CN114645037A - 用于使赭曲霉毒素a解毒的工具和方法 - Google Patents
用于使赭曲霉毒素a解毒的工具和方法 Download PDFInfo
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- CN114645037A CN114645037A CN202111558833.6A CN202111558833A CN114645037A CN 114645037 A CN114645037 A CN 114645037A CN 202111558833 A CN202111558833 A CN 202111558833A CN 114645037 A CN114645037 A CN 114645037A
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Abstract
本发明涉及能够使赭曲霉毒素A(OTA)解毒的新型多肽和基于其的方法(例如用于使霉菌毒素解毒)。本发明还涉及组合物、试剂盒、转基因植物、转基因种子、转基因花粉粒、食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂、益生元、中间益生元和/或它们的混合物,其包含能够使赭曲霉毒素A(OTA)解毒的多肽中的一种或多种。
Description
相关申请的交叉引用
本申请要求2020年12月18日向欧洲专利局提交的欧洲专利申请EP20215495的优先权,所述欧洲专利申请的全部内容并入本文用于所有目的。
序列表
本申请包含计算机可读形式的序列表,其通过引用并入本文。
技术领域
本发明涉及能够使赭曲霉毒素A(OTA)解毒的新型多肽和基于其的方法(例如用于使OTA解毒)。本发明进一步涉及包含能够使赭曲霉毒素A(OTA)解毒的一种或多种本发明的多肽的组合物、试剂盒、转基因植物、转基因种子、转基因花粉粒、转基因宿主细胞、转基因孢子、食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂、益生元、中间益生元和/或它们的混合物。
背景技术
霉菌毒素是由主要属于曲霉属(Aspergillus)和青霉属(Penicillium)的真菌物种产生的次级低分子量代谢物。霉菌毒素赭曲霉毒素A(OTA;也称为例如N-{[(3R)-5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢-1H-2-苯并吡喃-7-基]羰基}-L-苯丙氨酸,(-)-N-((5-氯-8-羟基-3-甲基-1-氧代-7-异色满基)羰基)-3-苯丙氨酸,(2S)-2-{[(3R)-5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢-1H-2-苯并吡喃-7-羰基]氨基}-3-苯基丙酸,(R)-N-((5-氯-3,4-二氢-8-羟基-3-甲基-1-氧代-1H-2-苯并吡喃-7-基)羰基)苯丙氨酸,N-(((3R)-5-氯-8-羟基-3-甲基-1-氧代-7-异色满基)羰基)-3-苯基-L-丙氨酸,N-[(3R)-5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢-1H-2-苯并吡喃-7-羰基]-L-苯丙氨酸,N-{[(3R)-5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢-1H-异色烯-7-基]羰基}-L-苯丙氨酸),CAS No.303-47-9,由真菌大量产生并且是赭曲霉毒素组中毒性最大的成员,所述赭曲霉毒素组尤其包括赭曲霉毒素B、赭曲霉毒素C等。特别地,由于对人类和动物的严重副作用,包括肾毒性、免疫毒性和致癌性(Carballo等人,2019;Malier等人,2016),OTA对食品和饲料安全性产生了严重的关注。在这方面,OTA已被国际癌症研究机构(IARC)在2B组中分类为可能的人类致癌物(IARC,2012)。
可食用作物、植物和相关产品的收获前和收获后阶段的环境条件影响产OTA真菌的繁殖,这导致食品和饲料材料中OTA和可能的其它霉菌毒素的污染。值得注意的是,由于动物被喂被污染饲料时的遗留现象,在基于谷物的食品和饲料以及蛋、肉、奶和由其衍生的产品中也已经报道了OTA的存在。此外,报道了OTA存在于各种食品中,例如咖啡、葡萄酒、啤酒、葡萄、豆类、可可等。由于OTA给人类和动物健康和幸福造成的相关风险,欧洲委员会已经提供了指导方针来控制其在食品(EC 1881/2006)和饲料(EC 2016/1319)中的存在。其中,报道了每kg体重120ng OTA的可耐受每周摄入量。特别是就动物饲料而言,谷物/谷物产品的指导值是0.25mg OTA/kg饲料,猪、家禽和猫/狗用的配合饲料的指导值分别是0.05mg/kg、0.1mg/kg和0.01mg/kg。
通常,食品和饲料材料中霉菌毒素含量、特别是OTA含量的降低是食品和饲料行业努力确保安全供应链的未满足的需要。已有报道利用不动苯基杆菌(Phenylobacteriumimmobile)或解毒毛孢酵母(Trichosporon mycotoxinivorans)的全细胞进行OTA水解,对OTA进行微生物解毒(Wegst和Lingens 1983;US 2009/0098244 A1)。然而,由于法规和安全要求,微生物在食品和饲料应用中用于OTA水解的适用性是具有挑战性的。此外,使用全细胞微生物与以确保所述微生物的足够生存力和活性的方式来培养和配制微生物的复杂和昂贵的要求相关。
作为OTA的微生物解毒的替代方式,需要开发一种基于酶的策略用于生物化学OTA降解。在这方面,以前报道了来自黑曲霉(Aspergillus niger)的称为赭曲霉毒素酶(ochratoxinase)的酶具有OTA水解活性(例如Dobrtzsch等,2014,Biochem J.15;462(3):441-52)。然而,尚未证明在食品和饲料生产线中所需的真实条件下应用这种酶,并且认为这是不可能的。Delafioria等(Toxins 2020,12,258)报道了猪羧肽酶B作为OTA水解酶。EP2 613 647 B1公开了一种能够降解OTA的酰胺酶。尽管如此,由于活性、稳定性和/或重组还原能力不足,迄今为止报道的OTA水解酶不能期望在应用条件下有效地发挥作用。
因此,需要提供具有改善的功能性(例如酶动力学和/或效率)和/或稳定性(例如热稳定性)的进一步改善的OTA水解酶。
发明内容
本发明涉及一种能够使赭曲霉毒素A(OTA)和/或至少一种OTA衍生物解毒的多肽,其中所述多肽是以下中的一种或多种:(a)与选自SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4的氨基酸序列具有至少60%序列同一性(例如至少64%、70%、74%、80%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%)的多肽;(b)多肽(a)的变体,其中所述变体在一个或多个位置处包含取代、缺失和/或插入;(c)(a)或(b)的多肽的片段,其中所述片段能够使OTA和/或至少一种OTA衍生物解毒。
本申请通过提供本文下文描述的多肽满足了这种需要,所述多肽在权利要求中表征并通过所附实施例和附图说明。
序列表概述
如本文所述,可以参考UniProtKB登录号(http://www.uniprot.org/,例如如在2020年12月2日发布的UniProtKB release 2020_06中可得到)。
SEQ ID NO:1是本发明的OTA水解多肽1的氨基酸序列。
SEQ ID NO:2是本发明的OTA水解多肽2的氨基酸序列。
SEQ ID NO:3是本发明的OTA水解多肽3的氨基酸序列。
SEQ ID NO:4是本发明的OTA水解多肽4的氨基酸序列。
SEQ ID NOs:5-23是本发明的示例性氨基酸基序。
附图说明
图1:赭曲霉毒素A水解为苯丙氨酸和赭曲霉毒素α的示例性方案(Dellafiora等,Toxins 2020,12,258)。
具体实施方式
定义
如本文所述,根据2020年2月26日公布的酶命名数据库(例如可在https://enzyme.expasy.org/获得),“EC编号”(酶学委员会编号)可用于指酶活性。EC编号是指来自NC-IUBMB,Academic Press,San Diego,Calif.的酶命名法1992,包括分别在Eur.J.Biochem.1994,223,1-5;Eur.J.Biochem.1995,232,1-6;Eur.J.Biochem.1996,237,1-5;Eur.J.Biochem.1997,250,1-6;和Eur.J.Biochem.1999,264,610-650中发表的增刊1-5。
术语“多肽”在本文中与术语“蛋白质”等同地使用。蛋白质(包括其片段、优选生物活性片段,和肽,其通常具有小于30个氨基酸)包含一个或多个彼此通过共价肽键偶联的氨基酸(产生氨基酸链)。如本文所用,术语“多肽”描述一类分子,其例如由大于30个氨基酸组成。多肽还可以形成多聚体,例如二聚体、三聚体和更高的低聚体,即,由大于1个多肽分子组成。形成此类二聚体、三聚体等的多肽分子可以是相同的或不同的。相应的这些多聚体更高级的结构因此称作同-或异二聚体、同-或异三聚体等。一种异多聚体的实例是以其天然存在形式由两个相同的轻多肽链和两个相同的重多肽链组成的抗体分子。术语“多肽”和“蛋白质”也指天然修饰的多肽/蛋白质,其中所述修饰受例如翻译后修饰(如糖基化、酰基化、磷酸化等)的影响。此类修饰是本领域熟知的。
