脂分離所合成胜肽。
5)將預先冷卻之二***添加至所獲得之混合物中,
及隨後使用離心沉澱所聚集之胜肽。
6)在藉由製備型HPLC純化後,藉由LC/MS確認分子量及經凍乾以粉末形式產生。
實例2:確認PEP1對抑制腎缺血性再灌注傷害模型中的腎傷害之效果
測試實例1:缺血性再灌注之誘發
藉由雙側夾緊腎蒂30分鐘及在30分鐘後藉由移除夾具恢復血流誘發缺血性再灌注來建立腎缺血性再灌注傷害小鼠模型。測試群組被分成施用群組(PEP 1)、對照群組(沒有PEP 1的PBS)及假手術群組(無雙側夾緊)。在誘發缺血性再灌注前的30分鐘及誘發缺血性再灌注12小時後以1000nmol/kg之濃度皮下注射PEP 1。
使用C57BL/6小鼠(8週大;Charles River Laboratories,Wilmington,MA)誘發腎缺血性再灌注傷害。在藉由血管鉗夾緊腎蒂阻斷血流及誘發缺血28分鐘後,執行再灌注。
在PBS中稀釋胜肽PEP 1至1000nmol/kg之濃度,並在缺血性再灌注前的30分鐘及缺血性再灌注12小時後於腹腔內(intraperitoneally;i.p.)注射兩次。針對施用群組(PEP 1)、對照群組(PBS)及假手術群組(無缺血性再灌注)實施測試。
測試實例2:PEP 1對預防IRI誘發腎衰竭之效果
在缺血性再灌注24小時後採集血液及量測血尿素氮(BUN)及肌酸之水平作為腎毒性標記。採集腎組織及製備成
石蠟塊用於免疫組織化學及組織學研究。隨後,萃取蛋白質及量測細胞因子之水平。使用自動分析器(Technicon RA-1000;Bayer,Tarrytown,NY)量測肌酸及BUN之濃度。
結果是,施用PEP 1群組展示出與PBS對照群組相比明顯減少的BUN及肌酸水平(第1圖)。
測試實例3:PEP 1對預防腎組織傷害之效果
在缺血性再灌注24小時後根據製造商(Polysciences,Inc.,華盛頓,PA,美國)之協定用過碘酸-希夫氏(PAS)對腎組織染色。在染色後,經由腎組織傷害計分評估腎組織傷害。施用PEP 1群組展示出與PBS對照群組相比顯著減少的腎組織傷害(第2圖及第3圖)。
測試實例4:抑制腎細胞死亡之效果
藉由在缺血性再灌注24小時後用TUNEL染色劑對腎組織染色評估腎細胞死亡。使用TUNEL染色試劑盒(Roche Applied Science,印第安娜波利斯,IN,美國)用TUNEL對腎石蠟切片染色。
結果是,施用PEP 1群組展示出與PBS對照群組相比顯著減少的TUNEL陽性細胞,指示PEP 1抑制腎組織之細胞死亡(第4圖及第5圖)。
測試實例5:抑制腎組織中的先天性免疫細胞之過濾之效果
在缺血性再灌注24小時後藉由用F4/80(巨噬細胞標記物)及Gr-1(嗜中性白細胞標記物)從免疫組織學上對腎組織染色來評估先天性免疫細胞之浸潤。特定而言,使用
巨噬細胞特異性抗體(F4/80;Abcam,Cambridge,MA)從免疫組織學上對石蠟切片中的浸潤巨噬細胞及嗜中性白細胞染色。
施用PEP 1群組展示出與PBS對照群組相比巨噬細胞及嗜中性白細胞至腎組織中之顯著減少的浸潤(第6圖及第7圖)。
測試實例6:抑制炎性細胞因子之分泌之效果
在缺血性再灌注24小時後從腎組織中萃取蛋白質及根據流式微珠陣列法量測IL-6、MCP-1及TNF-α之水平。小鼠IL-6、MCP-1、TNF-α ELISA試劑盒購自R&D Systems及根據製造商協定實施測試。
結果是,施用PEP 1群組展示出與PBS對照群組相比明顯減少的IL-6及MCP-1水平,但對於TNF-α未觀察到明顯差異(參看第8圖至第10圖)。
如上文所描述,藉由測試腎衰竭(BUN及肌酸)、腎組織傷害(管狀傷害)、腎細胞死亡、免疫細胞浸潤及腎組織中的細胞因子之分泌評估PEP 1對預防腎缺血性再灌注傷害之效果。
PBS對照群組展示出與假手術群組相比增加的血清BUN及肌酸水平及增加的腎組織傷害。相比之下,施用PEP 1群組展示出與對照群組相比明顯減少的BUN及肌酸水平及減少的腎組織傷害及腎細胞死亡。又,施用PEP 1群組展示出與PBS對照群組相比炎性細胞(嗜中性白細胞及巨噬細胞)之抑制浸潤及腎臟中的炎性細胞因子(白介素-6及單核細胞
趨化蛋白-1)之明顯抑制分泌。
實例3:PEP 1對改良缺血性再灌注傷害模型中的腹直肌肌皮皮瓣存活性之效果
測試實例1:缺血性再灌注之誘發
從Sprague-Dawley大鼠(體重180-230g)之腹部獲得5cm×5cm皮瓣,施用PEP1或鹽水,經由夾緊誘發局部缺血及隨後在7小時後藉由移除夾具恢復血流來建立缺血性再灌注傷害大鼠模型(參看第11圖)。
測試群組被分成施用群組(PEP 1)、對照群組(沒有PEP 1的PBS)及假手術群組(未誘發缺血性再灌注傷害)。在誘發缺血性再灌注前的30分鐘及誘發缺血性再灌注1、2、3、4、5及7天後肌內注射PEP 1(10mg/500μL)或PBS(500μL)。
測試實例2:PEP1對改良皮瓣存活性之效果
在誘發缺血性再灌注7天後量測皮瓣存活性。經由使用imageJ程式分析數位影像量測皮瓣存活率。
結果是,PBS治療群組之皮瓣存活率為34.69%±16.44%及PEP1治療群組展示出58.88%±11.44%之改良的皮瓣存活率(參看第12圖)。在群組之間發現了統計顯著性(p<0.05)。
