CN105163748B - 用于肥胖症的功能性多肽 - Google Patents
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Abstract
本发明涉及特定多肽，其可通过属于乳杆菌属或链球菌属的菌株的培养上清液作用自大豆球蛋白水解而获得。这些多肽、含有其的提取物和含有其的食品产品可用于治疗和/或预防肥胖和氧化应激。
Description
技术领域
本发明涉及特定多肽，其可通过属于乳杆菌属(Lactobacillus)或链球菌属(Streptococcus)的菌株的培养上清液作用自大豆球蛋白水解而获得。
这些多肽、含有其的提取物和含有其的食品产品可用于治疗和/或预防肥胖和氧化应激。
背景技术
如今的现代社会中，肥胖是一种导致多重有害病理发展的严重流行病。肥胖相关病症可导致多重长期并发症，诸如II型糖尿病、心血管疾病、多种类型的癌症和许多其他疾病。很显然，饮食和能量消耗行为的改变可导致体重减轻或在能量摄入超过能量消耗的情况下引起肥胖。针对肥胖的潜在药物治疗已经引起了大量关注，特别是立足于探索能够抑制膳食脂质消化的功能性化合物的新方法(Shi Y,Burn P；2004；Lipid metabolicenzymes:emerging drug targets for the treatment of obesity；Nat.Rev.DrugDiscover.3:695-710)。
近几十年来，已经纯化和表征了大量涉及脂质代谢的酶。能够消化三酰甘油和磷脂两种脂肪的脂酶是肥胖的主要研究兴趣。一种最重要的脂酶是胰脂酶(pancreaticlipase，PL)，负责水解50-70％的膳食脂肪(Mukherjee M；2003；Human digestive andmetabolic lipases:a brief review；J.Mol.Catal.Enzym.B 22:369-376)。在探索抗肥胖化合物的过程中，PL抑制曾经是最广泛研究的目标机制之一(Birari RB,Bhutani KK；2007；Pancreatic lipase inhibitors from natural sources:unexplored potential；Drug Discover.Today 12:879-889)。如今，奥利司他(Orlistat)是欧洲接受的唯一一种通过外周作用机制降低脂肪吸收的药物(Lunder M,Bratkovic,T,Kreft,S and Strukelj,B；2005；Peptide inhibitor of pancreatic lipase selected by phage display usingdifferent elution strategies；Journal of Lipid Research 46:1512-1516)。
此外，来自细胞和动物研究的相当多的证据表明了胰磷脂酶A2(pancreaticphospholipase A2,PLA2)在脂质消化和吸收中的重要性。该磷脂酶A2(PLA2)家族催化膜磷脂水解，释放花生四烯酸(AA)、廿二碳六烯酸(DHA)和其他多元不饱和脂肪酸(PUFAs)。所释放的PUFAs是各种类花生酸的前体，所述类花生酸是20碳化合物，包括负责炎症反应的前列腺素(prostaglandins)、血栓素(thromboxanes)、白三烯(leukotrienes)和脂氧素(lipoxins)。已证明PLA2及其下游产物在脂肪组织中能作为重要的生物媒介，PLA2可由多种细胞因子激活表明该酶的功能是作为炎症通路和脂质代谢的细胞联系，因而该酶成为肥胖的关键靶标(Abbott M,Tang T mad Sul H；2010；The role of phospholipase A2-derived mediators in obesity；Drug Discovery Today:Disease Mechanisms 7:3-4)。
