TW201717996A - 長效胜肽類似物 - Google Patents
長效胜肽類似物 Download PDFInfo
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- TW201717996A TW201717996A TW105130619A TW105130619A TW201717996A TW 201717996 A TW201717996 A TW 201717996A TW 105130619 A TW105130619 A TW 105130619A TW 105130619 A TW105130619 A TW 105130619A TW 201717996 A TW201717996 A TW 201717996A
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- peptide
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- acid
- hypertension
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Abstract
本發明提供在活體內具有延長之半衰期的用於CLR/RAMP受體之長效激動劑類似物。
Description
生理學的許多面向，包括飢餓、應激反應及繁殖係依賴控制用之激素平衡。此平衡可以對內部及外部刺激作出反應。例如，腦下垂體前葉激素的分泌大部分係由下丘腦(大腦中略高於該腺體之區域)控制。已知下丘腦神經元製造並釋出胜肽因子，該胜肽因子藉由腦下垂體中製造特定激素之特殊細胞組來刺激或抑制該特定激素之分泌。
多種下丘腦釋出之胜肽對調節不同的腦下垂體前葉激素(諸如GH、ACTH、TSH、LH及FSH)之分泌很重要。然而，由腦下垂體前葉調節催乳素之釋出更加複雜且涉及源於下丘腦及中葉二者之刺激因子(見Laudon et al.(1990)Endocrinology126：3185-3192；Ben-Jonathan and Hnasko(2001)Endocr.Rev.22：724-763)。雖然中葉在調節催乳素分泌中的作用是有據可查的，且中葉及後葉對由哺乳及雌二醇誘導的催乳素釋出增加是必要的，來自中葉之催乳素釋出因子的特性仍需定性(Allen et al.(1995)
Endocrinology136：3093-3099)。
腦下垂體降鈣素受體樣受體(CRLR)已被認為與催乳素之釋出相關聯(Meeran et al.1997.J.Clin.Endocrinol.Metab.82：95-100)，雖然大腦中降鈣素基因相關胜肽(CGRP)表現樣式與CGRP在大腦中之結合位點並無重疊(Kruger 1988.Brain Res.463：223-244)。降鈣素最初被分離出為用於平衡鈣之必要的多胜肽激素，其屬於胜肽激素之群體(包括αCGRP、βCGRP、腎上腺髓質素(ADM)及胰淀素(amylin))(Eto(2001)Peptides22：1693-1711)。這些組織特異性胜肽為維持血管及呼吸系統動態平衡之重要的內分泌及神經內分泌整合因子。
這些胜肽之生物作用係經由與兩種密切相關之第Ⅱ型G蛋白偶聯受體(GPCR)(降鈣素受體)及CRLR結合來介導(Christopoulos et al.(1999)Mol.Pharmacol.56：235-242；Poyner et al.(2002)Pharmacol.Rev.54：233-246)。雖然該降鈣素受體為降鈣素作用之主要介導者，其亦結合胰淀素。最近之選殖及功能研究顯示出CGRP、ADM及程度較輕之胰淀素與CRLR及三種受體活性修飾蛋白(RAMP)的不同組合交互作用；見，McLatchie et al.(1998)Nature393：333-339。
許多細胞表現數種RAMP。共同表現降鈣素受體樣受體(CRLR)和受體活性修飾蛋白(RAMPs)對於產生降鈣素基因相關胜肽(CGRP)及腎上腺髓質素(ADM)之功能性受體是必要的。RAMP與CRLR之間形成異二聚體對於適當細胞
表面標靶CGRP和ADM受體之藥理特性是必不可少。該RAMP家族包含三種成員(RAMP1、-2及-3)，其共享之序列同一性少於30%，但具有共通之拓撲組織。其為具有一個大胞外N端(~100胺基酸)、單一跨膜結構域及很短之胞內結構域(10個胺基酸)之小內在膜蛋白(預測大小：Mr14,000-17,000)。CRLR與RAMP1共同表現可導致形成CGRP受體，而RAMP2及RAMP3促進ADM受體表現。當降鈣素受體與RAMP1共同表現時，其提供CGRP/胰淀素受體，而與RAMP3共同表達時，其提供胰淀素受體。
使用缺少αCGRP、ADM或胰淀素之突變小鼠進行的研究表明，在不同系統中，CRLR對心血管生成、感覺神經傳導、炎症反應、痛覺行為及葡萄糖動態平衡很重要。因此，此家族中之胜肽的生理功能係由個別配體之受體結合特異性及組織表現型態決定。
胜肽激素對療法(包括治療高血壓及維持心血管動態平衡)之臨床用途及發展很重要。除了這些作用，對鑑定催乳素釋出因子具重要性。雖然催乳素在哺乳動物之懷孕和哺乳期中很重要，且涉及乳腺的發展及促進乳汁合成，特定催乳素釋出激素迄今仍不清楚。
Hay and Smith (2001) Trends Pharmacol. Sci. 22:57-59; and Shindo et al. (2001) Circulation104:1964-197 discuss the importance of adrenomedullin in the
vasculature. The role of a CGRP is discussed by Zhang et al. (2001) Pain89:265-273; Salmon et al. (1999) Neuroreport10:849-854; and Salmon et al. (2001) Nat. Neurosci. 4:357-358. The role of amylin is discussed by Mulder et al. (2000) Am. J. Physiol. Endocrinol. Metab. 278:E684-691.
GenBank entry AF529213.
