TWI457131B - 胜肽及其於抑制血管收縮素轉換酶之用途 - Google Patents
胜肽及其於抑制血管收縮素轉換酶之用途 Download PDFInfo
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- TWI457131B TWI457131B TW101132603A TW101132603A TWI457131B TW I457131 B TWI457131 B TW I457131B TW 101132603 A TW101132603 A TW 101132603A TW 101132603 A TW101132603 A TW 101132603A TW I457131 B TWI457131 B TW I457131B
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Description
本發明係有關可用於抑制血管收縮素轉換酶之新穎之胜肽。
血管收縮素轉換酶(Angiotensin Converting Enzyme,ACE)主要存在於人體的血管內皮細胞、肺部、腎臟及腦部。該酵素可將無活性的血管收縮素I上C-端的兩個胺基酸(His-Leu)移除，得到經活化的血管收縮素II，造成血管的收縮及血壓的上升(Maruyama,S.and Suzuki,H.,A peptide inhibitor of angiotensin I converting enzyme in the tryptic hydrolysate of casein,Agric.Biol.Chem.,1982,46：1393-1394)。Maruyama,S.等人(Angiotensin I-converting enzyme inhibitor derived from an enzymatic hydrolysate of casein.II.Isolation and bradykinin-potentiating activity on the uterus and the ileum of rats,Agric.Biol.Chem.,1985；49：1405-1409)發現ACE可將血管舒張激肽(具有血管擴張活性)去活化，而造成血壓升高的現象。因此，血管收縮素轉換酶抑制劑(ACEI)與ACE的結合，可減少血管收縮素II的形成及血管舒張激肽之去活化，故ACEI的施用可改善高血壓的症狀。
Krysiak,R.等人(The effect of angiotensin-converting enzyme inhibitors on plasma adipokine levels in normotensive patients with coronary artery disease,Polish
Journal of Endocrinology,2010,61：280-286)揭露ACE抑制劑對罹患冠狀動脈疾病(CAD)的病患為一種有效的治療劑，即使該等病患的血壓在正常的限制範圍內。美國專利第8,021,697 B2號揭示ACE抑制劑可藉由降低脂肪的整體百分率及/或增加瘦肉質量對脂肪質量的比例來改變身體質量的分布。換言之，ACE抑制劑可降低由膳食中所產生脂肪之量。
除化學合成的藥物外，已發現多種具有不同長度及胺基酸殘基的胜肽可有效抑制ACE。該等具有ACE抑制活性的胜肽可自食品中分離獲得，該等食品包含，如動物或植物蛋白質的水解物，例如酪蛋白(Maruyama及Suzuki,1982；Maruyama,S.及Suzuki,H.,1985；及Yamamoto,N.等人.,Antihypertensive effect of peptides derived from casein by an extracellular proteinase fromLactobacillus helveticus
CP790,J.Dairy Sci.,1994,77：917-922)、玉米蛋白(如α-玉米醇溶蛋白(α-zein))(Miyoshi等人，Structures and activity of angiotensin-converting enzyme inhibitors in an α-zein hydrolysate,Agric.Biol.Chem.,1991,55：1313-1318及Yano,S.等人，Isolation from α-zein of thermolysin peptides with angiotensin I-converting enzyme inhibitory activity,Biosci.Biotech.Biochem.,1996,60：661-663)、沙丁魚(Matsui,T.等人，Inhibition of angiotensin I-converting enzyme byBacillus licheniformis