另一方面，已经克隆和测序了来自包括人类的不同生物中编码脂质代谢的酶的大部分基因。系统发生的研究已经揭示脂质代谢是一个从酵母到人类相当保守的通路，这使得在抗肥胖药物研究中模式生物的使用成为可能。从这个意义上讲，秀丽隐杆线虫(Caenorhabditis elegans)是用于肥胖研究的一种最佳模式生物(Chiang SH,MacDougaldOA；2003；Will fatty worms help cure human obesity；Trends Genet.19:523-525)。实际上，在秀丽隐杆线虫中使用干扰RNA进行减脂基因失活分析已经鉴定了305个与体脂降低相关的基因和112个涉及脂肪储藏增加的基因，这些基因中的大多数具有哺乳动物同源基因(Ashrafi K et al.；2003；Genome-wide RNAi analysis of Caenorhabditis elegansfat regulatory genes；Nature 421:268-272)。而且，在秀丽隐杆线虫中，脂酶是肥胖的关键因素。几个研究组对于秀丽隐杆线虫的脂酶的最近报道表明，在该生物中脂肪代谢与肥胖，繁殖和衰老具有出乎意料的联系(Wang MC et al.；2008；Fat metabolism linksgermline stem cells and longevity in C.elegans；Science232:957-960；Xie T；2008；Burn fat,live longer；Science 232:865-866)。
已研究了能够潜在地预防肥胖及相关代谢紊乱的发展的天然化合物。Gargouri和其同事报道了某些大豆蛋白质对于胰脂酶具有抑制效果(Gragouri et al；1984；Studieson the inhibition of pancreatic and microbial lipases by soybean proteins；JLipid Res.,25:1214-1221)。这些分子对酶不具有直接的效果；他们修饰脂质乳液，避免酶和底物之间的接触。同样地，很多作者已经阐明在对脂酶活性具有抑制特性的某些种子中存在碱性蛋白，而且Miyazaki等随后在专利US5,411,956中描述了在肥胖治疗中用作脂酶抑制剂的某些蛋白质(Wang and Huang；1984；Inhibitors of lipase activities insoybean and other oil seeds；Plant Physiol.,76:929-934；Tani et al；1994；Purification and characterization of proteinous inhibitor of lipase fromwheat flour；J Agri Food Chem.,42:2382-2385；Tsujita et al；1996；Studies of theinhibition of pancreatic and carboxylester lipases by protamine；J Lipid Res.,37:1481-1487；Gragouri et al；1984；Inhibition of pancreatic and microbiallipases by proteins；Biochim.Biophys.Acta.,795:326-331)。
