CN114641484A - 肽、组合物及治疗、预防或改善心境障碍的方法 - Google Patents
肽、组合物及治疗、预防或改善心境障碍的方法 Download PDFInfo
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Abstract
本发明的技术问题在于,提供一种能够治疗、预防或改善心境障碍的新型肽。本发明提供一种肽,具有序列号1或序列号2所述的氨基酸序列,且为3以上且5以下的氨基酸长度。该肽可以由序列号1、序列号2、序列号3或序列号4所述的氨基酸序列构成。
Description
技术领域
本发明涉及一种肽、组合物、及治疗、预防或改善心境障碍的方法。
背景技术
反映当代的高压社会,以欲望降低或抑郁症等为代表的心境障碍的增加成为问题。对于作为心境障碍的病因之一的焦虑感而言,原本需要将其作为用于生物回避危险的警告,但过度的焦虑感会关系到心境障碍的发病或症状的发展,期待开发出一种缓解焦虑感的食品或药品。
例如,在专利文献1中记载了规定的二肽适合作为抗焦虑药等。
现有技术文献
专利文献
专利文献1:国际公开第2013/129220号公报
发明内容
发明所要解决的技术问题
但是,对能够治疗、预防或改善心境障碍的功能性原材料存在进一步的需求。
本发明是鉴于上述情况而作出的,其目的在于,提供一种能够治疗、预防或改善心境障碍的新型肽。
用于解决问题的技术方案
本发明人等发现根据由特定的氨基酸序列构成的肽能够解决上述技术问题,从而完成了本发明。具体而言,本发明提供以下的技术方案。
(1)一种肽,具有序列号1或序列号2所述的氨基酸序列,且为3以上且5以下的氨基酸长度。
(2)在(1)所述的肽中,所述肽由序列号1、序列号2、序列号3或序列号4所述的氨基酸序列构成。
(3)一种组合物,包含(1)或(2)所述的肽,且用于心境障碍的治疗、预防或改善。
(4)在(3)所述的组合物中,所述心境障碍为选自由欲望降低、抑郁及抑郁性心境障碍、以及基于它们的症状组成的组中的一种以上。
(5)在(3)或(4)所述的组合物中,所述组合物为药品。
(6)在(3)或(4)所述的组合物中,所述组合物为饮食品。
(7)一种治疗、预防或改善心境障碍的方法,将(3)~(5)中任一所述的组合物进行给药。
发明效果
根据本发明,提供一种能够治疗、预防或改善心境障碍的新型肽。
附图说明
图1是使用了口服给药各种肽的小鼠而得到的悬尾试验的结果。
具体实施方式
以下,详细地说明本发明的实施方式。此外,本发明并不限定于以下的实施方式。
<本发明的肽>
本发明的肽具有序列号1所述的氨基酸序列(QSQ)或序列号2所述的氨基酸序列(SQK),为3以上且5以下的氨基酸长度。此外,以下,将氨基酸序列的N末端置于左端,以从N末端到C末端的方式进行记载。
本发明人等基于各种肽混合物的同时分析信息、对情绪行为产生影响的已知的肽的结构-活性相关信息进行了研究,结果发现了对心境障碍的治疗等显示出效果的新型肽,即上述肽。
本发明的肽可以为由序列号1或2所述的氨基酸序列构成的肽(三肽),也可以为在序列号1或2所述的氨基酸序列的N末端侧和/或C末端侧附加任意的氨基酸而得到的肽。
此外,在序列号1所述的氨基酸序列中,N末端的氨基酸为Q(谷氨酰胺),C末端的氨基酸为Q(谷氨酰胺)。在序列号2所述的氨基酸序列中,N末端的氨基酸为S(丝氨酸),C末端的氨基酸为K(赖氨酸)。
本发明的肽的氨基酸长的上限为5以下的氨基酸长度,优选为4以下的氨基酸长度。最优选为,本发明的肽的氨基酸长度为3(即,最优选为,本发明的肽由序列号1或2所述的氨基酸序列构成)。
作为在序列号1或2所述的氨基酸序列的N末端侧和/或C末端侧附加氨基酸而得到的肽,虽然没有特别限定,但作为优选例,可列举出由序列号3所述的氨基酸序列(QSQSQ)构成的肽、由序列号4所述的氨基酸序列(SQSQK)构成的肽。