alkaline protease hydrolyzates derived from sardine muscle,Biosci.Biotech.Biochem.,
1993,57：922-925及Matsufuji,H.等人，Angiotensin I-converting enzyme inhibitory peptides in an alkaline protease hydrolyzate derived from sardine muscle,Biosci.Biotech.Biochem.,1994,58：2244-2245)及鰹魚(Matsumura,N.等人，Isolation and characterization of angiotensin I-converting enzyme inhibitory peptides derived from bonito bowels,Biosci.Biotech.Biochem.,1993,57：1743-1744及Fujita,H.等人，Antihypertensive effect of thermolysin digest of dried bonito in spontaneously hypertensive rat,Clin.Exp.Pharmacol.Physiol.Suppl.,1995,22：S304-S305)；及發酵食品，例如清酒與酒渣(Saito,Y.等人，Structure and activity of angiotensin I converting enzyme inhibitory peptides from sake and sake lees,Biosci.Biotechnol.Biochem.,1994,58：1767-1771)、醬油(Kinoshita,E.等人，Purification and identification of an angiotensin I-converting enzyme inhibitor from soy sauce,Biosci.Biotechnol.Biochem.,1993,57：1107-1110)、乳酪(Okamoto,A.等人，Angiotensin I converting enzyme inhibitory activities of various fermented foods,Biosci.Biotechnol.Biochem.,1995,59：1147-1149)及酸乳(Masuda,O.等人，Antihypertensive peptides are present in aorta after oral administration of sour milk containing these peptides to spontaneously hypertensive rats,J.Nutr.,1996,126：3063-3068)。
日本專利特開第7289281(A)號揭示將大豆以黑麴菌(Aspergillus niger
)發酵後的產物具有ACE抑制活性。日本專利特開第42999911(A)號揭示將大豆以鳳梨酶(bromelain；一種水解酶)水解後的胜肽產物具有ACE抑制活性。日本專利特開第2002053595(A)號揭示來自大豆水解物的胜肽可抑制ACE活性。日本專利特開第6298794(A)號揭示以源自動物及植物(如魚肉、豬肉及雞肉)的蛋白質來製備ACEI之方法。該水解物經離心、過濾、濃縮及樹脂吸附後，所獲得的胜肽具有ACE抑制活性。日本專利特開第5331192(A)號揭示將乾柴魚(katsuobushi)以嗜熱菌蛋白酶(thermolysin)水解後可產生具有ACE抑制活性的胜肽。日本專利特開第4264098(A)號揭示利用無脂肌肉製備具有ACE抑制活性胜肽的方法。美國專利第6,767,990 B1號揭示由雞殘渣水解物中分離出的之胜肽。美國公開第20120107409 A1揭示製備魚皮發酵產物之方法，該發酵產物可於抑制酪胺酸酶活性、抑制血管收縮素轉換酶活性及/或增進纖維母細胞之存活率。