同样地，上述及其他作者证明,在体外对于消化酯酶具有抑制效果的酚类物质(例如氯原酸、(+)儿茶酚、表儿茶酚、根皮苷、芸香苷和原花青素(缩合单宁酸))可降低肠道脂质吸收(Wang et al；2006；Green tea catechins inhibit pancreatic phospholipaseA2and intestinal absorption of lipids in ovariectomized rats；J Nutr Bioch.,17:492-498)，Juhel等(Juhel et al；2000；Green tea extract(AR25)inhibitslipolysis of triglycerides in gastric and duodenal medium in vitro；JNutr.Biochem.,11:45-51)，Sugiyama等(Sugiyama et al；2007；OligomericProcyanidins in Apple Polyphenol Are Main Active Components for Inhibition ofPancreatic Lipase and Triglyceride Absorption；J Agric Food Chem.,55:4604-4609)和Rahul等(Rahul et al；2007；Pancreatic lipase inhibitors from naturalsources:unexplored potential“Drug Discovery”today.,12:19-20)。
然而，尽管以化学方法、生物技术方法或自蛋白质通过酶处理手段获得与肥胖相关的功能多肽的研究正获得日益增多的关注，但其仍是一个有待开发的领域。本发明集中在用于治疗肥胖和氧化应激的功能性多肽，其通过使用乳酸菌菌株由大豆球蛋白进行微生物消化而获得。
发明内容
根据第一方面，本发明涉及具有PL(胰脂酶)和/或PLA2(胰磷脂酶)抑制活性的多肽，其可通过大豆球蛋白水解作用而获得。
在优选的方面，本发明涉及具有PL(胰脂酶)和/或PLA2(磷脂酶A2)抑制活性的多肽，其通过用嗜热链球菌CNCM I-2776和/或嗜热链球菌CNCM I-1630和/或副干酪乳杆菌副干酪亚种CNCM I-4270水解大豆球蛋白而获得，用于治疗或预防肥胖和/或氧化应激。
在第二方面，本发明涉及具有PL和/或PLA2抑制活性的多肽，其选自由以下序列组成的组群：SEQ ID No.1：EEEGGSVLSG，SEQ ID No.2：SDNFEY，SEQ ID No.3：EEDQPRPDHPPQRP，SEQ ID No.4：SVIKPPTD，SEQ ID No.5：QGENEEEDSGAIVTVK，SEQ ID No.6：QGENEGEDKGAIVT，SEQ ID No.7：QDEDEDEDEDKPRPSRP，SEQ ID No.8：DEDEDEDEDKPRPSRP，SEQID No.9：DEDEDEDKPRPSRP，SEQ ID No.10：DEDEDKPRPSRPSQG，SEQ ID No.11：GKREQDEDEDEDEDKPRPSRP，SEQ ID No.12：HQQEEENEGGSILSG，SEQ ID No.13：QGENEGEDKGAIVTVK，SEQ ID No.14：SVIKPPTDE，SEQ ID No.15：IKPPTDE，SEQ ID No.16：NEGDVLV，SEQ ID No.17：YNTGDEPVVA，SEQ ID No.18：HGKHEDDEDEDEEEDQPRPDHPPQRP，SEQID No.19：GKHEDDEDEDEEEDQPRPDHPPQRP，SEQ ID No.20：DDEDEDEEEDQPRPDHPPQRP，SEQ IDNo.21：HEDDEDEDEEEDQPRPDHPPQRP和SEQ ID No.22：SGPLVNP。
在优选的方面，所述多肽选自由以下序列组成的组群：SEQ ID No.1：EEEGGSVLSG，SEQ ID No.2：SDNFEY，SEQ ID No.3：EEDQPRPDHPPQRP，SEQ ID No.4：SVIKPPTD，SEQ IDNo.5：QGENEEEDSGAIVTVK和SEQ ID No.6：QGENEGEDKGAIVT，其为分离的形式和/或为提取物形式，可用于治疗和/或预防肥胖症以及对抗氧化应激。
