TW202132325A - 胜肽、組成物以及治療、預防或改善情緒障礙之方法 - Google Patents
胜肽、組成物以及治療、預防或改善情緒障礙之方法 Download PDFInfo
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Abstract
本發明的課題是提供一種能夠治療、預防或改善情緒障礙的新穎胜肽。本發明提供一種胜肽,具有序列識別號1或序列識別號2所載的胺基酸序列,且其胺基酸長度為3以上5以下。所述胜肽可由序列識別號1、序列識別號2、序列識別號3、或序列識別號4所載的胺基酸序列構成。
Description
本發明係有關於胜肽、組成物以及治療、預防或改善情緒障礙之方法。
反應現代的壓力社會,以動機低落(decrease in motivation)和憂鬱症等為代表之情緒障礙的增加已成為問題。作為生物體為了避免發生危險的警示,不安全感(情緒障礙的病因之一)原本是必要的,但過多的不安全感則關係到情緒障礙的發生和症狀的進展,因此期望開發出緩解不安全感的食品、醫藥品等。
例如,專利文獻1記載,既定的二肽適合作為抗焦慮藥等。
[先前技術文獻]
[專利文獻]
[專利文獻1]國際專利公開第2013/129220號公報
[發明所欲解決的課題]
但是,對於能夠治療、預防或改善情緒障礙的功能性材料有進一步的需求。
本發明是鑑於上述情況而完成的,其目的是提供一種能夠治療、預防或改善情緒障礙的新穎胜肽。
[解決課題的手段]
本發明人發現由特定的胺基酸序列構成的胜肽能夠解決上述問題,從而完成了本發明。具體地,本發明提供了以下內容。
(1)一種胜肽,具有序列識別號1或序列識別號2所載的胺基酸序列,且其胺基酸長度為3以上5以下。
(2)如(1)所述之胜肽,前述胜肽是由序列識別號1、序列識別號2、序列識別號3、或序列識別號4所載的胺基酸序列構成。
(3)一種用於治療、預防或改善情緒障礙的組成物,包括如(1)或(2)所述之胜肽。
(4)如(3)所述之組成物,前述情緒障礙係擇自於由動機低落、憂鬱、和憂鬱性情緒障礙、以及基於前述症狀所組成之群組的一種以上。
(5)如(3)或(4)所述之組成物,其為醫藥品。
(6)如(3)或(4)所述之組成物,其為飲食品。
(7)一種治療、預防或改善情緒障礙的方法,包括投予如(3)至(5)中任一項所述之組成物。
[發明的效果]
根據本發明,提供了能夠治療、預防或改善情緒障礙的新穎胜肽。
以下將詳細說明本發明的實施方式。惟、本發明不限於以下的實施方式。
<本發明的胜肽>
本發明的胜肽具有序列識別號1所載的胺基酸序列(QSQ)或序列識別號2所載的胺基酸序列(SQK),且其胺基酸長度為3以上5以下。以下,將從N端到C端描述胺基酸序列,其中N端位於左端。
基於對各種胜肽混合物的同步分析訊息、和影響情緒行為之已知胜肽的結構-活性相關訊息進行研究的結果,本發明人發現了對於情緒障礙的治療等有效之新穎胜肽,亦即,上述胜肽。
本發明的胜肽可為由序列識別號1或2所載的胺基酸序列所構成的胜肽(三肽),也可為在序列識別號1或2所載的胺基酸序列之N端側及/或C端側添加了任意胺基酸的胜肽。
在序列識別號1所載的胺基酸序列中,N端的胺基酸是Q(麩醯胺酸),C端的胺基酸是Q(麩醯胺酸)。在序列識別號2所載的胺基酸序列中,N端的胺基酸是S(絲胺酸),C端的胺基酸是K(離胺酸)。
本發明的胜肽之胺基酸長度上限為5以下的胺基酸長度,以4以下的胺基酸長度為佳。最佳地,本發明的胜肽之胺基酸長度為3(亦即,最佳地,本發明的胜肽是由序列識別號1或2所載的胺基酸序列所構成。)。
序列識別號1或2所載的胺基酸序列之N端側及/或C端側添加了胺基酸的胜肽並沒有特別限制,但作為較佳的例子,可列舉出由序列識別號3所載的胺基酸序列(QSQSQ)構成的胜肽、由序列識別號4所載的胺基酸序列(SQSQK)構成的胜肽。