惟在此ACE抑制劑之領域中，仍需要開發特別是來自天然來源，且較化學合成化合物更安全的胜肽。
本發明係關於可抑制ACE之新穎胜肽：Tyr-Tyr、Thr-Phe、Thr-Ser-Phe、Asn-Asp-Glu-Gly(SEQ ID NO：1)、Phe-Asp-Thr、Phe-Val-Asn-His-Phe(SEQ ID NO：2)、Gly-Leu-Phe、Val-Val-Asn、Thr-Tyr-Ala、Asn-Ser-Leu、Leu-
Phe、Gly-Asn-Phe、Lys-Lys、Val-Gly-Gly-Ser(SEQ ID NO：3)及Trp-Asn。
本發明之另一態樣係關於一種組合物，其包含有效量之一或多種選自下列之胜肽：Tyr-Tyr、Thr-Phe、Thr-Ser-Phe、Asn-Asp-Glu-Gly(SEQ ID NO：1)、Phe-Asp-Thr、Phe-Val-Asn-His-Phe(SEQ ID NO：2)、Gly-Leu-Phe、Val-Val-Asn、Thr-Tyr-Ala、Asn-Ser-Leu、Leu-Phe、Gly-Asn-Phe、Lys-Lys、Val-Gly-Gly-Ser(SEQ ID NO：3)、Trp-Asn、Phe-Val及Leu-Leu，及一或多種載劑、稀釋劑、溶劑、著色劑、抗氧化物、惰性物質及/或添加劑。
本發明之進一步態樣係提供用於預防及治療有此需要個體中一或多種與血管收縮素轉換酶有關之症狀的方法，其包含對該個體投與本發明之組合物或有效量之一或多種選自下列之胜肽：Tyr-Tyr、Thr-Phe、Thr-Ser-Phe、Asn-Asp-Glu-Gly(SEQ ID NO：1)、Phe-Asp-Thr、Phe-Val-Asn-His-Phe(SEQ ID NO：2)、Gly-Leu-Phe、Val-Val-Asn、Thr-Tyr-Ala、Asn-Ser-Leu、Leu-Phe、Gly-Asn-Phe、Lys-Lys、Val-Gly-Gly-Ser(SEQ ID NO：3)、Trp-Asn、Phe-Val及Leu-Leu。
本發明提供具有下列序列之經分離胜肽：Tyr-Tyr；Thr-Phe；Thr-Ser-Phe；Asn-Asp-Glu-Gly(SEQ ID NO：1)；
Phe-Asp-Thr；Phe-Val-Asn-His-Phe(SEQ ID NO：2)；Gly-Leu-Phe；Val-Val-Asn；Thr-Tyr-Ala；Asn-Ser-Leu；Leu-Phe；Gly-Asn-Phe；Lys-Lys；Val-Gly-Gly-Ser(SEQ ID NO：3)；及Trp-Asn。
此等胜肽可由天然物質(如動物(例如魚或雞)及植物(例如大豆)蛋白質)之水解物中分離並純化獲得。例如，該等蛋白質可根據美國專利第6,767,990 B1號、美國專利第8,021,697 B2號及美國公開第20120107409 A1所揭示之方法獲得，該等文獻的內容併入作為本案之部分。
本發明具有ACE抑制活性之胜肽亦可以習知化學合成法製備。例如，氮疊化合物法、酸氯化物法、酸酐法、混合酸酐法、DCC法、活性酯法、碳基咪唑法、氧化還原法或DCC活化法(參見如Schroder與Luhke,The Peptide,Vol.1(1966),Academic Press,New York,USA出版，或Izumiya等人，Peptide synthesis,Maruzen Co.,Ltd(1975)出版，該等文獻的內容併入作為本案之部分。)。此等胜肽之合成可在固相或液相中進行。具有側鏈官能基如色胺酸及絲胺酸之胺基酸，較佳係將其側鏈官能基團，以已知之保護基
團如苄氧羰基、第三丁氧基羰基或苄基等進行保護。此保護基團可再以任何習知之方法移除。
或者，根據胺基酸序列，其亦可藉由將該胜肽之胺基酸序列之對應核苷酸序列選殖入適當的載體，再由適當的細胞、植物或動物表現。
根據本發明，所謂「經分離」或「分離」意表該物質已由其原始環境(如其是天然存在之物質，意指天然環境)中移出。「經分離」並不意表其必然可擴張解釋為該物質中之所有其他物質(如雜質)已被移除而該物質已被純化。