本發明提供長效胜肽類似物，其提供中葉激素或腎上腺髓質素之生物活性，包括作為降鈣素受體樣受體之配體，但當與天然多胜肽相比較時，其在活體內提供大幅延長之半衰期。本發明之類似物提供活體內有效性之期間係至少較天然胜肽長2倍，且可能長5倍、長10倍、長20倍或更久。增加之活體內活性可能經由測定該多胜肽之穩定性、生理作用之期間等，在活體內或體外測量。
於本發明之一些體系中，該類似物包含N-末端已被修改之生物活性中葉激素或腎上腺髓質素多胜肽。所欲之N-端修改包括與脂肪酸(通常為C4至C30脂肪酸，其可能為不飽和或飽和的)共軛結合。所欲之脂肪酸包括，但不限於棕櫚酸；硬脂酸；花生酸；月桂酸；肉荳蔻酸；肉荳蔻油酸；棕櫚油酸；十六碳烯酸(sapienic acid)；油酸；亞麻油酸；α-亞麻油酸；花生四烯酸；二十碳五烯酸；芥酸；二十二碳六烯酸等。於其他體系中，該多胜肽係藉
由聚乙二醇化、糖基化、與大蛋白質(諸如白蛋白)共軛結合，或與聚合物共軛結合加上胺基酸修改(諸如使用D-胺基酸或β胺基酸)來進行修改以增加生物半衰期。
本發明之類似物提供CLR/RAMP受體之激動劑類似物。該類似物可能對心率之影響有限，但顯著影響血壓。該長效胜肽在血清中之區室化(compartmentalization)有效地降低在指定時間點用於刺激細胞的可用激動劑部分，從而減輕注射之胜肽的高峰及穿透效果並排除有害的副作用。
本發明提供者為降鈣素胜肽激素家族成員之中葉激素或腎上腺髓質素的新穎多胜肽類似物。
中葉激素為一種降鈣素受體樣受體之配體。人類中葉激素基因編碼一148個胺基酸的開放閱讀框構，其具有在N-端用於分泌之24個胺基酸的信號胜肽及成熟之醯胺化胜肽(顯示於SEQ ID NO：1和SEQ ID NO：2中)。成熟人中葉激素胜肽包括，但不限於如SEQ ID NO：3中所示之40個胺基酸胜肽(中葉激素-短或IMDS)，其對應於成熟蛋白質之殘基8-47；及如SEQ ID NO：4中所示之47個胺基酸胜肽(中葉激素-長或IMDL)。該中葉激素胜肽可能被終端賴胺酸殘基取代以便於修改。例如，所欲之中葉激素胜肽為如SEQ ID NO：7：K(mod)GCVLGTCQVQNLSHRLWQLMGPAGRQDSAPVDPSSPHSY
中所示者，其中該終端賴胺酸被修改，例如經由脂質或其他基團連接。
腎上腺髓質素為一種降鈣素受體樣受體之配體。ADM基因編碼前激素原(preprohormone)，其經轉譯後修改以產生2種生物活性胜肽：腎上腺髓質素及腎上腺髓質素前體(proadrenomedullin)N端20胜肽(PAMP)。腎上腺髓質素由52個胺基酸所組成，具有1個分子內二硫鍵並顯示出與降鈣素基因相關胜肽具些微之同源性。該先質(稱為腎上腺髓質素前體(preproadrenomedullin))為185個胺基酸長。見GenBank參考資料NM_001124，其藉引用方式併入本文。該先質多胜肽(SEQ ID NO：5)具胺基酸序列：
在本發明之目的方面，除非另有規定，“腎上腺髓質素胜肽”一詞可指任何衍生自腎上腺髓質素先質胜肽之活性胜肽。特別重要的為降血壓胜肽。該活性胜肽包括，但不限於具胺基酸序列(SEQ ID NO：6)K(mod)GCRFGTCTVQKLAHQIYQFTDKDKDNVAPRSKISPQGY之腎上腺髓質素胜肽，其中在殘基1處之賴胺酸被修改，例如經由脂質或其他基團連接。
於本發明之一些體系中係藉由本發明之方法修改一或多種中葉激素及腎上腺髓質素以提供長效類似物。
於本發明之一些體系中，該類似物包含N-端已經過修改之生物活性多胜肽(如構造I中所顯示者)。於其他體系中，該多胜肽可能藉由聚乙二醇化、糖基化、與大蛋白質(諸如白蛋白)共軛結合，或與聚合物共軛結合加上胺基酸修飾(諸如使用D-胺基酸或β胺基酸)來進行修改以增加生物半衰期。
其中R1為直鏈型或支鏈型C3-C100烷基；較佳為可選擇地被選自下列群組之取代基所取代的C4-C30烷基：鹵素、羥基、烷氧基、胺基、烷胺基、二烷胺基、硫酸酯或磷酸酯且其可能為飽和、或單-不飽和或二-不飽和的，例如18：0、24：0及24：1。所欲之脂肪酸包括，但不限於棕櫚酸；硬脂酸；花生酸；月桂酸；肉荳蔻酸；肉荳蔻油酸；棕櫚油酸；十六碳烯酸；油酸；亞麻油酸；α-亞麻油酸；花生四烯酸；二十碳五烯酸；芥酸；及二十二碳六烯酸等。
本發明之類似物所提供之活體內有效性持續期間係較天然胜肽所提供者長至少2倍，且可能長5倍、長10倍、長20倍或更久。所增加之活體內活性可經由測定該
多胜肽之穩定性、生理效果之持續期間等而在活體內或活體外測量。特別關注的為降血壓作用，其中能有效降低收縮壓至少約10%之單一劑量的胜肽類似物可有效維持降低之血壓至少約1小時、至少約2小時、至少約3小時、至少約4小時或更久。
中葉激素及腎上腺髓質素為CLR/RAMP受體之配體，並在結合時活化受體。被中葉激素活化可導致催乳素釋出、調控生長激素釋出，在血管系統之效果包括降低血壓及血管擴張。因此，中葉激素透過CRLR傳訊以調節與周圍血管擴張相關的過程。被腎上腺髓質素活化所產生之血管系統影響包括降低血壓及血管擴張。因此，腎上腺髓質素透過CRLR腎上腺髓質傳訊以調節與周圍血管擴張相關的過程。
在藉由本方法進行修改方面，可使用天然中葉激素、腎上腺髓質或其變體。所欲之胜肽包括具至少約12個連續胺基酸之片段，更常為至少約20個連續胺基酸，且可能包含30、35、40或更多之胺基酸，多至完整之胜肽，並可能進一步擴大到包含其他存在於先質蛋白中之序列。缺失可能從胜肽之殘基1延長至10，且可能進一步額外缺失在殘基10-15或更多之胺基酸。在N-端可能缺失具有1至5個胺基酸之較小的缺失段。用於治療目的之所欲胜肽可能包括所提供之胜肽的全部或其絕大部分，或可能包含彼等之保留中葉激素之生物活性的片段。