序列識別號3所載的胺基酸序列相當於在序列識別號1所載的胺基酸序列之N端側添加兩個胺基酸(QS)之胺基酸序列,或相當於在序列識別號1所載的胺基酸序列之C端側添加兩個胺基酸(SQ)之胺基酸序列。序列識別號4所載的胺基酸序列相當於在序列識別號1所載的胺基酸序列之N端側添加一個胺基酸(S)且在C端側添加一個胺基酸(K)之胺基酸序列,或相當於在序列識別號2所載的胺基酸序列之N端側添加兩個胺基酸(SQ)之胺基酸序列。
本發明人研究的結果顯示,構成本發明胜肽的三肽(由序列識別號1或2所載的胺基酸序列構成的胜肽)是達到動機提升效果的最小單位。本發明人發現構成本發明的胜肽之胺基酸長度為2以下的部分胜肽(例如QS、QK、SQ等二肽)不能達到足夠的動機提升效果。
本發明的胜肽可透過化學合成、水解天然蛋白質或多肽而獲得。
作為化學合成方法,可列舉出習知的胜肽合成法。具體地,胜肽合成常用的方法可列舉出液相法或固相法。更具體地,可列舉出Fmoc法、Boc法等。可將合成的胜肽純化。作為純化方法,可列舉出例如使用離子交換層析法(ion exchange chromatography)、逆相液相層析法(reversed phase liquid chromatography)、親和層析法(affinity chromatography)等的方法。
作為水解的方法,可列舉出使用水解酶的方法、使用強酸或強鹼的方法等。
在使用水解酶的方法中,能夠使用源自動物、植物或微生物的水解酶(胰蛋白酶、胰凝乳蛋白酶、木瓜蛋白酶、胃蛋白酶、羧肽酶、嗜熱菌蛋白酶等)。作為水解酶,可使用能作為食品使用的微生物(例如,麵包酵母、啤酒酵母等的食用酵母)。
使用水解酶進行水解的條件並沒有特別限制,可根據所使用的酶將pH調整至適當的值,在約30〜70℃的溫度下進行反應30分鐘〜48小時。可從所得的反應溶液將本發明的胜肽純化出來並使用。當水解對象是食品原料時,也能直接使用或是添加到其他食品原料中作為食品供應。
在使用強酸的方法中,能夠使用例如鹽酸、硝酸、硫酸等。在使用強鹼的方法中,能夠使用例如鹼金屬氫氧化物(氫氧化鈉、氫氧化鉀、氫氧化鋰等)、鹼金屬碳酸鹽(碳酸鈉、碳酸鉀等)、鹼金屬碳酸氫鹽(碳酸氫鈉、碳酸氫鉀等)。
使用強酸或強鹼進行水解的條件並沒有特別限制,但可於強酸或強鹼的存在下,在水中於1〜100℃的溫度下進行反應30分鐘〜48小時。調整pH後,可直接使用水解的反應產物,也可藉由純化將本發明的胜肽分離出來並使用。
藉由各種方法獲得的胜肽之胺基酸序列能夠以艾德曼降解法(Edman degradation)從C-端讀取胺基酸序列的蛋白質定序儀(protein sequencer)、GC-MS等分析。
<本發明的組成物>
本發明的組成物至少包括本發明的胜肽,其可由本發明的胜肽構成,也可包括其他成分。
經由攝取本發明的胜肽能夠治療、預防或改善情緒障礙。因此,本發明的組成物以能夠用於治療、預防或改善情緒障礙為佳。
在本發明中,「情緒障礙」是指具有與情緒(情感)相關的障礙的精神疾病。具體地,可列舉出動機低落、憂鬱、和憂鬱性情緒障礙、以及基於這些症狀中的一種以上。根據本發明,在情緒障礙中,能夠特別治療、預防或改善動機低落。
在本發明中,「治療」是指例如延緩情緒障礙的進展以及症狀的治癒等。「預防」是指例如抑制或延緩情緒障礙的發生等。「改善」是指例如緩解、減輕情緒障礙的症狀等。
本發明的組成物能夠製備為任何形式,可將其製備為醫藥品或飲食品。
當將本發明的組成物製備為醫藥品時,能夠製備為口服(oral)投予劑或非經口(parenteral)投予劑。例如,本發明的組成物能夠單獨或與載體、稀釋劑或賦形劑一起製備為以下製劑:錠(裸錠、糖衣錠、發泡錠、膜衣錠、咀嚼錠等)、膠囊、口含錠(troche)、粉末、細粒劑、顆粒劑、液劑、懸濁液(suspension)、乳濁液(emulsion)、糊劑(paste)、乳劑(cream)、注射劑(包括混合在胺基酸輸液和電解質輸液等的輸液中的情況)、腸溶性的錠劑、膠囊劑、緩釋製劑等。