在第三方面，本发明涉及一种食品产品，其包含具有PL(胰脂酶)和/或PLA2(胰磷脂酶)抑制活性的所述多肽中的至少一种，所述多肽选自由以下序列组成的组群：SEQ IDNo.1：EEEGGSVLSG，SEQ ID No.2：SDNFEY，SEQ ID No.3：EEDQPRPDHPPQRP，SEQ ID No.4：SVIKPPTD，SEQ ID No.5：QGENEEEDSGAIVTVK和SEQ ID No.6：QGENEGEDKGAIVT，或者一种提取物，其包含所提到用于治疗和/或预防肥胖症和氧化应激的多肽中的至少一种。
在第四方面，本发明涉及一种医药组合物，其包含具有PL(胰脂酶)和/或PLA2(胰磷脂酶)抑制活性的所述多肽中的至少一种，所述多肽选自由以下序列组成的组群：SEQ IDNo.1：EEEGGSVLSG，SEQ ID No.2：SDNFEY，SEQ ID No.3：EEDQPRPDHPPQRP，SEQ ID No.4：SVIKPPTD，SEQ ID No.5：QGENEEEDSGAIVTVK和SEQ ID No.6：QGENEGEDKGAIVT，或者一种提取物，其包含所提到用于治疗和/或预防肥胖症和氧化应激的多肽中的至少一种。
在进一步的方面，本发明涉及来自乳杆菌属和链球菌属的特定细菌，特别是嗜热链球菌CNCM I-2776、嗜热链球菌CNCM I-1630和副干酪乳杆菌CNCM I-4270，含有所述菌株蛋白酶的上清液或细胞的用途，用于获得包含具有PL(胰脂酶)和/或PLA2(胰磷脂酶)抑制活性的所述多肽的多肽和或提取物，所述多肽选自由以下序列组成的组群：SEQ ID No.1：EEEGGSVLSG，SEQ ID No.2：SDNFEY，SEQ ID No.3：EEDQPRPDHPPQRP，SEQ ID No.4：SVIKPPTD，SEQ ID No.5：QGENEEEDSGAIVTVK和SEQ ID No.6：QGENEGEDKGAIVT。
附图
图1显示了自大豆球蛋白获得并通过PLA2抑制分析挑选的多肽提取物对于秀丽隐杆线虫减少体脂的效果。
图2显示了在秀丽隐杆线虫中不同的多肽提取物预防急性氧化应激的效果。
具体实施方式
本发明提供不同的大豆球蛋白多肽，其通过使用不同的乳酸菌菌株进行水解作用而获得，用于治疗和/或预防肥胖症和氧化应激。这些多肽能够在体外抑制脂解酶类(PL和PLA2)，并且在使用秀丽隐杆线虫的体内模型中减少脂肪积累和预防急性氧化应激。
开展了体外研究，以挑选能够从大豆球蛋白释放能抑制与肥胖症相关酶活性的多肽的多种乳酸菌菌株。由属于乳杆菌属或链球菌属的10种不同菌株的培养物上清液水解大豆球蛋白72小时后获得了多肽提取物。针对所产生提取物体外抑制PL和PLA2酶的能力对其进行筛选。最后，再使用秀丽隐杆线虫体内模型针对所挑选的多肽提取物减少脂肪积累的能力对其进行筛选，并且接着使用同样的动物体系也检测所挑选的多肽提取物预防急性氧化应激的能力。
本研究的结果发现，用某些菌株的上清液来源的蛋白酶水解大豆球蛋白后获得的多肽提取物能够在体外抑制PL和PLA2，而且使用秀丽隐杆线虫体内模型时能够减少脂肪积累并预防氧化应激。然后鉴定了负责体外抑制PL和PLA2以及体内减少脂肪的抗氧化多肽。
罹患肥胖的个人或者具有罹患肥胖风险的个人，诸如具有肥胖家族病史的人或有脂质代谢困难的人使用这些特效的多肽提取物是有利的。
菌株的选择
为了挑选对大豆球蛋白具有蛋白酶活性的最高效乳酸菌，对乳杆菌属和链球菌属的不同菌株进行如下的水解分析。