多胜肽之序列可能藉由本技藝中已知用來產生成序列
中之針對性變化的各種方法被改變。該多胜肽通常將與此處所提供之序列大致相同，即，至少有一個胺基酸不同且可能至少有兩個胺基酸，但不超過約10個胺基酸不同。該序列變化可能為取代、插入或缺失。掃描系統上引入丙胺酸或其他殘基之突變，可能用於測定關鍵胺基酸。保守性胺基酸取代通常包括在下列群組內之取代：(甘胺酸，丙胺酸)；(纈胺酸，異白胺酸，白胺酸)；(天門冬胺酸，麩胺酸)；(天門冬醯胺，麩胺醯胺)；(絲胺酸，蘇胺酸)；(賴胺酸，精胺酸)；或(苯丙胺酸，酪胺酸)。
不改變主要序列之所欲修改包括多胜肽之化學衍化，例如乙醯化或羧基化。亦包括糖基化之修改，例如經由在多胜肽之合成和加工過程中，或在進一步之加工步驟中修改其糖基化樣式所做之修改；例如經由讓多胜肽接觸影響糖基化之酶(諸如哺乳動物之糖基化或去糖基化酶)所做之修改。亦包括具有磷酸化胺基酸殘基(如磷酸酪胺酸、磷酸絲胺酸或磷酸蘇胺酸)的序列。
本發明亦包括已使用一般分子生物技術及合成化學修改，從而改善其對蛋白質降解之抗性或優化溶解特性，或使其更適合作為治療劑的多胜肽。例如，胜肽之骨幹可能經環化以增加穩定性(見Friedler et al.(2000)J.Biol.Chem.275：23783-23789)。這類多胜肽之類似物包括那些含有除了天然L-胺基酸外之殘基(如D-胺基酸)，或非天然之合成胺基酸者。
本發明之胜肽可使用本技藝已知之習知方法經由體外
合成製備。有各種市售合成儀器可用，例如：由應用生物系統公司(加卅Foster市，Beckman)等提供之自動合成儀。經由使用合成儀器可以非天然胺基酸取代天然胺基酸。該特定序列及製備方式將取決於方便性、經濟、所要求之純度等。
若需要時可在胜肽合成或表現過程中將不同基團引入胜肽中，這些不同基團可允許鏈接至其他分子或某一表面。如此，可使用半胱胺酸製造硫醚，使用組胺酸以鏈接至金屬離子複合物，使用羧基形成醯胺或酯類，使用胺基形成醯胺等。
亦可以根據習知之重組合成方法分離並純化多胜肽。可以製備該表現宿主之溶胞產物並使用HPLC、排阻色層分析法、凝膠電泳法、親和力色層分析法或其他純化技術來純化該溶胞產物。大部分而言，在與產物之製備方法及其純化方法有關之污染物方面，所使用之組成物將包含至少20重量%之所需產物，更常至少約75重量%，較佳為至少約95重量%，且用於治療目的時常至少約99.5重量%。通常，該百分比係根據全部蛋白質。
中葉激素及腎上腺髓質在許多臨床適應症中之藥理活性很明顯，其包括但不限於高血壓，例如妊娠高血壓，肺動脈高血壓，與糖尿病相關之高血壓等；支氣管肺發育不良、傷口癒合等。例如，可能使用中葉激素或腎上腺髓質
素胜肽或其變體來治療臨床適應症，尤其是用於治療高血壓。本發明之類似物可用於降低血壓，例如降低收縮壓至少約5%、至少約10%、至少約15%、至少約20%或以上，但不影響心率。
高血壓為一種若不及時治療則很容易誘發動脈粥狀硬化性心血管病的疾病。據估計，多達1/4的美國成年人患有高血壓。高血壓在糖尿病患者中之普遍率約為沒有糖尿病的人之兩倍。高血壓患病率隨著年齡增加而增加。
高血壓不應根據單一測量做診斷。初次升高的讀值應根據接下去一週內至少兩次之訪視或更多次具有診斷高血壓所需的90毫米汞柱或更高之平均舒張壓，或140毫米汞柱或更高之收縮壓來確認。在診斷糖尿病患者之高血壓時必須特別小心，因為其血壓之變動性較大且很可能有單純收縮期高血壓(isolated systolic hypertension)。對這些患者之目標血壓的建議為小於130/85毫米汞柱。
除了改變飲食外，可能需要藥物治療以控制高血壓。投服本發明之胜肽可能降低動脈血壓。此外，降低高血壓的副效應為減輕水腫及炎性滲出量。
含中葉激素或腎上腺髓質素類似物之醫藥組成物可用來作為心臟保護劑，例如，以改善心肌缺血後之缺血性損傷或心肌梗塞面積。研發能夠在急性心肌缺血後限制心肌損傷之程度(即，心肌梗塞的程度)的新治療劑為現代心臟病學主要關注的問題。對於研發能夠提供額外之心肌保護作用且可與溶血栓療法一起投服或單獨投服的療法亦令
人感興趣，因為回顧性流行病學研究顯示在心肌梗塞後之最初幾年的死亡率似乎與原始心肌梗塞面積有關。
心肌缺血為心肌氧供需失衡的結果，包括運動性及血管痙攣性心肌功能障礙。運動性缺血一般係歸因於出現涉及大冠狀動脈的關鍵動脈粥狀硬化狹窄，造成心內膜下血流量降低。血管痙攣性缺血與病灶變化痙攣有關，其發病與運動或壓力不相關。痙攣之較佳定義為血管張力突然增加。
在治療需要心臟保護療法之患者時通常可經口或腸胃道外途徑投服本發明之化合物。該給藥方案為確保最大治療反應，直到得到改善，之後投予能使病情緩和之最低有效水準。因此，一般而言，該給藥量為能治療上有效地產生心臟保護作用的給藥量，即，減輕心肌缺血後隨之而來的缺血性損傷或心肌梗塞的面積。該胜肽亦被預期將可作為能在緊急情況下投予罹患心肌缺血等之患者的注射劑型。
該中葉激素或腎上腺髓質素胜肽及其衍生物亦可用於減輕水腫，例如在類風濕性關節炎中之水腫、繼發於腦腫瘤或癌症放射治療後之水腫、中風、頭部外傷或脊髓損傷造成之水腫、手術後的水腫、氣喘及其他呼吸系統疾病和眼睛的黃斑囊樣水腫。
本發明之化合物可以被納入用於治療性投藥之各種調