本發明之進一步態樣係提供一種組合物，其包含有效量之一或多種選自下列之胜肽：Tyr-Tyr、Thr-Phe、Thr-Ser-Phe、Asn-Asp-Glu-Gly(SEQ ID NO：1)、Phe-Asp-Thr、Phe-Val-Asn-His-Phe(SEQ ID NO：2)、Gly-Leu-Phe、Val-Val-Asn、Thr-Tyr-Ala、Asn-Ser-Leu、Leu-Phe、Gly-Asn-Phe、Lys-Lys、Val-Gly-Gly-Ser(SEQ ID NO：3)、Trp-Asn、Phe-Val及Leu-Leu。於本發明之另一態樣中，該組合物包含有效量之一或多種選自下列之胜肽：Tyr-Tyr、Thr-Phe、Thr-Ser-Phe、Asn-Asp-Glu-Gly(SEQ ID NO：1)、Phe-Asp-Thr、Phe-Val-Asn-His-Phe(SEQ ID NO：2)、Gly-Leu-Phe、Val-Val-Asn、Thr-Tyr-Ala、Asn-Ser-Leu、Leu-Phe、Gly-Asn-Phe、Lys-Lys、Val-Gly-Gly-Ser(SEQ ID NO：3)、Trp-Asn、Phe-Val及Leu-Leu，限制條件為Phe-Val及Leu-Leu不會同時存在。本發明之組合物係為醫藥組合物或食品組合物。本發明之醫藥組合物或食品組合物可
藉由本發明所屬技術領域中所普遍知悉之操作方法製備，如將胜肽產物與一或多種習知之載劑、稀釋劑、溶劑、著色劑、抗氧化劑、惰性物質及/或添加劑將組合物調配成錠劑、膠囊、粉劑、粒劑、沖劑、濃縮劑、飲料、健康食品、食品添加劑或飼料。
根據本發明，本發明所提供的活性成分的「有效量」意表該成分的量足以達到所欲之ACE活性的抑制。該所需的正確量可依不同個體的狀況而改變，如該個體之疾病狀態、生理條件、年齡、性別、種族及體重；特定的個人及組合物的配方等。因此，並無法特別界定確實的「有效量」為何。然而，本技術領域中之技藝人士可使用例行的實驗測定適當的有效量。
本發明之另一態樣係提供一種用於預防或治療有此需要個體中一或多種與血管收縮素轉換酶有關之症狀的方法，其包含對該個體投與本發明之組合物或有效量之一或多種選自下列之胜肽：Tyr-Tyr、Thr-Phe、Thr-Ser-Phe、Asn-Asp-Glu-Gly(SEQ ID NO：1)、Phe-Asp-Thr、Phe-Val-Asn-His-Phe(SEQ ID NO：2)、Gly-Leu-Phe、Val-Val-Asn、Thr-Tyr-Ala、Asn-Ser-Leu、Leu-Phe、Gly-Asn-Phe、Lys-Lys、Val-Gly-Gly-Ser(SEQ ID NO：3)、Trp-Asn、Phe-Val及Leu-Leu。
根據本發明，所謂「預防性(preventing)」或「預防(prevention)」意表當使用於有關病況時，包含在病況開始前向個體投與一藥劑後，相較於未接受該藥劑之個體，該
經投藥之個體藥理病況的症狀之出現頻率或嚴重度會減緩，或開始之時間會延後。
根據本發明，所謂「治療性(treating)」或「治療(treatment)」意表當施用時，可回轉疾病或病況或其之一或多種症狀、減輕疾病或病況或其之一或多種症狀、抑制疾病或病況或其之一或多種症狀的發展，或者改善疾病或病況或其之一或多種症狀。
根據本發明，所謂「個體」意表任何動物，較佳為哺乳動物，且更佳為人類。個體的例子包括人類、非人靈長類、齧齒類、天竺鼠、兔子、羊、豬、山羊、牛、馬、狗及貓。
本發明技術領域之技藝人士瞭解ACE與如心血管併發症及脂肪細胞肥大及/或增殖等症狀有關。因此，本發明之胜肽及組合物具有治療或預防動脈性高血壓、心臟收縮性高血壓、周邊血管疾病、動脈粥樣硬化、再狹窄症、心臟衰竭、心功能不全、血栓形成及任何血栓栓塞症、心絞痛、腦血管意外事件、冠狀動脈疾病、心肌梗塞、血管再造及其組合，及\或減少腹部脂肪及/或皮下脂肪之功效。
下列實施例係以進一步說明本發明之可實施性，俾使本發明技術內容更加具體，然非欲以侷限本發明之範圍。其它熟習該項技術者基於習知技藝之教示而可達成的本發明之種種變化及改良，皆應歸屬本發明範疇。
於25公斤之脫脂大豆粉(購自中聯油脂公司)中加入該脫脂大豆粉一半重量的水，並將其混合。將該混合物於100℃下蒸煮45分鐘後冷卻至45℃。將4.2克含Aspergillus sojae
之麴粉(購自日本樋口公司)加入該混合物中並混合均勻，且於相對濕度95%、溫度27℃下發酵48小時。於此發酵產物中加入發酵產物三倍重量的水，再將混合物於45℃下水解8小時。以濾布使水解物中之液體部分與大豆殘渣分離。
將實例1中所得之大豆殘渣與1 L的水混合均勻，並調整混合物之pH值至2.0。將0.5 g的胃蛋白酶加入混合物中，並使其在37℃下水解2小時獲得水解物。以NaHCO3