作為載體、稀釋劑或賦形劑,使用在製藥領域中常用並且不與本發明的胜肽反應的物質。例如,可列舉出以下物質:乳糖、葡萄糖、甘露醇(mannitol)、糊精(dextrin)、環糊精(cyclodextrin)、澱粉(starch)、蔗糖、偏矽酸鋁鎂(magnesium aluminometasilicate)、合成矽酸鋁(synthetic aluminum silicate)、羧甲基纖維素鈉(sodium carboxymethyl cellulose)、羥丙基澱粉(hydroxypropyl starch)、羧甲基纖維素鈣(calcium carboxymethyl cellulose)、離子交換樹脂、甲基纖維素(methyl cellulose)、明膠(gelatin)、阿拉伯樹膠(gum arabic)、羥丙基纖維素(hydroxypropyl cellulose)、羥丙基甲基纖維素(hydroxypropyl methylcellulose)、聚乙烯吡咯烷酮(polyvinylpyrrolidone)、聚乙烯醇(polyvinyl alcohol)、輕質無水矽酸(light anhydrous silicic acid)、硬脂酸鎂(magnesium stearate)、滑石粉(talc)、西黃蓍膠(tragacanth)、膨潤土(bentonite)、矽酸鋁鎂(veegum)、氧化鈦(titanium oxide)、去水山梨醇脂肪酸酯(sorbitan fatty acid ester)、硫酸月桂酯鈉(sodium lauryl sulfate)、甘油(glycerin)、脂肪酸甘油酯(fatty acid glycerin ester)、純化的羊毛脂(purified lanolin)、甘油明膠(glycerogelatin)、聚山梨醇酯(polysorbate)、聚乙烯二醇(macrogol)、植物油、蠟(wax)、液體石蠟(liquid paraffin)、白軟石蠟(white petrolatum)、氟碳化物(fluorocarbon)、非離子界面活性劑、丙二醇(propylene glycol)、水等。
當將本發明的組成物製備為飲食品時,能夠將其製備為任何形式,例如,可列舉出以下飲食品:飲料類(咖啡、可可、果汁、清涼飲料、礦物質飲料、茶飲料、綠茶、紅茶、烏龍茶、乳飲料、乳酸菌飲料、優酪乳飲料、碳酸飲料等)、米餅(仙貝、米菓、小米菓等)、口香糖、軟糖、果凍、糖果、餅乾、鹹餅乾(cracker)、甜餅乾(biscuit)、冰品(冰淇淋、冰棒、雪酪(sherbet)、刨冰等)、即食食品(retort food)、果凍狀食品(果凍、寒天、果凍狀飲料等)等。
可將本發明的飲食品製備為所謂的健康食品、機能性食品、營養補助食品、補充劑、特定保健用食品、機能性標示食品、病人用食品、病人用組合食品(厚生勞動省,一種特別用途食品)或高齡者用食品(厚生勞動省,一種特別用途食品)。
能夠根據所得的效果等適當地設定本發明的組成物中之本發明胜肽的量。例如,相對於組成物,本發明的胜肽以調配0.01質量%以上為佳、以1.00質量%以上較佳。再者,相對於組成物,本發明的胜肽以調配100質量%以下為佳、以90質量%以下更佳。當本發明的組成物包括本發明胜肽以外的胜肽時,上述的值為換算成本發明胜肽的量之值。
能夠根據成分的種類、組成物的形式、所得的效果等適當地設定本發明的組成物中除了本發明胜肽之外的成分的量。
本發明組成物的投予方法並沒有特別限制,可為口服給予或非經口給予(注射等)。從容易達到本發明效果的觀點而言,本發明的組成物以口服投予為佳。
本發明組成物的投予量依據投予方法、投予對象的狀態和年齡等而不同,例如,換算為本發明胜肽的量,成年人每1天以0.01 mg/kg~500 mg/kg為佳,以0.05 mg/kg~100 mg/kg較佳,以0.1~30 mg/kg更佳。在上述範圍內,有投予量越多,越容易達到本發明效果的傾向。
作為本發明組成物的製造方法,能夠根據所欲得到的形式採用習知的方法。