配劑中。尤其是，調控中葉激素或腎上腺髓質素活性，或中葉激素或腎上腺髓質素多胜肽及其類似物之作用劑係調配成用於投予患者以治療中葉激素或腎上腺髓質功能障礙(其中該活性為不希望地高或低)。更特別地，本發明之化合物可經由與適當之藥學上可接受的載體或稀釋劑組合來配製成醫藥組成物且可能配製成固態、半固態、液態或氣態形式，諸如片劑、膠囊、粉末、顆粒、油膏、溶液、栓劑、注射劑、吸入劑、凝膠、微球及氣溶膠。因此，可以各種方式投服該化合物，包括經口、口腔、直腸、胃腸道外、腹膜內、皮內、透皮、椎管內等途徑投服。活性劑可能在投服後全身性作用或可能經由使用將該活性劑保留在植入部位的植入劑來局部作用。
在製藥劑量型中，該化合物可能以其藥學上可接受之鹽的形式投服，或者其亦可單獨使用，或與其他藥物活性化合物適當聯結或組合。下列方法及賦形劑僅作為示範，而非有任何限制。
在口服製劑方面，該化合物可以單獨使用或與適當之添加劑組合以製造片劑、粉末、顆粒或膠囊，例如：與習知之添加劑組合，諸如乳糖、甘露醇、玉米澱粉或馬鈴薯澱粉；與結合劑組合，諸如結晶型纖維素、纖維素衍生物、洋槐、玉米澱粉或明膠；與崩散劑組合，諸如玉米澱粉、馬鈴薯澱粉或羧甲基纖維素鈉；與潤滑劑組合，諸如滑石粉或硬脂酸鎂；若需要時，可與稀釋劑、緩衝劑、潤濕劑、防腐劑和調味劑組合。
該化合物可經由溶解、懸浮或乳化在水性或非水性溶劑中味配製成注射製劑，該水性或非水性溶劑為諸如蔬菜油或其他類似之油、合成之脂肪酸甘油酯、較高脂肪酸或丙二醇之酯類；若需要時可與習知之添加劑，諸如助溶劑、等張劑、懸浮劑、乳化劑、穩定劑及防腐劑一起調配。
該化合物可用於氣溶膠調配劑中以經由吸入投服。本發明之化合物可配製在經加壓之可接受的推進劑中，諸如二氯二氟甲烷、丙烷、氮等。
此外，該化合物可經由與多種底質(諸如乳化底質或水溶性底質)混合而配製成栓劑。本發明之化合物可藉由栓劑通過直腸投服。栓劑可包含載劑，諸如可可脂、聚乙二醇(carbowaxe)及聚乙二醇(polyethylene glycol)，該載劑在體溫下會融化，但在室溫下會固化。
可能提供用於口服或直腸投服之單位劑量型(諸如糖漿、酏劑及懸浮液)，其中各劑量單位，例如茶匙量、湯匙量、片劑或栓劑包含預定量之含有一或多種本發明化合物之組成物。同樣地，用於注射或靜脈內投服之單位劑量型可能包含在組成物(如：在無菌水、生理鹽水或其他藥學上可接受之載體中的溶液)中之本發明化合物。
用於緩釋調配劑之植入物為本技藝所熟知。植入物係與可生物降解或不可生物降解之聚合物配製成微球、厚片等。例如，乳酸/乙醇酸之聚合物形成可被宿主良好耐受之易侵蝕的(erodible)聚合物。該植入物係被放置在接近受
感染的部位，從而使活性劑的局部濃度相對於身體的其餘部分提高。
此處所使用之“單位劑量型”一詞係指適合作為用於人類及動物個體之單一劑量的生理上離散單位，各單位包含經計算足以產生所需效果之預定量的本發明化合物及藥學上可接受之稀釋劑、載體或載劑。本發明之新類單位劑量型的規格係取決於所使用之特定化合物和欲取得之效果，以及與宿主中之各化合物有關的藥物動力學。
該藥學上可接受之賦形劑，諸如載劑、佐劑、載體或稀釋劑可被公眾輕易地取得。此外，藥學上可接受之輔助物質，諸如pH值調整劑及緩衝劑、張力調節劑、穩定劑、潤濕劑，等可被公眾輕易地取得。
用於全身性投服之典型劑量範圍為每次投服，每公斤個體體重從0.1微克至100毫克。典型劑量可能為每次一個片劑，每日服用2至6次，或每次一個緩釋膠囊或片劑，每日服用一次且含有比例上較高含量之活性成分。緩釋效果可能藉由在不同pH值溶解的膠囊材料、藉由滲透壓緩慢釋出之膠囊，或藉由任何其他已知之控釋方式取得。
那些技術熟習人士可很容易地理解劑量水準可作為該特定化合物、症狀之嚴重性及個體對副作用之易感性的函數而有所變化。該特定化合物中有些較其他化合物更有效。熟習本技藝之人士可透過各種方式輕易地測定指定化合物之較佳劑量。較佳方式為測量指定化合物之生理效
力。
脂質體可用於在活體內和體外遞送蛋白質。本發明所使用之脂質體可採用各種習知之脂質體製備技術之一來製備。熟習本技藝之人士可輕易察知這類習知技術，包括超音波處理、螯合物透析、均質化、溶劑輸液結合擠壓、凍融擠壓、微乳化等。這些及其他技術討論於例如：US4,728,578、英國專利申請號G.B.2193095 A、US4,728,575、US4,737,323、國際申請號PCT/US85/01161、Mayer et al.,Biochimica et Biophysica Acta,Vol.858,pp.161-168(1986),Hope et al.,Biochimica et Biophysica Acta,Vol.812,pp.55-65(1985),U.S.Pat.No.4,533,254,Mahew et al.,Methods In Enzymology,Vol.149,pp.64-77(1987),Mahew et al.,Biochimica et Biophysica Acta,Vol.75,pp.169-174(1984),and Cheng et al.,Investigative Radiology,Vol.22,pp.47-55(1987)。類似於國際申請號PCT/US85/01161中描述之無溶劑系統可用來製備脂質體構造。
用於製備脂質體之物質包括熟習本技藝之人士已知之適合建構脂質體的任何物質或組合。所使用之脂質可能為天然或人工合成來源。這類物質包括，但不限於脂質，諸如膽固醇、磷脂醯膽鹼、磷脂醯乙醇胺、磷脂醯絲胺酸、磷脂醯甘油、磷脂酸、磷脂醯肌醇、脫脂脂質(lysolipid)、脂肪酸、鞘脂、糖鞘脂、糖脂(glucolipid)、醣脂(glycolipid)、硫脂(sulphatide)、帶有醯胺之脂質、乙