此外,序列号3所述的氨基酸序列相当于在序列号1所述的氨基酸序列的N末端侧附加两个氨基酸(QS)而得到的氨基酸序列,或者相当于在序列号1所述的氨基酸序列的C末端侧附加了两个氨基酸(SQ)而得到的氨基酸序列。序列号4所述的氨基酸序列相当于在序列号1所述的氨基酸序列的N末端侧附加一个氨基酸(S),且在C末端侧附加一个氨基酸(K)而得到的氨基酸序列,或者相当于在序列号2所述的氨基酸序列的N末端侧附加两个氨基酸(SQ)而得到的氨基酸序列。
本发明人等的研究结果表明,构成本发明的肽的三肽(由序列号1或2所述的氨基酸序列构成的肽)为用于实现欲望提高效果的最少单位。可知构成本发明的肽的2氨基酸长度以下的部分肽(例如,QS、QK、SQ等二肽)无法实现充分的欲望提高效果。
本发明的肽能够通过化学合成、天然的蛋白质或多肽的水解而得到。
作为化学合成的方法,可列举出公知的肽合成法。具体而言,可列举出作为在肽合成中通常使用的方法的液相法或固相法。更具体而言,可列举出Fmoc法、Boc法等。合成的肽可以进行纯化。作为纯化方法,例如可列举出使用了离子交换色谱、反相液相色谱、亲和色谱等的方法。
作为水解的方法,可列举出使用了水解酶的方法、使用了强酸或强碱的方法等。
在使用了水解酶的方法中,可以使用源自动物、植物或微生物的水解酶(胰蛋白酶、糜蛋白酶、木瓜蛋白酶、胃蛋白酶、羧肽酶、嗜热菌蛋白酶等)。作为水解酶,可以使用能够作为食品使用的微生物(例如,面包酵母、啤酒酵母等食用酵母)等。
作为使用了水解酶的水解的条件,虽然没有特别限定,但可以根据使用的酶将pH调节为适当的值,在30~70℃左右的温度下反应30分钟~48小时。也可以从得到的反应液中对本发明的肽进行纯化来使用。在水解的对象为食品原材料的情况下,也可以直接或添加于其他的食品原材料中将其用作食品。
在使用了强酸的方法中,例如可以使用盐酸、硝酸、硫酸等。在使用了强碱的方法中,例如可以使用碱金属氢氧化物(氢氧化钠、氢氧化钾、氢氧化锂等)、碱金属碳酸盐(碳酸钠、碳酸钾等)、碱金属碳酸氢盐(碳酸氢钠、碳酸氢钾等)。
作为使用了强酸或强碱的水解的条件,虽然没有特别限定,但可以在强酸或强碱的存在下,在水中,于1~100℃的温度下使其反应30分钟~48小时。水解的反应产物可以在对pH进行调节之后直接使用,也可以通过纯化将本发明的肽离析来使用。
通过各种方法得到的肽的氨基酸序列可以通过利用埃德曼降解法从C-末端读取氨基酸序列的蛋白质测序仪、GC-MS等进行分析。
<本发明的组合物>
本发明的组合物至少包含本发明的肽,可以由本发明的肽构成,也可以包含其他的成分。
通过摄取本发明的肽,可以治疗、预防或改善心境障碍。因此,本发明的组合物可以优选用于心境障碍的治疗、预防或改善。
在本发明中,“心境障碍”是指,具有与情感(感情)有关的障碍的精神疾病。具体而言,可列举出欲望降低、抑郁及抑郁性心境障碍、以及基于他们的症状中的一种以上。根据本发明,可以治疗、预防或改善心境障碍中的尤其欲望降低。
在本发明中,“治疗”是指,例如心境障碍的发展的延缓以及症状的治愈等。“预防”是指,例如心境障碍的发病的抑制或延缓等。“改善”是指,例如心境障碍的症状的缓解、减轻等。
本发明的组合物可以制备为任意的形态,也可以制备为药品、饮食品。
在将本发明的组合物制备为药品的情况下,可以将其制备为口服给药剂或非口服给药剂。本发明的组合物例如可以单独用本发明的肽,或者与载体、稀释剂或赋形剂一起制备为以下的制剂:片剂(素片、糖衣片、泡腾片、薄膜包衣片、咀嚼片等)、胶囊、含片、粉末、细粒剂、颗粒剂、液体剂、悬浊液、乳浊液、糊剂、膏剂、注射剂(包括与氨基酸输液、电解质输液等输液配混的情况)、肠溶性的片剂、胶囊剂、缓释性制剂等。