挑选的用于进行水解过程的底物是大豆球蛋白。大豆球蛋白是如Thanh V.H.等的描述将大豆粉用巯基乙醇处理并接着进行两次离心步骤之后提取的主要大豆蛋白质(Major proteins of soybean seeds:a straightforward fractionation and theircharacterization.1976.J Agric Food Chem 24:1117–1121)。在用于降解大豆球蛋白的酶源之中检测了10个菌株：6个链球菌属的菌株(菌株2、3、4、5、6、7)和4个乳杆菌属的菌株(菌株8、9、10和11)。所有这些菌株均在最佳培养基中(乳杆菌菌株为MRS和链球菌菌株为BHI)于37℃培养17小时，并且将上清液和细胞二者中分子量大于10KDa的蛋白酶浓缩用作大豆球蛋白水解分析中的酶源。一方面，4000rpm离心15分钟后获得上清液中的蛋白酶。然后对上清液以10KDa进行超滤，并且将上层用50mM pH7的柠檬酸磷酸盐缓冲液重悬为2ml。另一方面，用盐溶液清洗自不同培养物中获得的细胞，4000rpm 15分钟并在50mM pH7的柠檬酸磷酸盐缓冲液中重悬，以评估细胞和上清液中的蛋白酶活性(表1)。
表1：来自不同培养物保藏LAB菌株的蛋白酶活性。
由上可知，发现乳酸菌菌株的培养物上清液能够最有效地提供最高的蛋白酶活性，并从而产生用于肥胖的功能性多肽。
获得多肽提取物
用13.5ml 50mM pH7的柠檬酸磷酸盐缓冲液溶解的1％大豆球蛋白和所研究的10kDa浓缩培养物上清液各1.5ml在37℃进行酶水解72小时。通过用3KDa过滤器进行超滤以终止反应，并且将含有水解后释放的多肽的较低分子量组份进行体外评估，以检测其抑制如PL和PLA2的脂解酶的能力，并研究其在秀丽隐杆线虫模型中减少体内脂肪积累的能力。
针对多肽提取物体外抑制PL和PLA2酶活性的能力对其进行筛选
如Sugiyama等的描述并稍有修改，以4-甲基伞酮油酸盐(4-methyl umbelliferyloleate,4MUO)为底物测定PL抑制(Oligomeric procyanidins in apple polyphenol aremain active components for inhibition of pancreatic lipase and triglycerideabsorption.J Agric Food Chem(2007)；55:4604-4609)。将各多肽提取物以25μl的量与25μl PL溶液(1mg/ml)孵育并在26℃预孵育10分钟，以500rpm搅拌。通过加入50μl溶解于Dulbecco缓冲液中的4MUO(0.1mM)而起始反应。持续搅拌(500rpm)下在26℃孵育20分钟后，通过加入100μl 0.1M柠檬酸钠缓冲液(pH4.2)而终止反应。酶所释放的4-甲基伞酮的量由荧光测定。多肽提取物在酶分析中作为抑制剂，但是，鉴于荧光与含有多肽的缓冲液之间相互干扰，需要将多肽提取物稀释为1/20或1/50。
如Singh等的描述用高效液相色谱(HPLC)以1,2-二油酰基-sn-甘油基-3-磷酸胆碱(1,2-dioleoyl-sn-glycero-3-phosphocholine，DOPC)为底物测定PLA2酶的抑制(Arapid isocratic high-performance liquid chromatography method fordetermination of cholesterol and 1,2-dioleoyl-sn-glycero-3-phosphocholine.Journal of Chromatography(2005)；1073:347-353)。使用配备了Waters2996光电二极管阵列检测器和Hypersil BDS C8色谱柱(250x 4.6mm,5uM)的Waters2695HPLC进行由50mM pH2.7的磷酸铵缓冲液：甲醇(15:85，v/v)的混合物形成的等度洗脱方法。表2中包含了自大豆球蛋白获得的多肽提取物的PL抑制数值。表3包含了自大豆球蛋白获得的多肽提取物的PLA2抑制数值。