將水解物的之pH值調整至7.2。將0.5 g胰蛋白酶及0.5 g胰凝乳蛋白酶加入該水解物中，並使其在37℃下進一步水解2.5小時以獲得一進一步水解物。將該進一步水解物以沸水浴加熱15分鐘以使酵素去活化。冷卻後，將該進一步水解物在10,000 rpm下離心10分鐘，以使上清液與固體沉澱物分離。將該上清液冷凍乾燥而獲得43 g之乾粉末，其中蛋白質的含量為24.5%。
將乾粉末溶於水中以配製成1%(w/v)之水溶液。將該水溶液以孔徑為0.45 μm的薄膜過濾。將濾液以高效率液相層析質譜儀(HPLC)進行分析。所使用尺寸篩除管柱(size exclusion column)的條件如下：系統：AKTA純化器(purifier)
沖離管柱：Superdex Peptide HR 10/30
樣品量：500 μL
溶離液：5%醇溶於純水
流速：0.25 mL/min
檢出器：214 nm。
每20分鐘收取5 mL由管柱中沖離出的樣本，並總共收取7個沖離餾份。上述HPLC程序重複60次，將所有收取的對應餾份分別混合在一起，並經凍乾後獲得7個乾粉末樣本。再將各乾粉末樣本溶於水中以製備1%(w/v)之水溶液。所有水溶液之ACE抑制活性係個別以Vermeirssen,V.等人(Optimisation and validation of an angiotensin-converting enzyme inhibition assay for the screening of bioactive peptides,J.Biochem.Biophys.Methods,2002,51：75-87)所揭示之方法測量。如表1所示，於所有溶液中，餾份3、4及5之溶液的ACE抑制活性較強，且以餾份3之溶液的活性最強。
將第3餾份之溶液再以Sephasil Peptide RP-18管柱，依下列條件沖離：系統：AKTA純化器
沖離管柱：Sephasil Peptide RP-18
樣品量：100 μL
溶離液A：含有0.1%三氟乙酸的H2
O
溶離液B：含有0.1%三氟乙酸的MeOH
梯度：0%的B為時5min
0-100%的B為時30 min
100%的B為時10 min
流速：1 mL/min
檢出器：214 nm。
每5分鐘收取由管柱中沖離出的樣本，並總共收取6個沖離餾份。上述沖離程序重複250次。將所有的6個沖離餾份分別混合在一起，並經凍乾後獲得6個乾粉末樣本。再將各乾粉末樣本溶於1 mL水中以製備水溶液。測量各餾份之水溶液之ACE抑制活性。其結果顯示，餾份3-2、3-3及3-4之抑制活性較佳，且以餾份3-4之抑制活性最佳(見下示之表2)。
將餾份3-4經Luna C18(2)管柱以下列條件沖離後，再以質譜儀檢測m/z 100-800之物質：泵：Water 600
沖離管柱：Luna C18(2)150＊
2 mm,3 μ
樣品量：20 μL
溶離液A：含有0.1%甲酸的H2
O
溶離液B：含有0.1%甲酸的乙腈
梯度：5%的B為時5 min
5-95%的B為時24 min
95%的B為時10 min
流速：0.2 mL/min
檢出器：Quattro LC MS/MS。
結果鑑定出17個胜肽。根據Pripp,A.H.等人(Quantitative structure-activity relationship modeling of ACE-inhibitory peptides derived from milk proteins,Eur.Food Res.Technol.,2004,219：579-583)所揭示的方法計算該17個胜
肽的ACE抑制活性。根據下示表3所示的結果可發現，所有的該17個胜肽皆可有效地抑制ACE之活性，且因此可用作ACE抑制劑。
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<120> 貹肽及其於抑制血管收縮素轉換酶之用途
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Claims (17)
- 一種經分離之胜肽，其係選自下列所組成之群：Tyr-Tyr、Thr-Phe、Thr-Ser-Phe、Asn-Asp-Glu-Gly(SEQ ID NO：1)、Phe-Asp-Thr、Phe-Val-Asn-His-Phe(SEQ ID NO：2)、Val-Val-Asn、Thr-Tyr-Ala、Asn-Ser-Leu、Gly-Asn-Phe、Lys-Lys、Val-Gly-Gly-Ser(SEQ ID NO：3)及Trp-Asn。