氨基酸基序:如本文所用的术语“氨基酸基序”或“基序”可以指多肽的特别定义的氨基酸区段。因此,本发明的氨基酸基序(例如如SEQ ID NOs:5-23所示)可涉及多肽(例如SEQ ID NOs:1-4)内的短氨基酸序列。
序列同一性:两个氨基酸序列之间或两个核苷酸序列之间的相关性由参数“序列同一性”描述。出于本发明的目的,使用在EMBOSS软件包(EMBOSS:The European MolecularBiology Open Software Suite,Rice等人,2000,Trends Genet.16:276-277)的Needle程序、优选5.0.0版或更新版本中执行的Needleman-Wunsch算法(Needleman和Wunsch,1970,J.Mol.Biol.48:443-453)来确定两个氨基酸序列之间的序列同一性。所使用的参数可以是空位开放罚分10,空位延伸罚分0.5,以及EBLOSUM62(BLOSUM62的EMBOSS版)取代矩阵。将标记为“最长同一性”的Needle输出(使用非简化(no-brief)选项获得)用作同一性百分比并且是如下计算的:
(相同的残基×100)/(比对长度-比对中的空位总数)。
替代地,所使用的参数可以是空位开放罚分10,空位延伸罚分0.5,以及EDNAFULL(NCBI NUC4.4的EMBOSS版)取代矩阵。将标记为“最长同一性”的Needle输出(使用非简化(no-brief)选项获得)用作同一性百分比并且是如下计算的:
(相同的脱氧核糖核苷酸×100)/(比对长度-比对中的空位总数)。
表达:术语“表达”包括涉及于变体(多肽)产生的任何步骤,其包括、但不限于转录、转录后修饰、翻译、翻译后修饰和分泌。
表达载体:术语“表达载体”可以指线性或环状DNA分子,其包含编码变体(多肽)的多核苷酸并可操作地连接至控制序列以提供其表达,特别是提供其转录。
片段:术语“片段”可以指一种自成熟多肽的氨基和/或羧基端缺失一个或多个(例如若干个,例如1、2、3、4、5、6、7、8、9或10、多至15或多至20个等)氨基酸的多肽;其中所述片段具有如本文其它地方所述的活性。
宿主细胞:术语“宿主细胞”可以指易于用包含本发明的多核苷酸的核酸构建体或表达载体进行转化、转染、转导等的任何细胞类型。术语“宿主细胞”涵盖由于复制期间出现的突变而与亲本细胞不相同的亲本细胞的任何子代,例如重组或转基因宿主细胞(例如如本文实施例1中)。
核酸构建体:术语“核酸构建体”可以指单链或双链的核酸分子,该核酸分子是从天然存在的基因中分离的,或者以一种本来不存在于自然界中的方式被修饰成含有核酸区段,或者是合成的,该核酸分子包含一个或多个控制序列。
可操作地连接:术语“可操作地连接”可以指这样一种构造,在该构造中,将控制序列相对于多核苷酸的编码序列安置在适当位置处,使得该控制序列指导该编码序列的表达。
控制序列:如本文所用的术语“控制序列”可以指对于表达编码本发明的变体(多核苷酸)的多核苷酸所必需的核酸序列。每个控制序列对于编码该变体的多核苷酸来说可以是同源(native)的(即,来自相同基因)或外源的(即,来自不同基因),或相对于彼此是同源(native)的或外源的。此类控制序列包括、但不限于前导子、聚腺苷酸化序列、前肽序列、启动子、信号肽序列以及转录终止子。至少,控制序列包括启动子,以及转录和翻译终止信号。出于引入有利于将这些控制序列与本发明的多核苷酸的编码区连接的特异性限制位点的目的,可以提供具有接头的控制序列。
如本文所用,术语“对应于”可以是指确定序列中的特定氨基酸(其中参考了特定氨基酸序列(如US2020071638))的方式。例如出于本发明的目的,当参考特定氨基酸位置时,技术人员将能够将另一氨基酸序列与所述已经被参考的氨基酸序列进行比对,从而确定哪一个特定氨基酸可能是在所述另一个氨基酸序列中所关注的。已经在本文其它地方描述了另一氨基酸序列与例如如在SEQ ID NOs:1、2、3或4所示的序列或本文列出的任何其它序列的比对。可使用替代性比对方法,并且这些比对方法是本领域技术人员熟知的。
当根据本发明使用时,术语“位置”可以是指本文所描绘的氨基酸序列中氨基酸的位置。在本上下文中术语“对应于”可包括位置不仅由前面的核苷酸/氨基酸的数量决定的情况。
如本文所用,“沉默”突变意指核酸序列中的碱基置换,该置换不会改变由该核酸序列编码的氨基酸序列。“保守性或等价”置换(或突变)意指如下表1中作为“示例性置换”列出的置换。如本文所用的“高度保守性”置换意指如下文表I中标题“优选置换”下示出的置换。
表I氨基酸置换
原始 | 示例性置换 | 优选置换 |
Ala(A) | val;leu;ile | Val |
Arg(R) | lys;gln;asn | lys |
Asn(N) | gln;his;asp,lys;arg | gln |
Asp(D) | glu;asn | glu |
Cys(C) | ser;ala | ser |
Gln(Q) | asn;glu | asn |
Glu(E) | asp;gln | asp |
Gly(G) | ala | ala |
His(H) | asn;gln;lys;arg | arg |
Ile(I) | leu;val;met;ala;phe; | leu |
Leu(L) | norleucine;ile;val;met;ala; | ile |
Lys(K) | arg;gin;asn | arg |
Met(M) | leu;phe;ile | leu |
Phe(F) | leu;val;ile;ala;tyr | tyr |
Pro(P) | ala | ala |
Ser(S) | thr | thr |
Thr(T) | ser | ser |
Trp(W) | tyr;phe | tyr |
Tyr(Y) | trp;phe;thr;ser | Phe |
Val(V) | ile;leu;met;phe;ala; | leu |
变体:术语“变体”可以指在一个或多个(例如若干个,例如1、2、3、4、5、6、7、8、9或10、多至15或多至20个等)位置处包含改变(即,置换、插入和/或缺失)的如本文所述的具有特异性活性的多肽。置换意指用一个不同氨基酸替换占据一个位置的氨基酸;缺失意指移除占据一个位置的氨基酸;插入意指在邻接和紧随占据一个位置的氨基酸之后添加一个氨基酸。
如本文所用,术语“转基因(的)”可以指一种例如通过转化或重组引入异源基因材料或同源基因材料的另外拷贝而使其基因组得到改变的生物体(例如US7410800B2)。转基因生物体可以是植物、哺乳动物、真菌、细菌或病毒。如本文所用,“转基因植物、种子或花粉粒”可以指植物、种子或花粉粒或衍生自它们的任何后代的子代植物、种子或花粉粒,其中所述植物、种子或花粉粒或其子代的DNA包含相同植株的非转基因植物、种子或花粉粒中初始不存在的引入的外源DNA。转基因植物、种子或花粉粒可另外地包含对被转化的植物而言为天然的序列,但是其中为了改变编码序列的表达水平或模式已改变了外源DNA。
术语“食物”可以指具有食用价值的物质。
术语“草料”可以指喂养家畜的物质。
术语“饲料”可以指用作牲畜食物的物质。
术语“添加剂”可以指例如以少量添加至另一产品或物质中以实现期望的性质和/或特性的化合物或物质。
术语“益生元”可以指能够诱导有益微生物的生长和/或活性的化合物或物质。
术语“解毒剂”可以指能够降低和/或抑制毒性的化合物或物质。
术语“营养补充剂”可以指能够支持膳食中营养含量的化合物或物质,例如维生素和矿物质。
术语“藻植酸物质(phycophytic substance)”可以指来源于海草或藻类物种的物质。
术语“中间(体)(intermediate)”可以指在获得本发明的终产物的过程(例如在该过程的中间阶段)中产生的化合物或物质,所述终产物例如本发明的食物、草料、草料;饲料、添加剂(如食物、草料或饲料添加剂)、解毒剂、营养补充剂或益生元。
如本文所用,术语“OTA衍生物”可以指选自以下的化合物或物质:呋喃基丙烯酰基苯丙氨酸(也称为例如(2S)-2-[3-(呋喃-2-基)丙-2-烯酰氨基]-3-苯基丙酸),N-(3-(2-呋喃基)丙烯酰基)苯丙氨酸(也称为例如(2S)-2-[[(E)-3-(呋喃-2-基)丙-2-烯酰基]氨基]-3-苯基丙酸),N-(2-羟基苯甲酰基)-L-苯丙氨酸(也称为例如(2S)-2-[(2-羟基苯甲酰基)氨基]-3-苯基丙酸),(2S)-2-[(4-乙炔基苯甲酰基)氨基]-3-苯基丙酸(也称为例如(2S)-2-[(4-乙炔基苯甲酰基)氨基]-3-苯基丙酸),肉桂酰基-(反式)-L-苯丙氨酸(也称为例如(2S)-3-苯基-2-(3-苯基丙-2-烯酰氨基)丙酸),2-(2-苯氧基-乙酰氨基)-3-苯基-丙酸(也称为例如2-[(2-苯氧基乙酰基)氨基]-3-苯基丙酸),N-(苯氧基乙酰基)苯丙氨酸(也称为例如(2S)-2-[(2-苯氧基乙酰基)氨基]-3-苯基丙酸),N-(2-甲氧基苯甲酰基)-L-苯丙氨酸(也称为例如(2S)-2-[(2-甲氧基苯甲酰基)氨基]-3-苯基丙酸),3-苯基-2-[[(E)-3-噻吩-2-基丙-2-烯酰基]氨基]丙酸(也称为例如3-苯基-2-[[(E)-3-噻吩-2-基丙-2-烯酰基]氨基]丙酸),N-[(E)-3-(2-噻吩基)丙烯酰基]-L-Phe-OH(也称为例如(2S)-3-苯基-2-[[(E)-3-噻吩-2-基丙-2-烯酰基]氨基]丙酸),(2S)-3-苯基-2-(3-噻吩-2-基丙-2-烯酰氨基)丙酸(也称为例如(2S)-3-苯基-2-(3-噻吩-2-基丙-2-烯酰氨基)丙酸),2-(1H-吲哚-4-羰基氨基)-3-苯基丙酸(也称为例如2-(1H-吲哚-4-羰基氨基)-3-苯基丙酸),(2S)-2-(1H-吲哚-4-羰基氨基)-3-苯基丙酸(也称为例如(2S)-2-(1H-吲哚-4-羰基氨基)-3-苯基丙酸),2-[(1