醚及與酯連接之脂肪酸、可聚合之脂質及彼等之組合。熟習本技藝之人士將可辨知，脂質體可在不存有或存有併入之醣脂、複合碳水化合物、蛋白質或合成之聚合物下採用習知程序合成。脂質體表面亦可能藉由聚合物進行修改，諸如，例如，採用熟習本技藝之人士可容易明白之程序使用聚乙二醇(PEG)進行修改。任何種類之脂質均可使用，唯一的先決條件為該脂質或脂質與納入脂質基質中之聯結物質的組合應該在生理相關條件下形成雙層相。如熟習本技藝之人士將察知者，該脂質體之組成物可能被改變以調控所產生之脂質體的生物分佈及清除性能。
在這些構造中之膜雙層通常包封一水液體積並在該包封之體積與外部溶液之間形成一滲透屏障。分散在水溶液中之脂質自發形成烴尾朝內而極性頭基朝外以與水相互作用之雙層。簡單攪動該混合物通常會產生多層狀囊泡(MLV)，直徑為1-10.mu.m(1000-10,000毫微米)之具有許多雙層的洋蔥狀形式結構。以超音波或本技藝已知之其他方法處理這些結構可形成平均直徑約30-300毫微米之單層囊泡(UV)。然而從，例如體內最大循環時間的角度來看，50至200毫微米之範圍被認為是最佳的。該實際平衡直徑大部分取決於所使用之磷脂的性質及納入其他脂質(諸如膽固醇)之程度。形成脂質體之標準方法為本技藝所已知，例如，用於商業化生產脂質體的方法描述於US4,753,788及US4,935,171中。
聚合化之脂質體為脂質分子自行組裝之聚集物，並描
述於US5,512,294、6,132,764及US20020071843中。該可聚合之脂質的疏水性尾基係以可聚合之基團(諸如聯乙炔基團)衍生，該可聚合之基團當接觸紫外線或其他自由基、陰離子或陽離子性起始物種時以不可逆轉之方式交聯或聚合化，但仍維持官能基分佈在脂質體之表面。所產生之聚合化的脂質體顆粒對與細胞膜或其他脂質體融合保持穩定且對酶降解穩定。聚合化之脂質體的大小可經由擠壓或其他熟習本技藝之人士所已知之方法控制。聚合化之脂質體可能包含可聚合之脂質，但亦可能包含飽和及非炔之不飽和脂質。聚合化之脂質體可為脂質之混合物，其在親水性暴露之表面提供不同的官能基。例如，一些親水性頭基可具有官能表面基團，例如生物素、胺、氰基、羧酸、異硫氰酸酯、硫醇、二硫化物、α-鹵羰基化合物、α,β-不飽和羰基化合物及烷基肼。這些基團可用於連接核酸序列。
為了用於上述調配劑中，可合成中葉激素或腎上腺髓質或由此衍生之衍生物並以固態凍乾粉末之形式儲存，其可在使用前不久在藥學上可接受之液體中新建。這類調配劑通常較佳，因為熟習本技藝之人士認為凍乾製劑隨著時間的推移保持藥物活性的能力通常優於其液態對應物。
此外，中葉激素或腎上腺髓質素及其類似物可局部施用在皮膚上及以氣溶膠噴霧之形式投服。
或者，該胜肽可配製成液體形式，如：包含濃度為約1mM至約50mM用於維持pH值之緩衝劑，其中該緩衝劑
之陰離子可選自如下群組：醋酸鹽、磷酸鹽、碳酸鹽、琥珀酸鹽、檸檬酸鹽、硼酸鹽、酒石酸鹽、富馬酸鹽和乳酸鹽；及醇，其可選自如下群組：甘露醇、山梨醇、核糖醇(ribotol)、阿拉伯糖醇、木糖醇、肌醇、半乳糖醇、甲醇、乙醇及甘油。其他添加劑可能包括胺基酸，諸如蛋胺酸、精胺酸、賴胺酸、麩胺酸、半胱胺酸、穀胱甘肽等，其中胺基酸之存在濃度一般為約1mM至約100mM。調配劑中可選擇性包含各種糖類，包括，例如葡萄糖、蔗糖、乳糖、果糖、海藻糖、甘露糖等。添加之糖類的存在濃度一般為約1%至約10%。
第1A-1C圖為在SHR大鼠中以長效中葉激素胜肽(棕櫚酸改質之IMD，IMD-PA)治療後之血壓測量實例，A.30毫微莫耳/公斤體重；B/C 100毫微莫耳/公斤體重。
第2A-2B圖為在SHR大鼠中以野生型中葉激素胜肽(IMD，100毫微莫耳/公斤體重)治療後之血壓測量實例。
IMD-PA胜肽之降血壓效果在活體內持續超5小時，然而改質之IMD胜肽持續不到1小時。
第3A-3B圖為在對照組動物中注射PBS後之血壓測量值。
第4圖顯示IMD及IMD-PA在表現三種不同受體(CLR/RAMP1、CLR/RAMP2、CLR/RAMP3)之293T細胞中的刺激效果。
第5A-5C圖顯示SHR大鼠在注射長效腎上腺髓質素胜肽(與棕櫚酸共軛結合之ADM，ADM-PA，100毫微莫耳/公斤體重)後之收縮壓測量值實例。此胜肽之降血壓效果在活體內持續超過5小時。透過對比，未改質之ADM胜肽的降血壓效果之持續時間通常少於1.5小時。
第6A-6B圖顯示SHR大鼠在注射對照組生理鹽水後之收縮壓測量值實例。
第7圖顯示在表現重組腎上腺髓質素受體1(CLR/RAMP2)及2(CLR/RAMP3)之293T細胞中的ADM及ADM-PA之刺激效果。雖然ADM-PA胜肽在體外之刺激效果低於野生型ADM，但其在活體內具有顯著較長之有效期。
第8圖顯示在經腹膜內途徑注射12小時後，與ADM胜肽相比較，活體內所保留之免疫反應性ADM-PA的水準顯著較高。
下列實例係用於提供本技藝之一般技術人士完整的揭示內容並說明如何製作及使用本發明，而不欲限制本發明者所認為之發明範圍，亦不欲表示下列實驗為所有或僅執行之實驗。所使用之數字(例如，量、溫度等)已盡力確保準確性，但一些實驗誤差及偏差仍應考慮。除非另有說明，份數為按重量計算之份數，分子量為平均分子量，溫度為攝氏溫度且壓力為在或接近大氣壓力。