- 一種用於預防或治療一或多種與血管收縮素轉換酶有關之症狀的醫藥組合物，其包含有效量之一或多種選自下列之胜肽：Tyr-Tyr、Thr-Phe、Thr-Ser-Phe、Asn-Asp-Glu-Gly(SEQ ID NO：1)、Phe-Asp-Thr、Phe-Val-Asn-His-Phe(SEQ ID NO：2)、Val-Val-Asn、Thr-Tyr-Ala、Asn-Ser-Leu、Gly-Asn-Phe、Lys-Lys、Val-Gly-Gly-Ser(SEQ ID NO：3)、Trp-Asn及Phe-Val，及一或多種載劑、稀釋劑、溶劑、著色劑、抗氧化物、惰性物質及/或添加劑。
- 如請求項2之醫藥組合物，其中該症狀為心血管併發症。
- 如請求項3之醫藥組合物，其中該心血管併發症係選自動脈性高血壓、心臟收縮性高血壓、周邊血管疾病、動脈粥樣硬化、再狹窄症、心臟衰竭、心功能不全、血栓形成及任何血栓栓塞症、心絞痛、腦血管意外事件、冠狀動脈疾病、心肌梗塞、血管再造及其組合。
- 如請求項2之醫藥組合物，其中該症狀為脂肪細胞肥大 及/或增殖。
- 如請求項2或5之醫藥組合物，其係用於減少腹部脂肪及/或皮下脂肪。
- 一種用於預防或治療一或多種與血管收縮素轉換酶有關之症狀的食品組合物，其包含有效量之一或多種選自下列之胜肽：Tyr-Tyr、Thr-Phe、Thr-Ser-Phe、Asn-Asp-Glu-Gly(SEQ ID NO：1)、Phe-Asp-Thr、Phe-Val-Asn-His-Phe(SEQ ID NO：2)、Val-Val-Asn、Thr-Tyr-Ala、Asn-Ser-Leu、Gly-Asn-Phe、Lys-Lys、Val-Gly-Gly-Ser(SEQ ID NO：3)、Trp-Asn及Phe-Val，及一或多種載劑、稀釋劑、溶劑、著色劑、抗氧化物、惰性物質及/或添加劑。
- 如請求項7之食品組合物，其係為健康食品或食品添加劑。
- 如請求項7或8之食品組合物，其中該症狀為心血管併發症。
- 如請求項9之食品組合物，其中該心血管併發症係選自動脈性高血壓、心臟收縮性高血壓、周邊血管疾病、動脈粥樣硬化、再狹窄症、心臟衰竭、心功能不全、血栓形成及任何血栓栓塞症、心絞痛、腦血管意外事件、冠狀動脈疾病、心肌梗塞、血管再造及其組合。
- 如請求項7之食品組合物，其中該症狀為脂肪細胞肥大及/或增殖。
- 如請求項7或11之食品組合物，其係用於減少腹部脂肪 及/或皮下脂肪。
- 一種一或多種選自Tyr-Tyr、Thr-Phe、Thr-Ser-Phe、Asn-Asp-Glu-Gly(SEQ ID NO：1)、Phe-Asp-Thr、Phe-Val-Asn-His-Phe(SEQ ID NO：2)、Gly-Leu-Phe、Val-Val-Asn、Thr-Tyr-Ala、Asn-Ser-Leu、Leu-Phe、Gly-Asn-Phe、Lys-Lys、Val-Gly-Gly-Ser(SEQ ID NO：3)、Trp-Asn及Phe-Val的胜肽之用途，其係用以製備用於預防或治療一或多種與血管收縮素轉換酶有關之症狀的藥物。
- 如請求項13之用途，其中該症狀為心血管併發症。
- 如請求項14之用途，其中該心血管併發症係選自動脈性高血壓、心臟收縮性高血壓、周邊血管疾病、動脈粥樣硬化、再狹窄症、心臟衰竭、心功能不全、血栓形成及任何血栓栓塞症、心絞痛、腦血管意外事件、冠狀動脈疾病、心肌梗塞、血管再造及其組合。
- 如請求項13之用途，其中該症狀為脂肪細胞肥大及/或增殖。
- 如請求項13或16之用途，其係用於減少腹部脂肪及/或皮下脂肪。
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Non-Patent Citations (2)
| Title |
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| 21世紀營養革命-生物活性胜肽【www.grobest.com/yecherng/pdf/ani2006023.pdf】,2007/01/03 * |
| 黑龙江医学，第27卷，第3期，2003年，第184-185頁 * |
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