-苯并呋喃-2-基)甲酰胺基]-3-苯基丙酸(也称为例如2-(1-苯并呋喃-2-羰基氨基)-3-苯基丙酸),(2S)-2-(2,3-二氢-1H-茚-5-羰基氨基)-3-苯基丙酸(也称为例如(2S)-2-(2,3-二氢-1H-茚-5-羰基氨基)-3-苯基丙酸),N-[3-(4-甲基苯基)-1-氧代-2-丙烯基]-L-苯丙氨酸(也称为例如(2S)-2-[3-(4-甲基苯基)丙-2-烯酰氨基]-3-苯基丙酸),2-(1,3-二氢异吲哚-2-羰基氨基)-3-苯基丙酸(也称为例如2-(1,3-二氢异吲哚-2-羰基氨基)-3-苯基丙酸),(2S)-2-[3-(4-羟基苯基)丙-2-烯酰氨基)-3-苯基丙酸(也称为例如(2S)-2-[3-(4-羟基苯基)丙-2-烯酰氨基]-3-苯基丙酸),N-[(4-甲基苯氧基)乙酰基]苯丙氨酸(也称为例如2-[[2-(4-甲基苯氧基)乙酰基]氨基]-3-苯基丙酸),N-[3-(4-氟苯基)-1-氧代-2-丙烯基]-L-苯丙氨酸(也称为例如(2S)-2-[3-(4-氟苯基)丙-2-烯酰氨基]-3-苯基丙酸),3-苯基-2-[(3,4,5-三羟基苯甲酰基)氨基]丙酸(也称为例如3-苯基-2-[(3,4,5-三羟基苯甲酰基)氨基]丙酸),(2S)-3-苯基-2-[(3,4,5-三羟基苯甲酰基)氨基]丙酸(也称为例如(2S)-3-苯基-2-[(3,4,5-三羟基苯甲酰基)氨基]丙酸),(2S)-2-[[3-(氯甲基)苯甲酰基]氨基]-3-苯基丙酸(也称为例如(2S)-2-[[3-(氯甲基)苯甲酰基]氨基]-3-苯基丙酸),(2S)-2-[(5-甲基-1H-吲哚-2-羰基)氨基]-3-苯基丙酸)(也称为例如(2S)-2-[(5-甲基-1H-吲哚-2-羰基)氨基]-3-苯基丙酸),N-[(4-丁基苯基)羰基]苯丙氨酸(也称为例如2-[(4-丁基苯甲酰基)氨基]-3-苯基丙酸),(2S)-3-(4-羟基苯基)-2-[3-(4-甲基苯基)丙-2-烯酰氨基]丙酸(也称为例如(2S)-3-(4-羟基苯基)-2-[3-(4-甲基苯基)丙-2-烯酰氨基]丙酸),N-(4-羟基肉桂酰基)酪氨酸(也称为例如3-(4-羟基苯基)-2-[[(E)-3-(4-羟基苯基)丙-2-烯酰基]氨基]丙酸),N-[3-(4-羟基苯基)丙烯酰基]-L-酪氨酸(也称为例如(2S)-3-(4-羟基苯基)-2-[3-(4-羟基苯基)丙-2-烯酰氨基]丙酸),(2S)-3-(4-羟基苯基)-2-[(2-羟基-3-苯基丙-2-烯酰基)氨基]丙酸(也称为例如(2S)-3-(4-羟基苯基)-2-[(2-羟基-3-苯基丙-2-烯酰基)氨基]丙酸),N-((5-氯-8-羟基-3-甲基-1-氧代-7-异色满基)羰基)-丙氨酸(也称为例如(2S)-2-[[(3R)-5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]丙酸),N-[3-(4-氯苯基)-1-氧代-2-丙烯基]-L-苯丙氨酸(也称为例如(2S)-2-[3-(4-氯苯基)丙-2-烯酰氨基]-3-苯基丙酸),2-[[4-(2-氟乙氧基)苯甲酰基]氨基]-3-苯基丙酸(也称为例如2-[[4-(2-氟乙氧基)苯甲酰基]氨基]-3-苯基丙酸),(2S)-2-(4-氯苯氧基)乙酰基]氨基]-3-苯基丙酸(也称为例如(2S)-2-[[2-(4-氯苯氧基)乙酰基]氨基]-3-苯基丙酸),(2S)-3-苯基-2-[[4-(三氟甲基)苯甲酰基]氨基]丙酸(也称为例如(2S)-3-苯基-2-[[4-(三氟甲基)苯甲酰基]氨基]丙酸),(2S)-3-苯基-2-[[(2S)-1,2,3,4-四氢化萘-2-羰基]氨基]丙酸甲酯(也称为例如(2S)-3-苯基-2-[[(2S)-1,2,3,4-四氢化萘-2-羰基]氨基]丙酸甲酯),2-[(5-甲氧基-1-苯并呋喃-2-羰基)氨基]-3-吡啶-2-基丙酸(也称为例如2-[(5-甲氧基-1-苯并呋喃-2-羰基)氨基]-3-吡啶-2-基丙酸),(2S)-2-[(5-甲氧基-1-苯并呋喃-2-羰基)氨基]-3-吡啶-2-基丙酸(也称为例如(2S)-2-[(5-甲氧基-1-苯并呋喃-2-羰基)氨基]-3-吡啶-2-基丙酸),2-[(5-甲氧基-1-苯并呋喃-2-羰基)氨基]-3-吡啶-3-基丙酸(也称为例如2-[(5-甲氧基-1-苯并呋喃-2-羰基)氨基]-3-吡啶-3-基丙酸),(2S)-2-[(5-甲氧基-1-苯并呋喃-2-羰基)氨基]-3-吡啶-3-基丙酸(也称为例如(2S)-2-[(5-甲氧基-1-苯并呋喃-2-羰基)氨基]-3-吡啶-3-基丙酸),2-[(5-氯-1H-吲哚-2-羰基)-氨基]-3-苯基-丙酸(也称为例如2-[(5-氯-1H-吲哚-2-羰基)氨基]-3-苯基丙酸),2-[(5-氟-1-苯并噻吩-2-基)甲酰胺基]-3-苯基丙酸(也称为例如2-[(5-氟-1-苯并噻吩-2-羰基)氨基]-3-苯基丙酸),(S)-2-(5-氟苯并[b]噻吩-2-甲酰胺基)-3-苯基丙酸(也称为例如(2S)-2-[(5-氟-1-苯并噻吩-2-羰基)氨基]-3-苯基丙酸),2-[(6-氟-1-苯并噻吩-2-羰基)氨基]-3-苯基丙酸(也称为例如2-[(6-氟-1-苯并噻吩-2-羰基)氨基]-3-苯基丙酸),N-((5-氯-8-羟基-3-甲基-1-氧代-7-异色满基)羰基)丝氨酸(也称为例如(2S)-2-[[(3R)-5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-羟基丙酸),2-(S)-[(5-氯-1H-吡咯并[2,3-c]吡啶-2-羰基)氨基]-3-苯基丙酸(也称为例如(2S)-2-[(5-氯-1H-吡咯并[2,3-c]吡啶-2-羰基)氨基]-3-苯基丙酸),(2S)-2-[[(Z)-3-氯-3-(4-甲基苯基)丙-2-烯酰基]氨基]-3-苯基丙酸(也称为例如(2S)-2-[[(Z)-3-氯-3-(4-甲基苯基)丙-2-烯酰基]氨基]-3-苯基丙酸),(2S)-3-苯基-2-[(4-苯基苯甲酰基)氨基]丙酸(也称为例如(2S)-3-苯基-2-[(4-苯基苯甲酰基)氨基]丙酸),(2S)-3-(3-氯苯基)-2-[[5-(二甲基氨基)吡啶-2-羰基]氨基]丙酸(也称为例如(2S)-3-(3-氯苯基)-2-[[5-(二甲基氨基)吡啶-2-羰基]氨基]丙酸),N-[(5-甲氧基-1-甲基-1H-吲哚-2-基)羰基]-L-苯丙氨酸(也称为例如(2S)-2-[(5-甲氧基-1-甲基吲哚-2-羰基)氨基]-3-苯基丙酸),(2S)-2-[(2-甲基-1-氧代-3,4-二氢异喹啉-3-羰基)氨基]-3-苯基丙酸(也称为例如(2S)-2-[(2-甲基-1-氧代-3,4-二氢异喹啉-3-羰基)氨基]-3-苯基丙酸),1-((5-氯-8-羟基-3-甲基-1-氧代-7-异色满基)羰基)-脯氨酸(也称为例如(2S)-1-[(3R)-5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]吡咯烷-2-羧酸),3-(3-氟苯基)-2-[[4-(三氟甲基)苯甲酰基]氨基]丙酸(也称为例如3-(3-氟苯基)-2-[[4-(三氟甲基)苯甲酰基]氨基]丙酸),N-((5-氯-8-羟基-3-甲基-1-氧代-7-异色满基)羰基)缬氨酸(也称为例如(2S)-2-[[(3R)-5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-甲基丁酸),N-[(5-氯-1-甲基-1H-吲哚-2-基)羰基]-L-苯丙氨酸(也称为例如(2S)-2-[(5-氯-1-甲基吲哚-2-羰基)氨基]-3-苯基丙酸),3-(2-氟苯基)-2-[(5-甲氧基-1-苯并呋喃-2-羰基)氨基]丙酸(也称为例如3-(2-氟苯基)-2-[(5-甲氧基-1-苯并呋喃-2-羰基)氨基]丙酸),(2S)-3-(2-氟苯基)-2-[(5-甲氧基-1-苯并呋喃-2-羰基)氨基]丙酸(也称为例如(2S)-3-(2-氟苯基)-2-[(5-甲氧基-1-苯并呋喃-2-羰基)氨基]丙酸),N-((5-氯-8-羟基-3-甲基-1-氧代-7-异色满基)羰基)苏氨酸(也称为例如(2S,3R)-2-[[(3R)-5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-羟基丁酸),(2S)-2-[(2,3,4,5,6-五氟苯甲酰基)氨基]-3-苯基丙酸(也称为例如(2S)-2-[(2,3,4,5,6-五氟苯甲酰基)氨基]-3-苯基丙酸),N-((5-氯-8-羟基-3-甲基-1-氧代-7-异色满基)羰基)半胱氨酸(也称为例如2-[(5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基)氨基]-3-硫烷基丙酸),(2S)-2-[(3-氯-4-丙-2-烯氧基苯甲酰基)氨基]-3-苯基丙酸(也称为例如(2S)-2-[(3-氯-4-丙-2-烯氧基苯甲酰基)氨基]-3-苯基丙酸),2-[(6-甲基-5,8-二氧代萘-2-羰基)氨基]-3-苯基丙酸(也称为例如2-[(6-甲基-5,8-二氧代萘-2-羰基)氨基]-3-苯基丙酸),(S)-2-[(2-丁基-4-氯-1-甲基-1H-咪唑-5-基)羰基氨基]-3-苯基丙酸(也称为例如(S)-2-[(2-丁基-5-氯-3-甲基咪唑-4-羰基)氨基]-3-苯基丙酸),赭曲霉毒素B(也称为例如(2S)-2-[[(3R)-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-苯基丙酸),2-[(8-羟基-3-甲基-1-氧代异色满-7-羰基)氨基]-3-苯基丙酸(也称为例如2-[(8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