表2：用所分析菌株的上清液和细胞自大豆球蛋白获得的多肽提取物抑制PL的百分比。
表3：用所分析菌株的上清液和细胞自大豆球蛋白获得的多肽提取物抑制PLA2的百分比。
挑选自大豆球蛋白获得的最好抑制活性的多肽提取物，用秀丽隐杆线虫模型进行体内检测。这些多肽提取物及其所指定的编号概括于表4中。
表4：所挑选的用于体内分析的多肽提取物组群。
针对多肽提取物体内减少脂肪积累的能力对其进行筛选
以前述自大豆球蛋白获得的5种多肽提取物为一组分析其在秀丽隐杆线虫中减少体脂含量的能力(参见表4)。这些样品由于其在体外高效抑制PL和PLA2而被挑选。具体而言，5种多肽提取物是从PLA2抑制分析中挑选出来的(M20G、M5G、M31G、M27G和M29G)。在秀丽隐杆线虫野生型菌株N2中用活线虫尼罗红(Red Nile)染色分析体脂含量。使用龄期同步化的群体开展实验，从卵阶段开始到幼成体阶段(3日龄成体)。在实验期间，将幼虫培养在作为对照条件的NGM琼脂板上，含有相应多肽提取物(100μl/平板)的NGM和含有6μg/mL奥利司他的NGM作为阳性对照。将尼罗红以0.05μg/mL的终浓度加在已经接种了大肠杆菌(Escherichia Coli)OP50菌株的NG平板表面。在20℃孵育后，将幼成虫(每种条件60条幼虫)取下在一VersaFluorTM荧光光度计系统中测量体内荧光。根据对照条件下饲喂的幼虫(参照样品)的荧光值计算经处理的幼虫中获得的荧光值。实验设置了重复。
评价5种多肽提取物所获得的全部结果显示，具有PLA2抑制能力的那些多肽提取物对于减少体脂具有较好的效果(表5和图1)。
一般来说，由于其PLA2抑制效果而被挑选的多肽提取物能够在秀丽隐杆线虫中更有效地减少脂质(表5)。如图1所示，荧光减少的百分比从16.2％到37.7％。需要重点指出的是M5G、M27G和M31G分别具有降低37.7％、31.6％和28.6％荧光的效果。
综上所述，已发现具有显著的体外PLA2抑制效果的一组多肽提取物对于体内减体脂也具有重要的效果。
表5：由前述酶抑制分析挑选的多肽提取物引起秀丽隐杆线虫体脂减少的百分比
针对多肽提取物预防急性氧化应激的能力对其进行筛选
在秀丽隐杆线虫体内模型中分析所挑选的5种多肽提取物预防急性氧化应激的情况。
用龄期同步化的秀丽隐杆线虫野生型菌株N2的群体开展实验。用不同的多肽提取物(100μL/平板)饲喂从卵阶段到5-日龄成体阶段的线虫。包括对照饲喂条件(NGM)和阳性对照(维生素C，0.1μg/mL)。在20℃孵育后，通过将幼虫转移到含有H2O2(2mM)的新平板上而使其处于氧化应激。在各培养条件中孵育5小时后测定幼虫群体的生存能力。实验设置了重复。
在两个不同的试验中分析所述5种挑选的多肽提取物。第一个(参见图2)包括那些引起最高的PLA2体外抑制的样品(它们体内减少体脂介于28.6和39.1％之间)。样品M5G、M31G、M27G自大豆球蛋白底物获得，而且他们都对线虫中的氧化应激显示高效的预防效果。与对照条件(39.5％)相比，我们在氧化应激之后观察到高存活百分比(介于53和64％之间)。这结果表明，多肽提取物M5G、M31G y M27G能高效预防氧化应激并且具有减少线虫中体脂含量的能力(图2)。
综上所述，使用菌株嗜热链球菌6、副干酪乳杆菌副干酪亚种10和嗜热链球菌7水解大豆球蛋白而获得的M5G、M31G、M27G 3种多肽提取物的组能够高效减脂和显著预防秀丽隐杆线虫体内模型中的氧化应激，证明它们对于两种功能均具有有益的效果(表6)。
表6：由PLA2分析挑选的多肽提取物对氧化应激的预防。
然后，优选地挑选如下的菌株用于本发明的目的：
菌株6：嗜热链球菌CNCM I-2776
菌株7：嗜热链球菌CNCM I-1630
菌株10：副干酪乳杆菌副干酪亚种CNCM I-4270