作为载体、稀释剂或赋形剂,可以使用在制剂领域中常用且不与本发明的肽反应的物质。例如,可列举出以下的物质:乳糖、葡萄糖、甘露醇、糊精、环糊精、淀粉、蔗糖、偏硅酸铝酸镁、合成硅酸铝、羧甲基纤维素钠、羟丙基淀粉、羧甲基纤维素钙、离子交换树脂、甲基纤维素、明胶、阿拉伯胶、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、聚乙烯醇、轻质硅酸酐、硬脂酸镁、滑石、黄蓍胶、膨润土、蜂胶、氧化钛、山梨糖醇酐脂肪酸酯、月桂基硫酸钠、甘油、脂肪酸甘油酯、精制羊毛脂、甘油明胶、聚山梨酸酯、聚乙二醇、植物油、蜡、液体石蜡、白色凡士林、氟代烃、非离子性表面活性剂、丙二醇、水等。
在将本发明的组合物制备为饮食品的情况下,可以将其制备为任意的形态,例如,可以列举出以下的饮食品:饮料类(咖啡、可可、果汁、清凉饮料、矿物质饮料、茶饮料、绿茶、红茶、乌龙茶、乳饮料、乳酸菌饮料、酸奶饮料、碳酸饮料等)、米饼(仙贝、烤年糕片、小米饼等)、口香糖、橡皮糖、果冻、糖果、曲奇饼、脆饼、饼干、冰点(冰淇淋、雪糕、冰沙、刨冰等)、蒸煮袋食品、果冻状食品(果冻、琼脂、果冻状饮料等)等。
本发明的饮食品也可以制备为所谓的健康食品、功能性食品、营养辅助食品、膳食补充剂、特定保健用食品、功能性显示食品、患者用食品-患者用组合食品(厚生劳动省、特別用途食品的一种)或老年人用食品(厚生劳动省、特別用途食品的一种)。
本发明的组合物中的本发明的肽的量可以根据想要得到的效果等适当设定。例如,可以相对于组合物配混优选0.01质量%以上,更优选1.00质量%以上的本发明的肽。另外,也可以相对于组合物配混优选100质量%以下,更优选90质量%以下的本发明的肽。此外,当在本发明的组合物中包含除了本发明的肽以外的肽时,上述的值是换算为本发明的肽的量而得到值。
本发明的组合物中的除了本发明的肽以外的成分的量可以根据该成分的种类、组合物的形态、想要得到的效果等适当设定。
本发明的组合物的给药方法没有特别限定,可以为口服给药或非口服给药(注射等)中的任一种。从易于实现本发明的效果的观点出发,本发明的组合物优选被口服给药。
本发明的组合物的给药量根据给药方法、给药对象的状态或年龄等而不同,但例如换算为本发明的肽的量,成人每天优选为0.01mg/kg~500mg/kg,更优选为0.05mg/kg~100mg/kg,进一步优选为0.1~30mg/kg。在上述范围内,存在给药量越多,则越易于实现本发明的效果的倾向。
作为本发明的组合物的制造方法,可以根据想要得到的形态采用公知的方法。
<治疗、预防或改善心境障碍的方法>
通过将本发明的组合物向对象进行给药,可以治疗、预防或改善心境障碍。
给药方法可以根据组合物的形态而适当选择。
给药次数、给药间隔、给药量可以根据给药对象的状态(症状、年龄、体重等)而适当选择。
作为给药对象没有特别限定,但可列举出人、除了人以外的哺乳类(狗、猫、家畜(牛、猪、绵羊、山羊等)等)等。
实施例
以下,示出实施例来具体地说明本发明,但本发明并不限定于这些实施例。
〈肽的制作〉
通过Fmoc法合成以下的八种肽,接着,通过由反相HPLC实现的纯化制作而成。肽1至4相当于本发明的肽。
(肽1)由序列号1所示的氨基酸序列(QSQ)构成的肽
(肽2)由序列号2所示的氨基酸序列(SQK)构成的肽
(肽3)由序列号3所示的氨基酸序列(QSQSQ)构成的肽
(肽4)由序列号4所示的氨基酸序列(SQSQK)构成的肽
(肽5)由序列号5所示的氨基酸序列(QS)构成的肽
(肽6)由序列号6所示的氨基酸序列(QK)构成的肽
(肽7)由序列号7所示的氨基酸序列(SQ)构成的肽
(肽8)由序列号8所示的氨基酸序列(QSQSQK)构成的肽
将制作成的各肽利用以下的方法对小鼠(ddy小鼠(5周龄的雄性、体重24~28g))进行给药,通过悬尾试验评价了欲望提高效果。将其结果在图1中示出。
<肽的给药>