基)氨基]-3-苯基丙酸),2-[(8-羟基-5-甲基-1-氧代-3,4-二氢异色烯-7-羰基)氨基]-3-苯基丙酸(也称为例如2-[(8-羟基-5-甲基-1-氧代-3,4-二氢异色烯-7-羰基)氨基]-3-苯基丙酸),1-((5-氯-8-羟基-3-甲基-1-氧代-7-异色满基)羰基)-4-羟基脯氨酸(也称为例如1-(5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基)-4-羟基吡咯烷-2-羧酸),N-((5-氯-8-羟基-3-甲基-1-氧代-7-异色满基)羰基)-亮氨酸(也称为例如(2S)-2-[[(3R)-5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-4-甲基戊酸),2-[(1-氯-4-羟基异喹啉-3-羰基)氨基]-3-苯基丙酸(也称为例如2-[(1-氯-4-羟基异喹啉-3-羰基)氨基]-3-苯基丙酸),3-(4-氯苯基)-2-[[4-(三氟甲基)苯甲酰基]氨基]丙酸(也称为例如3-(4-氯苯基)-2-[[4-(三氟甲基)苯甲酰基]氨基]丙酸),N-((5-氯-8-羟基-3-甲基-1-氧代-7-异色满基)羰基)-天冬氨酸(也称为例如(2S)-2-[[(3R)-5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]丁二酸),2-(5H-色烯并[3,4-c]吡啶-8-羰基氨基)-3-苯基丙酸(也称为例如2-(5H-色烯并[3,4-c]吡啶-8-羰基氨基)-3-苯基丙酸),(S)-2-(3-氯-5-氟苯并[b]噻吩-2-甲酰胺基)-3-苯基丙酸(也称为例如(2S)-2-(3-氯-5-氟-1-苯并噻吩-2-羰基)氨基]-3-苯基丙酸),N-[(4,7-二甲氧基-1-甲基-1H-吲哚-2-基)羰基]-L-苯丙氨酸(也称为例如(2S)-[(4,7-二甲氧基-1-甲基吲哚-2-羰基)氨基]-3-苯基丙酸),赭曲霉毒素B甲酯(也称为例如(2S)-2-[[(3R)-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-苯基丙酸甲酯),(3R-反式)-N-((3,4-二氢-4,8-二羟基-3-甲基-1-氧代-1H-2-苯并吡喃-7-基)羰基)-L-苯丙氨酸(也称为例如(2S)-2-[[(3R,4S)-4,8-二羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-苯基丙酸),4-羟基赭曲霉毒素B(也称为例如(2S)-2-[[(3R)-4,8-二羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-苯基丙酸),(4R)-4-羟基赭曲霉毒素B(也称为例如(2S)-2-[[(3R,4R)-4,8-二羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-苯基丙酸),赭曲霉毒素氢醌(也称为例如(2S)-2-[[(3R)-5,8-二羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-苯基丙酸),N-((5-氯-8-羟基-3-甲基-1-氧代-7-异色满基)羰基-谷氨酸(也称为例如(2S)-2-[[(3R)-5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-戊二酸),2-[(1-氯-4-羟基异喹啉-3-羰基)氨基]-3-(4-羟基苯基)丙酸(也称为例如2-[(1-氯-4-羟基异喹啉-3-羰基)氨基]-3-(4-羟基苯基)丙酸),N-((5-氯-8-羟基-3-甲基-1-氧代-7-异色满基)羰基)甲硫氨酸(也称为例如(2S)-2-[[(3R)-5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-4-甲基硫烷基丁酸),2-[[(3R)-5-氯-8-羟基-3-甲基-3,4-二氢-1H-异色烯-7-羰基]氨基]-3-苯基丙酸(也称为例如2-[[(3R)-5-氯-8-羟基-3-甲基-3,4-二氢-1H-异色烯-7-羰基]氨基]-3-苯基丙酸),(2S)-2-[[(3R)-5-氯-8-羟基-3-甲基-3,4-二氢-1H-异色烯-7-羰基]氨基]-3-苯基丙酸(也称为例如(2S)-2-[[(3R)-5-氯-8-羟基-3-甲基-3,4-二氢-1H-异色烯-7-羰基]氨基]-3-苯基丙酸),(2S)-2-[(5-氯-8-羟基-1-氧代-3,4-二氢异色烯-7-羰基)氨基]-3-苯基丙酸(也称为例如(2S)-2-[(5-氯-8-羟基-1-氧代-3,4-二氢异色烯-7-羰基)氨基]-3-苯基丙酸),(2S)-2-[(4-碘苯甲酰基)氨基]-3-苯基丙酸(也称为例如(2S)-2-[(4-碘苯甲酰基)氨基]-3-苯基丙酸),赫曲霉毒素B乙酯(也称为例如2-[(8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基)氨基]-3-苯基丙酸乙酯),(R)N-(5-氯-3,4-二氢-8-羟基-3-甲基-1-氧代-1H-2-苯并吡喃-7-基)苯丙氨酸(也称为例如2-[(5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基)氨基]-3-苯基丙酸),苯丙氨酸-赭曲霉毒素A(也称为例如2-[[(3R)-5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-苯基丙酸),N-[(3R)-5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢-1H-2-苯并吡喃-7-羰基]-D-苯丙氨酸(也称为例如(2R)-2-[[(3R)-5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-苯基丙酸),3S14S-赭曲霉毒素A(也称为例如(2S)-2-[[(3S)-5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-苯基丙酸),(R)-N-[(5-氯-3,4-二氢-8-羟基-3-甲基-1-氧代-1H-苯并(c)吡喃-7-基)羰基]-3-苯丙氨酸(也称为例如(2R)-2-[(5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基)氨基]-3-苯基丙酸),N-[(5-氯-3,4-二氢-8-羟基-3-甲基-1-氧代-1H-2-苯并吡喃-7-基)羰基]-L-苯丙氨酸(也称为例如(2S)-2-[(5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基)氨基]-3-苯基丙酸),3S14R-赭曲霉毒素A(也称为例如(2R)-2-[[(3S)-5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-苯基丙酸),N-((5-氯-3,4-二氢-3-甲基-1-氧代-1H-2-苯并吡喃-7-基)羰基)-L-酪氨酸(也称为例如(2S)-2-[(5-氯-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基)氨基]-3-(4-羟基苯基)丙酸),2-[(8-羟基-5-甲基氯酸基-1-氧代-3,4-二氢异色烯-7-羰基)氨基]-3-苯基丙酸(2-[(8-Hydroxy-5-methylchloranuidyl-1-oxo-3,4-dihydroisochromene-7-carbonyl)amino]-3-phenylpropanoic acid)(也称为例如2-[(8-羟基-5-甲基氯酸基-1-氧代-3,4-二氢异色烯-7-羰基)氨基]-3-苯基丙酸(2-[(8-hydroxy-5-methylchloranuidyl-1-oxo-3,4-dihydroisochromene-7-carbonyl)amino]-3-phenylpropanoic acid)),赫曲霉毒素A-D4(也称为例如(2S)-2-[[(3R)-5-氯-3-氘代-8-羟基-1-氧代-3-(三氘代甲基)-4H-异色烯-7-羰基]氨基]-3-苯基丙酸),赫曲霉毒素A-d5溶液,在乙腈中10mug/mL,分析标准(也称为例如(2S)-2-[[(3R)-5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-(2,3,4,5,6-五氘代苯基)丙酸),(S)-3-(4-溴苯基)-2-(5-(叔丁基)噻吩-2-甲酰胺基)丙酸(也称为例如(2S)-3-(4-溴苯基)-2-[(5-叔丁基噻吩-2-羰基)氨基]丙酸),BrC1=CC=C(C=C1)CC(C(=O)O)NC(=O)C=1SC(=CC=1)C(C)(C)C(也称为例如3-(4-溴苯基)-2-[(5-叔丁基噻吩-2-羰基)氨基]丙酸),5-氯-8-羟基-3-甲基-N-[(2S)-1-(甲基氨基)-1-氧代-3-苯基丙-2-基]-1-氧代-3,4-二氢异色烯-7-甲酰胺(也称为例如5-氯-8-羟基-3-甲基-N-[(2S)-1-(甲基氨基)-1-氧代-3-苯基丙-2-基]-1-氧代-3,4-二氢异色烯-7-甲酰胺),赫曲霉毒素A甲酯(也称为例如(2S)-2-[[(3R)-5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-苯基丙酸甲酯),(R)-N-((5-氯-3,4-二氢-8-羟基-3-甲基-1,4-二氧代-1H-2-苯并吡喃-7-基)羰基)-L-苯丙氨酸(也称为例如(2S)