<治療、預防或改善情緒障礙之方法>
透過將本發明的組成物投予至對象,能夠治療、預防或改善情緒障礙。
能夠根據組成物的形式適當地選擇投予方法。
能夠根據投予對象的狀態(症狀、年齡、體重等)適當地選擇投予次數、投予間隔、投予量。
投予對象並沒有特別限制,可列舉出人類、人類以外的哺乳類(狗、貓、家畜(牛、豬、綿羊、山羊等)等)等。
[實施例]
以下將顯示實施例並具體地說明本發明,但本發明不限於這些實施例。
<胜肽的製作>
透過Fmoc方法合成,接著以逆相HPLC進行純化而製作了以下8種胜肽。胜肽1至4相當於本發明的胜肽。
(胜肽1)由序列識別號1所示的胺基酸序列(QSQ)構成的胜肽。
(胜肽2)由序列識別號2所示的胺基酸序列(SQK)構成的胜肽。
(胜肽3)由序列識別號3所示的胺基酸序列(QSQSQ)構成的胜肽。
(胜肽4)由序列識別號4所示的胺基酸序列(SQSQK)構成的胜肽。
(胜肽5)由序列識別號5所示的胺基酸序列(QS)構成的胜肽。
(胜肽6)由序列識別號6所示的胺基酸序列(QK)構成的胜肽。
(胜肽7)由序列識別號7所示的胺基酸序列(SQ)構成的胜肽。
(胜肽8)由序列識別號8所示的胺基酸序列(QSQSQK)構成的胜肽。
透過以下方法將製作好的各個胜肽投予至小鼠(ddy小鼠(5週大的雄鼠,體重24~28g)),並且藉由尾部懸吊試驗評估動機提升效果。其結果顯示於圖1。
<胜肽的投予>
將各個胜肽溶解在生理食鹽水中,將胜肽3、4、8以每公斤體重0.3 mg的量、將胜肽1、2、5、6、7以每公斤體重0.2 μmol的量口服投予至小鼠(n=5)。作為對照,準備了僅口服生理食鹽水的小鼠(n=5)。對每隻小鼠進行下述的尾部懸吊試驗,評估本發明胜肽的動機提升效果。
<尾部懸吊試驗(Tail suspension test):動機提升效果的評估>
自投予胜肽30分鐘後,將每隻小鼠的尾巴懸吊在地板上方30 cm處。接下來,從試驗開始(0分鐘)的6分鐘內,測量逃避行為開始之後確認到小鼠處於靜止狀態的時間(靜止時間;Immobility time),並計算平均值。靜止狀態被認為是「絕望狀態」,靜止時間越短,則可評估為越能改善絕望狀態、越能提升動機。因此,在這項試驗中,具有動機提升效果的物質對於治療、預防或改善情緒障礙是有效的。
<結果>
圖1的結果顯示出將對照的靜止時間當作「100」時,投予了各個胜肽的小鼠的靜止時間之相對值。圖1中的值越小,可評估為越能改善絕望狀態、越能提升動機。
如圖1所示,與對照相比,投予了本發明胜肽(胜肽1至4)的小鼠之靜止時間較短。因此,顯示出本發明的胜肽達到了動機提升效果,對於情緒障礙的治療和預防是有用的。
此外,在本發明的胜肽中,指定的三肽(胜肽1和2)的動機提升效果特別好。
另一方面,與對照相比,投予了具有以QS、QK、SQ所示之胺基酸序列的二肽(胜肽5至7)的小鼠之靜止時間幾乎沒有減少。
從以上的結果可知,本發明的胜肽具有動機提升效果,並且,構成本發明胜肽的三肽(胜肽1和2)是達到動機提升效果的最小單位。
無。
﹝圖1﹞使用已口服給予各種胜肽的小鼠進行尾部懸吊試驗的結果。
Claims (7)
- 一種胜肽,具有序列識別號1或序列識別號2所載的胺基酸序列,且其胺基酸長度為3以上5以下。
- 如請求項1所述之胜肽,該胜肽是由序列識別號1、序列識別號2、序列識別號3、或序列識別號4所載的胺基酸序列所構成。
- 一種用於治療、預防或改善情緒障礙的組成物,包括如請求項1或2所述之胜肽。
- 如請求項3所述之組成物,該情緒障礙係擇自於由動機低落、憂鬱、和憂鬱性情緒障礙、以及基於前述症狀所組成之群組的一種以上。
- 如請求項3或4所述之組成物,其為醫藥品。
- 如請求項3或4所述之組成物,其為飲食品。
- 預防或改善情緒障礙之方法,包括投予如請求項3至請求項5中任一項所述之組成物。
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