使各肽溶解于生理盐水,肽3、4、8相对于体重以0.3mg/kg的量,肽1、2、5、6、7以0.2μmol/kg的量对小鼠进行了口服给药(n=5)。作为对照,准备了仅口服给药生理盐水的小鼠(n=5)。将各小鼠用于以下的悬尾试验,评价了由本发明的肽实现的欲望提高效果。
<悬尾试验(Tail suspension test):欲望提高效果的评价>
在对各小鼠进行肽给药30分钟之后,在距离地板上方30cm的位置处使其用尾悬挂悬垂。接着,从试验开始(0分钟)经过6分钟,测定在开始逃避行为之后确认为无动状态的时间(无动时间(Immobility time)),求出平均值。无动状态已知为“绝望状态”,无动时间越短,则越改善绝望状态,可以评价为欲望提高。因此,在该试验中带来欲望提高效果的物质能够有效地治疗、预防或改善心境障碍。
<结果>
图1的结果是以对照的无动时间为“100”的情况下的、对各肽进行给药的小鼠的无动时间作为相对值表示的结果。在图1中值越小,则绝望状态越改善,可以评价为欲望提高。
如图1所示,与对照相比,对本发明的肽(肽1至4)进行给药的小鼠的无动时间短。因此,表示本发明的肽实现欲望提高效果,对于心境障碍的治疗或预防有用。
而且,本发明的肽中的规定的三肽(肽1和2)的欲望提高效果尤其良好。
另一方面,与对照相比,对具有由QS、QK、SQ所示的氨基酸序列的二肽(肽5至7)进行给药的小鼠几乎没有确认到无动时间的减少。
以上的结果表明,本发明的肽具有欲望提高效果,而且,构成本发明的肽的三肽(肽1和2)为用于实现欲望提高效果的最少单位。
序列表
<110> 京都大学
<110> 公益财团法人上总DNA研究所
<110> 龟田制菓株式会社
<120> 肽、组合物及治疗、预防或改善心境障碍的方法
<130> KMS1-0032
<160> 8
<170> PatentIn version 3.5
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Claims (7)
1.一种肽,具有序列号1或序列号2所述的氨基酸序列,且为3以上且5以下的氨基酸长度。
2.根据权利要求1所述的肽,其中,
所述肽由序列号1、序列号2、序列号3或序列号4所述的氨基酸序列构成。
3.一种组合物,包含权利要求1或2所述的肽,且用于心境障碍的治疗、预防或改善。
4.根据权利要求3所述的组合物,其中,
所述心境障碍为选自由欲望降低、抑郁及抑郁性心境障碍、以及基于它们的症状组成的组中的一种以上。
5.根据权利要求3或4所述的组合物,其中,
所述组合物为药品。
6.根据权利要求3或4所述的组合物,其中,
所述组合物为饮食品。
7.一种治疗、预防或改善心境障碍的方法,包括将权利要求3至5中任一项所述的组合物进行给药。
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- 2020-11-05 US US17/774,093 patent/US20220370546A1/en active Pending
- 2020-11-05 CN CN202080075756.6A patent/CN114641484A/zh active Pending
- 2020-11-05 JP JP2021555111A patent/JP7398716B2/ja active Active
- 2020-11-05 WO PCT/JP2020/041417 patent/WO2021090894A1/ja active Application Filing
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US20220370546A1 (en) | 2022-11-24 |
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