-2-[[(3R)-5-氯-8-羟基-3-甲基-1,4-二氧代异色烯-7-羰基]氨基]-3-苯基丙酸),O-甲基赫曲霉毒素A(也称为例如(2S)-2-[[(3R)-5-氯-8-甲氧基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-苯基丙酸),(2R)-2-[(5-氯-8-羟基-3,3-二甲基-1-氧代-4H-异色烯-7-羰基)氨基]-3-苯基丙酸(也称为例如(2R)-2-[(5-氯-8-羟基-3,3-二甲基-1-氧代-4H-异色烯-7-羰基)氨基]-3-苯基丙酸),(2S)-2-[[(3R)-5-氯-3-乙基-8-羟基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-苯基丙酸(也称为例如(2S)-2-[[(3R)-5-氯-3-乙基-8-羟基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-苯基丙酸),4-羟基赭曲霉毒素A(也称为例如(2S)-2-[[(3R,4R)-5-氯-4,8-二羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-苯基丙酸),(2S)-2-[[(3R)-5-氯-8-羟基-3-(羟甲基)-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-苯基丙酸(也称为例如(2S)-2-[[(3R)-5-氯-8-羟基-3-(羟甲基)-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-苯基丙酸),(4S)-4-羟基赭曲霉毒素A(也称为例如(2S)-2-[[(3R,4S)-5-氯-4,8-二羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-苯基丙酸),N-((5-氯-8-羟基-3-甲基-1-氧代-7-异色满基)羰基)酪氨酸(也称为例如赭曲霉毒素TA,或(2S)-2-[(5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基)氨基]-3-(4-羟基苯基)丙酸),2-[[3,4-二氢-1-氧代-3-甲基-4,8-二羟基-5-氯-1H-2-苯并吡喃-7-基]羰基氨基]-3-苯基丙酸(也称为例如2-[(5-氯-4,8-二羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基)氨基]-3-苯基丙酸),10-羟基赫曲霉毒素A(也称为例如(2S)-2-[[(3S)-5-氯-8-羟基-3-(羟基甲基)-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-苯基丙酸),2-[(8-羟基-5-甲基氯酸基-1-氧代-3,4-二氢异色烯-7-羰基)氨基]-3-(4-羟基苯基)丙酸(2-[(8-Hydroxy-5-methylchloranuidyl-1-oxo-3,4-dihydroisochromene-7-carbonyl)amino]-3-(4-hydroxyphenyl)propanoic acid)(也称为例如2-[(8-羟基-5-甲基氯酸基-1-氧代-3,4-二氢异色烯-7-羰基)氨基]-3-(4-羟基苯基)丙酸(2-[(8-hydroxy-5-methylchloranuidyl-1-oxo-3,4-dihydroisochromene-7-carbonyl)amino]-3-(4-hydroxyphenyl)propanoicacid)),3-[[(1S)-1-羧基-2-苯基乙基]氨基甲酰基]-5-氯-2-羟基-6-[(2S)-2-羟基丙基]苯甲酸(也称为例如3-[[(1S)-1-羧基-2-苯基乙基]氨基甲酰基]-5-氯-2-羟基-6-[(2S)-2-羟基丙基]苯甲酸),赫曲霉毒素A13C20(也称为例如(2S)-2-[[(3R)-5-氯-8-羟基-3-(113C)甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-((1,2,3,4,5,6-13C6)环六三烯基)(1,2,3-13C3)丙酸),赫曲霉毒素C(也称为例如(2S)-2-[[(3R)-5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-苯基丙酸乙酯),赭曲霉毒素A-O-甲基甲酯(也称为例如(2S)-2-[[(3R)-5-氯-8-甲氧基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-苯基丙酸甲酯),2-[(5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢-1H-2-苯并吡喃-7-基)甲酰胺基]-3-苯基丙酸乙酯(也称为例如2-[(5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基)氨基]-3-苯基丙酸乙酯),赭曲霉毒素TC(也称为例如(2S)-2-[(5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基)氨基]-3-(4-羟基苯基)丙酸乙酯),N-[[3-(4-羧基丁基)-5-氯-3,4-二氢-8-羟基-1-氧代-1H-2-苯并吡喃-7-基]羰基]-L-苯丙氨酸(也称为例如5-[7-[[(1S)-1-羧基-2-苯基乙基]氨基甲酰基]-5-氯-8-羟基-1-氧代-3,4-二氢异色烯-3-基]戊酸),6-({(2S)-2-[(5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢-1H-2-苯并吡喃-7-羰基)氨基]-3-苯基丙酰基}氨基)己酸(也称为例如6-[[(2S)-2-[(5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基)氨基]-3-苯基丙酰基]氨基]己酸),4-(5-羧基戊基)-N-[(5-氯-3,4-二氢-8-羟基-3-甲基-1-氧代-1H-2-苯并吡喃-7-基)羰基]-L-苯丙氨酸(也称为例如6-[4-(2S)-2-羧基-2-[(5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基)氨基]乙基]苯基]己酸),6-[4-[2-[(5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基)氨基]-3-[(2-甲基丙-2-基)氧基]-3-氧代丙基]苯基]己酸(也称为例如6-[4-[2-[(5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基)氨基]-3-[(2-甲基丙-2-基)氧基]-3-氧代丙基]苯基]己酸),(2S)-2-[[3-[5-(1-氨基丁基氨基)-5-氧代戊基]-5-氯-8-羟基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-(3-丙-2-基苯基)丙酸(也称为例如(2S)-2-[[3-[5-(1-氨基丁基氨基)-5-氧代戊基]-5-氯-8-羟基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-(3-丙-2-基苯基)丙酸),赭曲霉毒素A纤维二糖酯(也称为例如[(2R,3S,4R,5R,6R)-4,5,6-三羟基-3-[(2S,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)氧杂-2-基]氧基氧杂-2-基]甲基(2S)-2-[[(3R)-5-氯-8-羟基-3-甲基-1-氧代-3,4-二氢异色烯-7-羰基]氨基]-3-苯基丙酸酯),赭曲霉毒素A苯酚-葡糖苷酸,赭曲霉毒素A氨基-葡糖苷酸,赭曲霉毒素A酰基-葡糖苷酸。特别地,术语“OTA衍生物”可以指选自赭曲霉毒素B和赭曲霉毒素C的化合物或物质。
注意如本文所用,单数形式“一个/一种”和“所述/该”包括复数指代,除非上下文另有明确指示。因此,例如提及“试剂”包括一种或多种这样的不同试剂,提及“方法”包括提及本领域普通技术人员已知的等同步骤和方法,其可以被修饰或替代本文所述的方法。
除非另有说明,在一系列要素之前的术语“至少”应理解为是指该系列中的每个要素。本领域技术人员将认识到或能够使用不超过常规实验确定本文所述的本发明的具体实施方案的许多等同方案。这些等同方案也意在被本发明涵盖。
术语“和/或”无论在本文何处使用都包括“和”、“或”和“由所述术语连接的要素的全部或任何其它组合”的含义。
当在本文使用时,术语“约”或“大约”意指在给定值或范围的20%内,优选地在10%内和更优选地在5%内。
在整个说明书和随后的权利要求书中,除非上下文另有要求,词语“包含(comprise)”及其诸如“包含(comprises)”和“包含(comprising)”的变形应理解为暗示包括所述的整数或步骤或者整数或步骤的组,但不排除任何其它整数或步骤或者整数或步骤的组。当在本文使用时,术语“包含”可以用术语“含有”或“包括”代替,或者有时当在本文使用时用术语“具有”代替。
当在本文使用时,“由…组成”排除未在请求保护的要素中指定的任何要素、步骤或成分。当在本文使用时,“基本上由…组成”不排除对请求保护的基本特征和新特征没有实质性影响的材料或步骤。
在本文的每个实例中,术语“包括(包含)”、“基本上由…组成”和“由…组成”中的任何一个都可以被其他两个术语中的任何一个代替。