本发明也包含上述菌株的用途，而且也包含突变菌株或遗传转化菌株，其源自所述母本菌株中的任一者并仍然具有针对大豆球蛋白的蛋白酶活性且产生本发明的功能性多肽。这些突变体或遗传转化菌株可以是那些比如为了修饰其某些代谢特性而将其中的一个或一个以上母本菌株内源基因突变了的菌株。他们也可以是比如为了赋予母本菌株额外的生理特征而对所述菌株的一个或一个以上感兴趣基因进行遗传转化而产生的菌株。
鉴定具有体外抑制PLA2，在秀丽隐杆线虫模型中减脂和预防氧化应激的能力的功能性多肽
挑选能体外抑制PLA2、在体内减脂和预防氧化应激的3种多肽提取物，用于鉴定其所呈现的功能性多肽序列。功能性多肽的鉴定通过使用M5G、M27G和M31G样品进行，并且由nESI-MS/MS获得结果。
表7包含自大豆球蛋白鉴定的多肽序列和其在各被评价的样品中出现的次数。表7中显示的所有多肽都仅仅存在于用嗜热链球菌菌株6和7以及副干酪乳杆菌副干酪亚种10处理的样品中，并且在未经水解处理的对照样品中未鉴定出。
表7.来自大豆球蛋白的多肽序列在M5G、M27G和M31G样品中被鉴定的频次。
选取来自嗜热链球菌6和副干酪乳杆菌副干酪亚种10菌株的M5G和M27G水解产物并通过反相色谱将其进一步纯化，以鉴定负责体内减脂的多肽。将反相色谱的组分针对秀丽隐杆线虫进行分析，以研究减脂作用并鉴定存在于嗜热链球菌6和副干酪乳杆菌副干酪亚种10菌株中的阳性菌株中的多肽(表8)。
表8：在嗜热链球菌6(M5G)和副干酪乳杆菌副干酪亚种10(M27G)的纯化组分中鉴定的大豆球蛋白多肽序列
从这些纯化的组分中总共挑选了11个多肽，将其合成并在秀丽隐杆线虫肥胖模型中进行体内评估(表9)。所有这些多肽均以1μg/mL的终浓度进行评估。
表9：挑选用其进行秀丽隐杆线虫体内评估的大豆球蛋白多肽。
其中，对能够减少大于30％的脂肪积累的多肽进行针对胰酯酶(PL)和磷酯酶A2(PLA2)的体外评估。对于PL，测定IC50值(表10)，并且在PLA2的研究中对各个多肽检测三种不同浓度(表11)。
表10：PL酶解分析中各个多肽的IC50值。
表11：在三种不同的检测浓度下各多肽抑制PLA2的百分比。
鉴定潜在负责减脂的抗性最强的多肽。
开发了一种体内消化道的体外酶解消化模型来模拟生理条件，以检查并证明消化过程在胃肠道全程中对各种所挑选的多肽进行不同的降解。根据一份公开发表的实验设计对胃蛋白酶、胰酶和胆汁浓缩物进行优化(Granado-Lorencio et al(2007).J.Agri.Food.Chem.,55,6387-6394)。
使用高效液相色谱(HPLC)技术，观察到多肽P14c和P16f在肠期起点处被完全降解，而P8a和P14a保持到这个过程的末端才在那里被最终降解(表12)。
表12：体外消化模型中多肽降解的百分比。
可以将本发明的多肽以分离的形式或以提取物形式加入食品基质中。可以将本发明的多肽单独或以混合物的形式加入食品基质中。
在一个优选的实施例中，可以通过本领域中已知的任何方法获得或制造所述多肽，包括合成纯化多肽和通过本申请说明书所描述的水解或发酵法产生蛋白质组份(由此分离)。
本发明的多肽可以多肽本身(例如来自于合成的纯化多肽)或作为蛋白组份的一部分(例如水解或发酵的蛋白质)存在于食品产品中。
在本发明的一个特殊实施例中，本发明的多肽存在于食品产品中的形式可能是通过将本发明的菌株加入相应的含有大豆球蛋白的食品基质中而实现的。
该食品产品优选是一种发酵产品。该发酵产品可以液体形式存在或者通过将所述发酵液干燥后以干粉形式存在。
所述发酵产品优选是一种新鲜的奶制品；更优选为发酵牛奶和/或发酵大豆。营养组分优选为巴氏消毒的无菌牛奶，酸奶和发酵牛奶，诸如：