<110> 韓商.凱爾傑姆維克斯有限公司 金商在
<120> 治療及預防缺血性傷害之組成物與方法
<130> 10-2013-0043636
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<211> 16
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<213> 智人
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Claims (11)
- 一種將一胜肽用於製造一組成物之用途,該組成物用於治療及預防一缺血性傷害,該胜肽由序列編號1之一胺基酸序列組成。
- 如請求項1所述之用途,其中該缺血性傷害由選自由以下組成之群組中的一或更多者引發:缺血性再灌注傷害、血管症、冠狀動脈血栓、腦血管血栓、動脈瘤破裂、全身性出血、擠壓傷害、敗血症、皮膚灼傷、血管結紮術、心肺分流術、器官移植、心肺衰竭(心源性猝死)及窒息。
- 如請求項2所述之用途,其中該缺血性傷害由缺血性再灌注傷害引發。
- 如請求項3所述之用途,其中該缺血性再灌注傷害選自由以下組成之群組:腦血管缺血性再灌注傷害、腎缺血性再灌注傷害、肝缺血性再灌注傷害、缺血性再灌注心肌症、缺血性再灌注皮膚傷害、腸胃缺血性再灌注傷害、腸道缺血性再灌注傷害、胃缺血性再灌注傷害、缺血性再灌注肺傷害、胰腺缺血性再灌注傷害、缺血性再灌注骨骼肌傷害、缺血性再灌注腹肌傷害、缺血性再灌注肢傷害、缺血性再灌注結腸炎、腸系膜缺血性再灌注傷害及無症狀缺血性再灌注傷害。
- 如請求項3所述之用途,其中該缺血性再灌注傷害由器官移植引發。
- 如請求項3所述之用途,其中該缺血性再灌注傷害發生在腎臟中。
- 如請求項3所述之用途,其中該缺血性再灌注傷害發生在一皮瓣中。
- 如請求項7所述之用途,其中該組成物係用於增進一皮瓣之存活率。
- 如請求項1所述之用途,其中該胜肽衍生自一人類端粒酶。
- 如請求項1所述之用途,其中該組成物係一醫藥組成物。
- 如請求項1所述之用途,其中該組成物係一食品組成物。
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KR (1) | KR102258864B1 (zh) |
CN (1) | CN105263508B (zh) |
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US11918624B2 (en) | 2020-06-10 | 2024-03-05 | Kelsius Laboratories LLC | Therapeutic composition for use in the treatment of COVID-19 and other cytokine storm associated disorders |
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WO2015167067A1 (ko) | 2014-04-30 | 2015-11-05 | 주식회사 카엘젬백스 | 장기, 조직 또는 세포 이식용 조성물, 키트 및 이식 방법 |
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Cited By (1)
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US11918624B2 (en) | 2020-06-10 | 2024-03-05 | Kelsius Laboratories LLC | Therapeutic composition for use in the treatment of COVID-19 and other cytokine storm associated disorders |
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ES2716870T3 (es) | 2019-06-17 |
US20160082089A1 (en) | 2016-03-24 |
KR20160008165A (ko) | 2016-01-21 |
US9907838B2 (en) | 2018-03-06 |
CN105263508B (zh) | 2019-10-25 |
CN105263508A (zh) | 2016-01-20 |
EP2987497A1 (en) | 2016-02-24 |
EP2987497A4 (en) | 2016-11-09 |
TW201521763A (zh) | 2015-06-16 |
JP6474786B2 (ja) | 2019-02-27 |
KR102258864B1 (ko) | 2021-06-01 |
WO2014171792A1 (ko) | 2014-10-23 |
EP2987497B1 (en) | 2018-12-26 |
JP2016518367A (ja) | 2016-06-23 |
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