本发明的目的已经通过提供如本文所述的手段和方法实现,例如,通过提供能够使赭曲霉毒素解毒的多肽,所述赭曲霉毒素例如赭曲霉毒素A(OTA)和/或至少一种OTA衍生物(例如如上文所列,例如选自以下的化合物或物质:呋喃基丙烯酰基苯丙氨酸(也称为例如(2S)-2-[3-(呋喃-2-基)丙-2-烯酰氨基]-3-苯基丙酸),N-(3-(2-呋喃基)丙烯酰基)苯丙氨酸(也称为例如(2S)-2-[[(E)-3-(呋喃-2-基)丙-2-烯酰基]氨基]-3-苯基丙酸),L-苯丙氨酸等,优选地,所述至少一种OTA衍生物是赭曲霉毒素B和/或赭曲霉毒素C),其中所述多肽是与选自SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4的氨基酸序列具有至少64%序列同一性的多肽。如下文实施例部分中所示,例如,当本发明的多肽(例如SEQID NOs:1-4)是膳食设置的一部分时,观察到血浆和尿液二者中OTA浓度的降低,证明了本发明的酶在食物/饲料中用于OTA解毒的适用性。
在一些实施方案/方面,本发明涉及一种能够使赭曲霉毒素(例如CN108120791)例如赭曲霉毒素A(OTA)和/或至少一种OTA衍生物(例如如本文所定义的,例如选自以下的化合物或物质:呋喃基丙烯酰基苯丙氨酸(也称为例如(2S)-2-[3-(呋喃-2-基)丙-2-烯酰氨基]-3-苯基丙酸)、N-(3-(2-呋喃基)丙烯酰基)苯丙氨酸(也称为例如(2S)-2-[[(E)-3-(呋喃-2-基)丙-2-烯酰基]氨基]-3-苯基丙酸),L-苯基丙酸等,优选地,所述至少一种OTA衍生物是赭曲霉毒素B和/或赭曲霉毒素C)解毒(例如修饰或水解)的多肽,其中所述多肽为以下中的一种或多种:(a)与选自SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4的氨基酸序列具有至少60%序列同一性(例如至少64%、65%、66%、67%、68%、69%、70%、71%、72%、73%、74%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%)的多肽;优选地,所述多肽具有选自SEQ ID NOs:1-4的氨基酸序列;进一步优选地,所述多肽具有SEQ ID NO:1;(b)多肽(a)的变体,其中所述变体在一个或多个位置处包含取代、缺失和/或插入;(c)(a)或(b)的多肽的片段,其中所述片段能够使OTA和/或至少一种OTA衍生物解毒;(d)包含以下氨基酸序列(例如保守基序)中的一个或多个的多肽:(i)GHACGHNLIA(SEQ ID NO:5);(ii)IGSPAEEGGGGK(SEQ ID NO:6);(iii)MAHP(SEQ ID NO:7);(iv)VNHT(SEQ ID NO:23);(v)KVAKGLA(SEQ IDNO:9);(vi)IGSPAEEGGGGKVIL(SEQ ID NO:10);(vii)AHAGAAPWLG(SE ID NO:11);(viii)PELGFHEVKA(SEQ ID NO:12);(ix)TNPTSLPTAFVAT(SEQ ID NO:13);(x)GGRTFGFNAEYDAL(SEQ ID NO:14);(xi)GHACGHNLIAIVAVASA(SEQ ID NO:15);(xii)IPGTIKVIGSPAEEGGGGKVILLNEG(SEQ ID NO:16);(xiii)DACVMAHPEGG(SEQ ID NO:17);(xiv)AHAGAAPWLGVNALDAAVQGY(SEQ ID NO:18);(xv)GHACGHNLIAXXAVAXAXGXKAAXXXXXIXGTXKXIGSPAEEGGGGKXILXNEGXYDXXDACXMAHPXGG(SEQ ID NO:19),其中X为任何氨基酸;(xvi)(i)、(ii)、(iii)和(iv),例如SEQ ID NOs:5、6、7和23;(xvii)AHAGAAPW(SEQ ID NO:8)。
在本发明的一些实施方案/方面,所述多肽选自SEQ ID NOs:1-4;优选地,所述多肽具有SEQ ID NO:1。
在本发明的一些实施方案/方面,所述多肽能够以至少0.01U/g(例如如本文实施例2中所示,例如至少0.05、0.1、0.5、0.75、1.0、1.2、2、5、7或10U/g)的比活性降解赭曲霉毒素A。
在本发明的一些实施方案/方面,所述多肽包含以下氨基酸序列(例如保守基序)中的一个或多个:(i)GHACGHNLIA(SEQ ID NO:5);(ii)IGSPAEEGGGGK(SEQ ID NO:6);(iii)MAHP(SEQ ID NO:7);(iv)VNHT(SEQ ID NO:23);(v)KVAKGLA(SEQ ID NO:9);(vi)IGSPAEEGGGGKVIL(SEQ ID NO:10);(vii)AHAGAAPWLG(SE ID NO:11);(viii)PELGFHEVKA(SEQ ID NO:12);(ix)TNPTSLPTAFVAT(SEQ ID NO:13);(x)GGRTFGFNAEYDAL(SEQ ID NO:14);(xi)GHACGHNLIAIVAVASA(SEQ ID NO:15);(xii)IPGTIKVIGSPAEEGGGGKVILLNEG(SEQID NO:16);(xiii)DACVMAHPEGG(SEQ ID NO:17);(xiv)AHAGAAPWLGVNALDAAVQGY(SEQ IDNO:18);(xv)GHACGHNLIAXXAVAXAXGXKAAXXXXXIXGTXKXIGSPAEEGGGGKXILXNEGXYDXXDACXMAHPXGG(SEQ ID NO:19),其中X为任何氨基酸;(xvi)(i)、(ii)、(iii)和(iv),例如SEQ IDNOs:5、6、7和23;(xvii)AHAGAAPW(SEQ ID NO:8);(xviii)与选自(i)-(xvii)的氨基酸序列具有至少70%序列同一性(例如至少71%、74%、80%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、100%)的多肽;(xix)与(xv)的氨基酸序列具有至少70%同一性的多肽;和/或与(viii)-(xiv)中的任一个具有至少80%同一性的多肽;和/或与(vi)和/或(vii)具有至少90%同一性的多肽;(xx)具有氨基酸序列(i)、(ii)、(iii)、(iv)、(v)、(vi)、(vii)、(viii)、(ix)、(x)、(xi)、(xii)、(xiii)或(xiv)的多肽的变体,其中所述变体在一个或多个位置处包含取代、缺失和/或插入;(xxi)包含氨基酸序列:(i)、(ii)、(iii)和(iv)的多肽。
在本发明的一些实施方案/方面,所述使赭曲霉毒素A(OTA)解毒包含水解OTA的酰胺键或由水解OTA的酰胺键组成。
在本发明的一些实施方案/方面,所述多肽具有酰胺水解酶活性(例如EC3.5.1.-,例如EC 3.5.1.14(氨基酰化酶1))。“EC 3.5.1.-”可以指EC编号,其中“-”可以是1至135中的任何数字。例如,在此上下文中“-”可以与“X”互换使用,即EC 3.5.1.-可以与EC 3.5.1.X互换使用,其中X可以是1至135中的任何数字。
在本发明的一些实施方案/方面,所述多肽是以下中的一种或多种:(a)所述多肽属于M20肽酶氨基酰化酶1样蛋白2样酰胺水解酶亚家族(例如M20肽酶ACY1L2酰胺水解酶亚家族,例如具有根据保守域数据库(Conserved Domain Database)(例如https://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=cd05672)的标识符cd05672),优选地所述M20肽酶ACY1L2酰胺水解酶亚家族的特征在于具有金属(例如Zn)结合位点,进一步优选地所述金属结合位点包含选自CHEH[K,H](SEQ ID NO:20)、CXHXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXE(SEQ ID NO:21)和CHEEH[K,H](SEQ ID NO:22)的氨基酸序列基序;和/或(b)所述多肽包含:在对应于SEQ ID NO:1的位置123的位置处的氨基酸C或等同氨基酸;在对应于SEQ ID NO:1的位置125的位置处的氨基酸H或等同氨基酸;在对应于SEQ IDNO:1的位置160和/或161的位置处、优选在对应于SEQ ID NO:1的位置161的位置处的氨基酸E或等同氨基酸;在对应于SEQ ID NO:1的位置185的位置处的氨基酸H或等同氨基酸;和在SEQ ID NO:1的位置383处的氨基酸H或K(优选H)或等同氨基酸;优选地,使用SEQ ID NO:1的编号。
在本发明的一些实施方案/方面,所述多肽不具有氨基肽酶活性(例如EC3.4.11.10)和/或(ii)所述多肽为非肽酶和酰胺水解酶。
在本发明的一些实施方案/方面中,所述多肽另外能够降解和/或水解非OTA(例如OTA无关的)霉菌毒素(例如单端孢霉烯霉菌毒素,诸如例如脱氧雪腐镰刀菌烯醇、雪腐镰刀菌烯醇、新茄镰孢菌醇、trichotecin、扁虫菌素(crotocin)、杆孢菌素(roridin)A、葡萄穗霉毒素H、二乙酰藨草镰刀烯醇、HT-2毒素或T-2毒素;黄曲霉毒素,诸如例如黄曲霉毒素B1、B2、G1或G2;烟曲霉毒素,诸如例如烟曲霉毒素B1、B2、B3或B4;多肽霉菌毒素,诸如例如白僵菌毒素或恩镰孢菌素;玉米赤霉烯酮;桔霉素;棒曲霉素;麦角生物碱,诸如例如麦角胺)和/或一种或多种植物或细菌衍生的毒素(例如内毒素等)。
在一些实施方案/方面,本发明涉及一种编码和/或能够表达一种或多种本发明的多肽的多核苷酸、核酸构建体或表达载体。