奶制品，诸如无菌的和/或巴氏消毒的牛奶，酸奶，发酵牛奶，牛奶为主的甜点。婴儿的第二代配方食品和幼儿食品。新鲜的和/或巴氏消毒的奶酪。蔬菜产品，诸如果汁产品、果露和/或水果香精、橘子酱、蜜饯和/或果酱。豆浆和/或提取物，油莎豆、谷物、坚果和干果、大豆为主的豆浆和发酵提取物，水果，坚果和干果和谷物。牛奶为主的婴儿配方，奶产品、水果、谷物、稻米、幼儿食品等。直接发行或通过食品产品发行的新鲜、干燥和/或冰冻的干制食品添加剂，以及用于普通人群或罹患体重问题或肥胖的人的特殊制剂。浓缩的和/或增补的水和饮品。一般而言，倾向于富含功能性多肽的主食和/或功能性产品来源于基本的产品发酵和/或功能性多肽的提取，其作为活性成分加入食品基质中。
根据本发明的多肽在食品产品中的量优选为至少0.01g/kg，更优选为从0.1到10g/kg，甚至更优选为从1到7g/kg，且最优选为从3到7g/kg所述多肽，例如为5g/kg。优选地，选择这些食品产品中多肽的量以使得每份所述食品产品总量中所述多肽的量为从0.01至0.1g，优选0.1到1g，更优选0.1到0.7g，以及最优选0.2到0.5g。
实施例
1.用所述多肽调配食品产品以及减脂效果
本研究的目的是评价自大豆球蛋白的多肽在将其加入食品基质后获得的较有效的抗肥胖效果。我们选择了用菌株6水解大豆球蛋白而获得的5种多肽(P8a、P6a、P14c、P16f、P14b)。将来自大豆球蛋白的所述多肽单独或以终浓度1μg/mL混合加入大豆发酵产品(Danone的)。用这些产品饲喂线虫，然后用尼罗红染色定量总脂质。
表13显示了在饲喂含有不同大豆球蛋白多肽或其组合的大豆发酵产品的线虫中荧光减少的水平。结果表明了所有大豆球蛋白多肽在将其加入大豆发酵产品时的体内有效性。将这5种多肽组合加入食品基质中也能导致荧光的显著降低。
表13：在饲喂含有所选择大豆球蛋白多肽P8a、P6a、P14c、P16f和P14b的(Danone)的线虫中荧光减少的百分比。
Claims (8)
1.一种具有PL(胰脂酶)和/或PLA2(磷脂酶A2)抑制活性的多肽，其通过用嗜热链球菌CNCM I-2776和/或副干酪乳杆菌副干酪亚种CNCM I-4270水解大豆球蛋白而获得，用于治疗或预防肥胖；所述多肽选自由以下序列组成的组群：
SEQ ID No.1：EEEGGSVLSG，
SEQ ID No.2：SDNFEY，
SEQ ID No.3：EEDQPRPDHPPQRP，
SEQ ID No.4：SVIKPPTD，
SEQ ID No.5：QGENEEEDSGAIVTVK，
SEQ ID No.6：QGENEGEDKGAIVT，
SEQ ID No.7：QDEDEDEDEDKPRPSRP，
SEQ ID No.8：DEDEDEDEDKPRPSRP，
SEQ ID No.9：DEDEDEDKPRPSRP，
SEQ ID No.11：GKREQDEDEDEDEDKPRPSRP，
SEQ ID No.12：HQQEEENEGGSILSG。
2.根据权利要求1所述的多肽，其选自由以下序列组成的组群：
SEQ ID No.1：EEEGGSVLSG，
SEQ ID No.2：SDNFEY，
SEQ ID No.3：EEDQPRPDHPPQRP，
SEQ ID No.4：SVIKPPTD，
SEQ ID No.5：QGENEEEDSGAIVTVK，和
SEQ ID No.6：QGENEGEDKGAIVT，
用于治疗或预防肥胖。
3.一种适于用作治疗肥胖的食品产品，其包含一种或一种以上根据权利要求1至2所述的多肽。
4.根据权利要求3所述的食品产品，其中所述多肽为提取物形式。
5.根据权利要求3所述的食品产品，其中所述多肽为分离的形式。
6.根据权利要求3至5中任一项所述的食品产品，其中每份所述食品产品总量中所述多肽的量为0.01至1g。
7.根据权利要求3至5中任一项所述的食品产品，其包含至少0.01g/kg所述多肽。
8.一种嗜热链球菌CNCM I-2776和/或副干酪乳杆菌副干酪亚种CNCM I-4270的用途，在存在大豆球蛋白的情况下用于制造根据前述权利要求1至2所述的多肽的方法中。
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