中葉激素改質。由史丹佛大學之Pan全體人員使用標準固相Fmoc胜肽化學在應用生物系統公司之自動化胜肽合成儀上合成胜肽(Fields GB,Noble RL.Solid phase peptide synthesis utilizing 9-fluorenylmethoxycarbonyl amino acids.Int J Pept Protein Res 35：161-214,1990)。該經改質之胜肽係經由在合成胜肽期間併入已與經Fmoc保護之[C16]棕櫚酸酯脂肪酸(Lys(PAL))共軛結合的賴胺酸殘基來合成。藉由逆相HPLC測定純度並隨後使用電噴霧電離質譜儀定性。
該經改質及天然之中葉激素的活體內生物活性顯示於第1-4圖中。將中葉激素胜肽以10微莫耳/升之濃度溶解於帶有10-20%DMSO之鹽溶液中。在注射前，將等分之胜肽溶解於PBS中使最終注射體積成為100微升。在預先適應測量程序之清醒的SHR大鼠(9-16週齡)中進行血壓測量。使用尾套法(tail-cuff method)，藉由編程之非侵入性血壓系統(Kent科學公司)測定間接收縮壓。在連接壓力傳感器後，令大鼠保持不受干擾10分鐘後再開始橫跨15-20分鐘之期間的基線測量。測量基線後，經由腹膜內途徑為大鼠注射不同劑量之胜肽，或帶有10%DMSO之生理鹽水。以每30秒的間隔監測血壓和心率共20-40分鐘。計算血壓之變化作為在給定之期間內所進行之測量的平均測量值。對照組動物之基礎血壓與那些以中葉激素胜
肽治療者相當。
如第1A-1C圖所示，當為大鼠注射經改質之中葉激素(IMD-棕櫚酸改質之IMD)且隨著時間的推移測量血壓時，收縮壓明顯且長期持續下降。此胜肽之降血壓效果在活體內持續超過5小時，而未改質之IMD胜肽持續不到1小時。來自注射PBS之對照組動物的結果顯示於第3圖中，而來自未改質之胜肽的結果顯示於第2圖中。
腎上腺髓質素改質。由史丹佛大學之Pan全體人員使用標準固相Fmoc胜肽化學在應用生物系統公司之自動化胜肽合成儀上合成胜肽(Fields GB,Noble RL.Solid phase peptide synthesis utilizing 9-fluorenylmethoxycarbonyl amino acids.Int J Pept Protein Res 35：161-214,1990)。該經改質之胜肽係經由在合成胜肽期間併入已與經Fmoc保護之[C16]棕櫚酸酯脂肪酸(Lys(PAL))共軛結合的賴胺酸殘基來合成。藉由逆相HPLC測定純度並隨後使用電噴霧電離質譜儀定性。
腎上腺髓質素在活體外之生物活性。ADM和ADM-PA之刺激效果的典型證明顯示於第7圖中。
腎上腺髓質素類似物在活體內之生物活性。將腎上腺髓質素胜肽以10微莫耳/升之濃度溶解於帶有10-20%DMSO之鹽溶液中。在注射前，將等分之胜肽溶解於PBS中使最終注射體積成為200微升。在預先適應測量
程序之清醒的SHR大鼠(9-16週齡)中進行血壓測量。使用尾套法，藉由編程之非侵入性血壓系統(Kent科學公司)測定間接收縮壓。在連接壓力傳感器後，令大鼠保持不受干擾10分鐘後再開始橫跨10-15分鐘之期間的基線測量。測量基線後，經由腹膜內途徑為大鼠注射不同劑量之胜肽，或帶有10%DMSO之生理鹽水。以每20秒的間隔監測血壓和心率共20-40分鐘。計算血壓之變化作為在給定之期間內所進行之測量的平均測量值。
該數據顯示SHR大鼠注射ADM-PA胜肽或生理鹽水後之收縮壓略圖。(見Roh et al.Mol Endocrinol.2005 Nov；19(11)：2824-38)。
如第5A-5C圖所示，當為大鼠注射100毫微莫耳/公斤體重之經改質的腎上腺髓質素(AMD-棕櫚酸改質之AMD)且隨著時間的推移測量血壓時，收縮壓明顯且長期持續下降。根據使用ELISA測量免疫活性ADM之結果，與ADM相比較，該ADM-PA胜肽具有長半衰期(第8圖)。
本專利說明書中所引用之所有出版物及專利申請案藉引用方式併入本文如同各別出版物或專利申請案被具體且單獨地併本文。
本發明已就本發明者所發現或建議之特殊體系描述以包含用於實踐本發明之較佳模式。熟習本技藝之人士可了解，鑑於本揭露內容可對示範之特殊體系做許多修改及變化，而不偏離本發明之所欲範圍。此外，由於生物功能等
效性考量，可以改變蛋白質的結構，但不影響生物作用之種類或量。所有這類修改意欲被包含在附加之申請專利範圍的範圍內。
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Claims (5)
- 一種胜肽用於製備降低為醫學病症之高血壓、高血壓危象、缺血性損傷及內皮功能障礙的組成物之用途，其中該胜肽以至少約0.5ug/kg體重之劑量投予到個體達足以降低平均動脈壓至少5%的期間，且其中序列如SEQ ID NO：3、SEQ ID NO：4或SEQ ID NO：7或SEQ ID NO：6所示。
- 如申請專利範圍第1項之用途，其中該胜肽具有與SEQ ID NO：3、SEQ ID NO：4、SEQ ID NO：6或SEQ ID NO：7之胺基酸序列大於60%序列同一性。
- 如申請專利範圍第1項之用途，其中該投予係藉由皮下注射或連續輸液。
- 如申請專利範圍第1項之用途，其中該高血壓為先兆子癇、頑固性高血壓、難治性高血壓、高血壓危象或原發性肺性高血壓。
- 如申請專利範圍第1項之用途，其中該醫學病症為先兆子癇、頑固性高血壓、難治性高血壓、高血壓危象、淋巴水腫、中風、心肌梗塞、周圍動脈狹窄、腎衰竭、心臟衰竭、終端器官衰竭、支氣管肺發育不良、糖尿病性潰瘍、或頸動脈狹窄。