在一些实施方案/方面,本发明涉及一种重组宿主细胞(例如分离的重组宿主细胞)、孢子、转基因植物、转基因种子或转基因花粉粒,其包含以下中的一种或多种:(i)一种或多种本发明的多肽;(ii)一种或多种本发明的多核苷酸;和/或(iii)一种或多种本发明的核酸构建体和/或表达载体。
在一些实施方案/方面,本发明涉及一种食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元、中间益生元和/或它们的混合物,其包含以下中的一种或多种:一种或多种本发明的多肽、多核苷酸、核酸构建体、表达载体、重组宿主细胞、孢子、转基因植物、转基因种子和/或转基因花粉粒。
在一些实施方案/方面,本发明涉及一种包含以下中的一种或多种的组合物或试剂盒:本发明的多肽、多核苷酸、核酸构建体、表达载体、重组宿主细胞、孢子、转基因植物、转基因种子和/或转基因花粉粒、食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂、益生元、中间益生元和/或它们的混合物。
在本发明的一些实施方案/方面,所述组合物或试剂盒是以下中的一种或多种:无细胞的、非天然存在的和/或分级分离的组合物或试剂盒。
在本发明的一些实施方案/方面,所述组合物或试剂盒进一步包含以下中的一种或多种:(i)能够使赭曲霉毒素A(OTA)和/或至少一种OTA衍生物(例如如本文所定义的,例如选自以下的化合物或物质:呋喃基丙烯酰基苯丙氨酸(也称为例如(2S)-2-[3-(呋喃-2-基)丙-2-烯酰氨基]-3-苯基丙酸)、N-(3-(2-呋喃基)丙烯酰基)苯丙氨酸(也称为例如(2S)-2-[[(E)-3-(呋喃-2-基)丙-2-烯酰基]氨基]-3-苯基丙酸),L-苯基丙酸等,优选地所述至少一种OTA衍生物为赭曲霉毒素B和/或赭曲霉毒素C)解毒(例如修饰和/或水解)和/或结合所述赭曲霉毒素A(OTA)和/或至少一种OTA衍生物的一种或多种其它多肽,进一步优选地所述一种或多种其它多肽包含羧肽酶活性(例如羧肽酶A和/或B活性,例如分别具有EC3.4.17.1和/或EC 3.4.17.2)和/或嗜热菌蛋白酶活性(例如具有EC 3.4.24.27);(ii)能够使一种或多种其它霉菌毒素(例如单端孢霉烯霉菌毒素,诸如例如脱氧雪腐镰刀菌烯醇、雪腐镰刀菌烯醇、新茄镰孢菌醇、trichotecin、扁虫菌素(crotocin)、杆孢菌素(roridin)A、葡萄穗霉毒素H、二乙酰藨草镰刀烯醇、HT-2毒素或T-2毒素;黄曲霉毒素,诸如例如黄曲霉毒素B1、B2、G1或G2;烟曲霉毒素,诸如例如烟曲霉毒素B1、B2、B3或B4;多肽霉菌毒素,诸如例如白僵菌毒素或恩镰孢菌素;玉米赤霉烯酮;桔霉素;棒曲霉素;麦角生物碱,诸如例如麦角胺)和/或一种或多种植物和/或细菌衍生的毒素(例如内毒素等)解毒的一种或多种其它多肽,特别是能够使一种或多种其它霉菌毒素和/或一种或多种植物和/或细菌衍生的毒素解毒的所述一种或多种其它多肽,例如伏马菌素酯酶(例如如WO 2016/134387 A1中公开)和/或玉米赤霉烯酮内酯酶(例如如WO 2020/025580 A1中公开)和/或ergopeptine水解酶(例如如WO 2014/056006 A1中公开);(iii)一种或多种有机吸收剂(例如活的、失活的、冻干的、休眠的和/或死的全酵母或酵母衍生的产物,诸如例如酵母细胞壁,或酵母寡糖,诸如例如甘露聚糖)和/或一种或多种无机吸收剂(例如硅藻土和/或粘土矿物,诸如例如高岭土或高岭石,绿土,诸如例如蒙脱石、伊利石或绿泥石;特别是膨润土);(iv)能够使一种或多种其它霉菌毒素(例如单端孢霉烯霉菌毒素,诸如例如脱氧雪腐镰刀菌烯醇、雪腐镰刀菌烯醇、新茄镰孢菌醇、trichotecin、扁虫菌素(crotocin)、杆孢菌素(roridin)A、葡萄穗霉毒素H、二乙酰藨草镰刀烯醇、HT-2毒素或T-2毒素;黄曲霉毒素,诸如例如黄曲霉毒素B1、B2、G1或G2;烟曲霉毒素,诸如例如烟曲霉毒素B1、B2、B3或B4;多肽霉菌毒素,诸如例如白僵菌毒素或恩镰孢菌素;玉米赤霉烯酮;桔霉素;棒曲霉素;麦角生物碱,诸如例如麦角胺)和/或一种或多种植物或细菌衍生的毒素(例如内毒素等)解毒的一种或多种活的、灭活的、冻干的和/或休眠的微生物,特别地所述微生物选自:毛孢子菌属(Trichosporon)和Apriotrichum属(例如如WO 03/053161 A1中公开)和红蝽菌科(Coriobacteriaceae)(例如如EP 3 501 526 A1中公开);(v)一种或多种植物产品(例如海草,优选海草粉;和/或藻类,优选藻粉;和/或蓟,优选蓟种子;和/或甘草属植物制剂,优选甘草粉和/或甘草提取物,例如如WO 2018/121881 A1中公开);(vi)一种或多种调味化合物(例如植物提取物,例如来自牛至、百里香、冬青、香菜、墨角兰、薄荷、茴芹、橙、柠檬、茴香、八角、丁香、肉桂和/或大蒜;和/或精油,诸如例如D-柠檬烯、γ-萜品烯、对-伞花烃、2-蒈烯、芳樟醇氧化物、异薄荷酮、樟脑、芳樟醇、萜品烯-4-醇、2-异丙基-1-甲氧基-4-甲基苯、L-薄荷醇、乙胺、α-萜品醇、β-石竹烯、D-香芹酮、水杨酸甲酯、α-石竹烯、乙酸薰衣草酯、氧化石竹烯、丁子香酚、百里酚和/或香芹酚);(vii)一种或多种维生素(例如维生素A、D、E、K、C、B1、B2、B3、B4、B5、B6、B7、B8、B9和/或B12;特别是维生素E)。
特别地,所述组合物或试剂盒进一步包含以下中的一种或多种:膨润土、伏马菌素酯酶和/或玉米赤霉烯酮内酯酶、能够使一种或多种霉菌毒素解毒的红蝽菌科微生物(例如选自红蝽菌科的微生物,例如https://lpsn.dsmz.de/family/coriobacteriaceae)、硅藻土、酵母(特别是灭活的酵母)、海草粉、蓟种子和一种或多种调味化合物。
除了根据本发明的至少一种多肽之外,本发明的其它组合物(例如下表II中的示例性组合物1-24)或试剂盒(对应于下表II中的示例性组合物1-24)还可以包含一种或多种其它组分。这些进一步的示例性组合物或试剂盒明确公开于本文的表II中,其显示了本发明的实施方案。
表II.包含一种或多种其它组分的本发明的示例性组合物或试剂盒。
在本发明的一些实施方案/方面,所述组合物或试剂盒是药物、兽医、诊断、解毒、监测和/或筛选组合物或试剂盒。
在一些实施方案/方面,本发明涉及用于生产食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元、中间益生元和/或它们的混合物的方法,所述方法包括:(a)提供:(i)一种或多种本发明的多肽;(ii)一种或多种本发明的多核苷酸;(iii)一种或多种本发明的核酸构建体和/或表达载体和/或(iv)一种或多种本发明的重组宿主细胞、孢子、转基因植物、转基因种子和/或转基因花粉粒;优选地,所述一种或多种多肽是一种或多种重组和/或分离的多肽;(b)将(a)应用于适用于生产食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元、中间益生元和/或它们的混合物的营养源或材料。
在本发明的一些实施例/方面,所述方法进一步包括:在适用于使赭曲霉毒素A(OTA)和/或至少一种赭曲霉毒素A衍生物解毒和/或改变OTA和/或OTA衍生物的毒性的条件下,将所述营养源或材料与(a)一起温育;优选地,所述方法进一步包括热处理和/或分级分离和/或干燥所述温育的产物。
在一些实施方案/方面,本发明涉及一种通过本发明的方法生产的食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元、中间益生元和/或它们的混合物。
在一些实施方案/方面,本发明涉及一种用于使赭曲霉毒素A(OTA)解毒和/或改变OTA和/或至少一种OTA衍生物的毒性的方法,所述方法包括:(a)提供:(i)根据前述项目中任一项所述的一种或多种多肽;(ii)根据前述项目中任一项所述的一种或多种多核苷酸;(iii)根据前述项目中任一项所述的一种或多种核酸构建体和/或表达载体和/或(iv)根据前述项目中任一项所述的一种或多种重组宿主细胞、孢子、转基因植物、转基因种子和/或转基因花粉粒;优选地,所述一种或多种多肽是一种或多种重组和/或分离的多肽;(b)将(a)应用于OTA和/或至少一种OTA衍生物。
在一些实施方案/方面,本发明的方法是体外或离体方法。
在本发明的一些实施方案/方面,本发明的多肽、多核苷酸、核酸构建体、表达载体、重组宿主细胞、孢子、转基因植物、转基因种子、转基因花粉粒、食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元、中间益生元或它们的混合物、组合物或试剂盒可以用于治疗、预防和/或作为药物(例如用于兽医用途)。
在本发明的一些实施方案/方面,本发明的多肽、多核苷酸、核酸构建体、表达载体、重组宿主细胞、孢子、转基因植物、转基因种子、转基因花粉粒、食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元、中间益生元或它们的混合物、组合物或试剂盒可以用于以下方法中的一种或多种:用于治疗、改善、预防和/或诊断霉菌毒素中毒、优选OTA霉菌毒素中毒的方法;用于监测霉菌毒素中毒的发展和/或评估霉菌毒素中毒预防和/或治疗、优选OTA霉菌毒素中毒预防和/或治疗的功效的方法;用于使赭曲霉毒素A(OTA)解毒和/或改变OTA和/或至少一种OTA衍生物的毒性的方法;生产以下中的一种或多种的方法:食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元,中间益生元;药物、兽医、诊断、解毒、监测和/或筛选组合物或试剂盒;本发明的任何方法;如上文所述的方法的任何组合;如上文所述的任何方法,其中所述方法是体外、离体或体内方法。