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| US9694051B2 (en) * | 2011-04-07 | 2017-07-04 | The Board Of Trustees Of The Leland Stanford Junior University | Long-acting peptide analogs |
| EP3127914A4 (en) * | 2014-03-20 | 2017-11-22 | University of Miyazaki | Long-acting adrenomedullin derivatives |
| CN107001440A (zh) * | 2014-09-26 | 2017-08-01 | 拜耳制药股份公司 | 稳定化的肾上腺髓质素衍生物及其用途 |
| WO2016183479A1 (en) * | 2015-05-13 | 2016-11-17 | The Board Of Regents Of The University Of Oklahoma | Variants of adrenomedullin and calcitonin gene-related peptide and methods of use |
| RU2738416C2 (ru) | 2015-09-18 | 2020-12-14 | Юниверсити Оф Миязаки | Длительно действующее производное адреномедуллина |
| CN116063580A (zh) * | 2016-01-04 | 2023-05-05 | 艾得佩索拉公司 | 肽类似物 |
| WO2017139154A1 (en) * | 2016-02-09 | 2017-08-17 | Adepthera Llc | Dosing and use of long-acting clr/ramp agonists |
| JP6781974B2 (ja) * | 2016-03-31 | 2020-11-11 | 国立大学法人 宮崎大学 | アドレノメデュリン凍結乾燥製剤の製造方法 |
| CN110678550B (zh) | 2017-03-29 | 2023-11-14 | 国立大学法人宫崎大学 | 长效肾上腺髓质素衍生物 |
| US20190153059A1 (en) * | 2017-06-30 | 2019-05-23 | Adepthera Llc | Peptide analogs |
| MX2020002247A (es) * | 2017-09-27 | 2021-03-25 | Novel Pharma Inc | Derivado de gnrh de conjugado a ácido palmítico de larga duración y composición farmacéutica que lo contiene. |
| US20190287217A1 (en) * | 2018-03-13 | 2019-09-19 | Microsoft Technology Licensing, Llc | Machine learning system for reduced network bandwidth transmission of content |
| CN108409834B (zh) * | 2018-03-23 | 2020-08-28 | 中国药科大学 | 一种寡肽及其衍生物和应用 |
| CN108484727B (zh) * | 2018-03-23 | 2020-08-28 | 中国药科大学 | 一种寡肽及其衍生物和应用 |
| EP3785734B1 (en) | 2019-03-26 | 2023-04-12 | Novel Pharma Inc. | Long-acting fatty acid-binding gnrh derivative and pharmaceutical composition comprising same |
| US20220387608A1 (en) * | 2019-06-18 | 2022-12-08 | Bayer Aktiengesellschaft | Adrenomedullin-analogues for long-term stabilization and their use |
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| AU5366296A (en) * | 1995-03-22 | 1996-10-08 | Trustees Of Boston University | Methods for the detection of paracoccidioides |
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| IL118003A0 (en) | 1996-04-23 | 1996-08-04 | Yeda Res & Dev | Novel vip fragments and pharmaceutical compositions comprising them |
| US6268474B1 (en) | 1998-04-30 | 2001-07-31 | Creighton University | Peptide antagonists of CGRP-receptor superfamily and methods of use |
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| JP2004510830A (ja) | 2000-10-11 | 2004-04-08 | ターゲサム・インコーポレーテッド | 標的化された治療用薬剤 |
| US20080026995A1 (en) * | 2003-07-25 | 2008-01-31 | Ac Immune Sa | Therapeutic vaccine targeted against p-glycoprotein 170 for inhibiting multidrug resistance in the treatment of cancers |
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| US8404637B2 (en) | 2005-02-11 | 2013-03-26 | Amylin Pharmaceuticals, Llc | GIP analog and hybrid polypeptides with selectable properties |
| AU2007227202B2 (en) | 2006-03-21 | 2013-08-22 | Amylin Pharmaceuticals, Llc | Peptide-peptidase inhibitor conjugates and methods of using same |
| WO2008022716A2 (en) * | 2006-08-22 | 2008-02-28 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Screening method for gpcr ligands |
| CN106008699A (zh) * | 2006-09-08 | 2016-10-12 | Ambrx公司 | 经修饰的人类血浆多肽或Fc骨架和其用途 |
| US7960336B2 (en) | 2007-08-03 | 2011-06-14 | Pharmain Corporation | Composition for long-acting peptide analogs |
| US9694051B2 (en) | 2011-04-07 | 2017-07-04 | The Board Of Trustees Of The Leland Stanford Junior University | Long-acting peptide analogs |
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| BR112013024784A2 (pt) | 2018-09-25 |
| US20170014485A1 (en) | 2017-01-19 |
| TWI635868B (zh) | 2018-09-21 |
| AU2012240144A1 (en) | 2013-10-03 |
| JP2017082000A (ja) | 2017-05-18 |
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| US11666633B2 (en) | 2023-06-06 |
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| US9694051B2 (en) | 2017-07-04 |
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| EP2696884A2 (en) | 2014-02-19 |
| US10058592B2 (en) | 2018-08-28 |
| CA2830372A1 (en) | 2012-10-11 |
| RU2013149397A (ru) | 2015-05-20 |
| EP2696884B1 (en) | 2019-04-03 |
| AU2017213562A1 (en) | 2017-08-31 |
| WO2012138867A3 (en) | 2012-12-13 |
| JP6522020B2 (ja) | 2019-05-29 |
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| TWI561242B (en) | 2016-12-11 |
| EP2696884A4 (en) | 2014-12-24 |
| CN103458916B (zh) | 2016-08-10 |
| AU2012240144B2 (en) | 2017-05-25 |
| CN103458916A (zh) | 2013-12-18 |
| US20190183978A1 (en) | 2019-06-20 |
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