在一些实施方案/方面,本发明涉及根据前述项目中任一项所述的多肽、多核苷酸、核酸构建体、表达载体、重组宿主细胞、孢子、转基因植物、转基因种子、转基因花粉粒、食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元、中间益生元或它们的混合物、组合物或试剂盒中的一种或多种,其用于以下中的一种或多种/在以下中的一种或多种中的用途:霉菌毒素中毒、优选OTA霉菌毒素中毒的治疗、改善、预防和/或诊断;监测霉菌毒素中毒的发展和/或评估霉菌毒素中毒预防和/或治疗、优选OTA霉菌毒素中毒预防和/或治疗的功效;使赭曲霉毒素A(OTA)解毒和/或改变OTA和/或至少一种OTA衍生物的毒性;生产以下中的一种或多种:食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元,中间益生元;药物、兽医、诊断、解毒、监测和/或筛选组合物或试剂盒;在如上所述的任何方法中;如上所述的方法的任何组合,如上所述的任何用途,其中所述用途是体外、离体或体内用途。
应当理解,本发明不限于本文所述的特定方法、方案和试剂等,因此可以变化。本文所用的术语仅用于描述特定实施方案的目的,而非旨在限制本发明的范围,本发明的范围仅由权利要求书限定。
本说明书全文中引用的所有出版物和专利(包括所有专利、专利申请、科学出版物、制造商的说明书、指导书等),无论在上文还是下文,均以其全文通过引用并入本文。本文中没有任何内容被解释为承认本发明无权凭借在先发明而早于这种公开。在通过引用并入的材料与本说明书矛盾或不一致的程度上,本说明书将取代任何这样的材料。
本发明的特征还在于以下项目:
1.一种能够使赭曲霉毒素A(OTA)和/或至少一种OTA衍生物(例如如上文所列,例如选自以下的化合物或物质:呋喃基丙烯酰基苯丙氨酸(也称为例如(2S)-2-[3-(呋喃-2-基)丙-2-烯酰氨基]-3-苯基丙酸),N-(3-(2-呋喃基)丙烯酰基)苯丙氨酸(也称为例如(2S)-2-[[(E)-3-(呋喃-2-基)丙-2-烯酰基]氨基]-3-苯基丙酸),L-苯丙氨酸等,优选地,所述至少一种OTA衍生物是赭曲霉毒素B和/或赭曲霉毒素C)解毒(例如修饰或水解)的多肽,其中所述多肽是以下中的一种或多种:
a)与选自SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4的氨基酸序列具有至少60%序列同一性(例如至少64%、65%、66%、67%、68%、69%、70%、71%、72%、73%、74%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的多肽;优选地,所述多肽具有选自SEQID NOs:1-4的氨基酸序列;进一步优选地,所述多肽具有SEQ ID NO:1;
b)多肽(a)的变体,其中所述变体在一个或多个位置处包含取代、缺失和/或插入(例如所述变体具有一个或多个保守或等同取代,例如如上文表I中所示);
c)(a)或(b)的多肽的片段,其中所述片段能够使OTA和/或至少一种OTA衍生物解毒;
d)包含以下氨基酸序列(例如保守基序)中的一个或多个的多肽:
i)GHACGHNLIA(SEQ ID NO:5);
ii)IGSPAEEGGGGK(SEQ ID NO:6);
iii)MAHP(SEQ ID NO:7);
iv)VNHT(SEQ ID NO:23);
v)KVAKGLA(SEQ ID NO:9);
vi)IGSPAEEGGGGKVIL(SEQ ID NO:10);
vii)AHAGAAPWLG(SE ID NO:11);
viii)PELGFHEVKA(SEQ ID NO:12);
ix)TNPTSLPTAFVAT(SEQ ID NO:13);
x)GGRTFGFNAEYDAL(SEQ ID NO:14);
xi)GHACGHNLIAIVAVASA(SEQ ID NO:15);
xii)IPGTIKVIGSPAEEGGGGKVILLNEG(SEQ ID NO:16);
xiii)DACVMAHPEGG(SEQ ID NO:17);
xiv)AHAGAAPWLGVNALDAAVQGY(SEQ ID NO:18);
xv)
GHACGHNLIAXXAVAXAXGXKAAXXXXXIXGTXKXIGSPAEEGGGGKXILXNEGXYDXXDACXMAHPXGG(SEQ ID NO:19),其中X为任何氨基酸;
xvi)(i)、(ii)、(iii)和(iv)(例如SEQ ID NOs:5、6、7和23);
xvii)AHAGAAPW(SEQ ID NO:8)。
2.根据前述项目中任一项所述的多肽,其中所述多肽选自SEQ ID NOs:1-4;优选地,所述多肽选自SEQ ID NOs:1-3;进一步优选地,所述多肽与SEQ ID NO:1的氨基酸序列具有至少69%序列同一性(例如SEQ ID NO:2与SEQ ID NO:1为69.1%相同;SEQ ID NO:3与SEQ ID NO:1为69.3%相同);最优选地,所述多肽具有SEQ ID NO:1。
3.根据前述项目中任一项所述的多肽,其中所述多肽能够/具有:(i)以至少0.01U/g(例如如本文实施例2中所示,例如至少0.05、0.1、0.5、0.75、1.0、1.2、2、5、7或10U/g)的比活性降解赭曲霉毒素A;(ii)热稳定性(例如丧失50%初始活性的温度范围,例如如本文实施例3中所示,例如在表2中,例如在55℃以上);和/或(iii)适用于食品和/或饲料的OTA解毒(例如如本文实施例4中所示)。
4.根据前述项目中任一项所述的多肽,其中所述多肽包含以下氨基酸序列(例如氨基酸基序,例如保守基序)中的一个或多个:
i)GHACGHNLIA(SEQ ID NO:5);
ii)IGSPAEEGGGGK(SEQ ID NO:6);
iii)MAHP(SEQ ID NO:7);
iv)VNHT(SEQ ID NO:23);
v)KVAKGLA(SEQ ID NO:9);
vi)IGSPAEEGGGGKVIL(SEQ ID NO:10);
vii)AHAGAAPWLG(SE ID NO:11);
viii)PELGFHEVKA(SEQ ID NO:12);
ix)TNPTSLPTAFVAT(SEQ ID NO:13);
x)GGRTFGFNAEYDAL(SEQ ID NO:14);
xi)GHACGHNLIAIVAVASA(SEQ ID NO:15);
xii)IPGTIKVIGSPAEEGGGGKVILLNEG(SEQ ID NO:16);
xiii)DACVMAHPEGG(SEQ ID NO:17);
xiv)AHAGAAPWLGVNALDAAVQGY(SEQ ID NO:18);
xv)
GHACGHNLIAXXAVAXAXGXKAAXXXXXIXGTXKXIGSPAEEGGGGKXILXNEGXYDXXDACXMAHPXGG(SEQ ID NO:19),其中X为任何氨基酸;
xvi)AHAGAAPW(SEQ ID NO:8);
xvii)与选自(i)-(xvi)的氨基酸序列具有至少70%序列同一性(例如至少70%、74%、80%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、100%)的多肽;
xviii)与(xv)的氨基酸序列具有至少70%同一性的多肽;和/或与(viii)-(xiv)中的任一个具有至少80%同一性的多肽;和/或与(vi)和/或(vii)具有至少90%同一性的多肽;
xix)具有氨基酸序列(i)、(ii)、(iii)、(iv)、(v)、(vi)、(vii)、(viii)、(ix)、(x)、(xi)、(xii)、(xiii)或(xiv)的多肽的变体,其中所述变体在一个或多个位置处包含取代、缺失和/或插入;
xx)包含氨基酸序列:(i)、(ii)、(iii)和(iv)的多肽。
5.根据前述项目中任一项所述的多肽,其中所述使赭曲霉毒素A(OTA)解毒包含使OTA的酰胺键水解或由使OTA的酰胺键水解组成。
6.根据前述项目中任一项所述的多肽,其中所述多肽具有酰胺水解酶活性(例如EC 3.5.1.-,例如EC 3.5.1.14(氨基酰化酶1))。
7.根据前述项目中任一项所述的多肽,其中所述多肽是以下中的一种或多种:
a)所述多肽属于M20肽酶氨基酰化酶1样蛋白2样酰胺水解酶亚家族(例如M20肽酶ACY1L2酰胺水解酶亚家族,例如具有根据保守域数据库(Conserved Domain Database)的标识符cd05672),优选地所述M20肽酶ACY1L2酰胺水解酶亚家族的特征在于具有金属(例如Zn)结合位点,进一步优选地所述金属结合位点包含选自CHEH[K,H](SEQ ID NO:20)、CXHXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXE(SEQ ID NO:21)和CHEEH[K,H](SEQ ID NO:22)的氨基酸序列基序;和/或
b)所述多肽包含:在对应于SEQ ID NO:1的位置123的位置处的氨基酸C或等同氨基酸;在对应于SEQ ID NO:1的位置125的位置处的氨基酸H或等同氨基酸;在对应于SEQ IDNO:1的位置160和/或161的位置处、优选在对应于SEQ ID NO:1的位置161的位置处的氨基酸E或等同氨基酸;在对应于SEQ ID NO:1的位置185的位置处的氨基酸H或等同氨基酸;和在SEQ ID NO:1的位置383处的氨基酸H或K(优选H)或等同氨基酸;优选地,使用SEQ ID NO:1的编号。
8.根据前述项目中任一项所述的多肽,其中:(i)所述多肽不具有氨基肽酶活性(例如EC 3.4.11.10)和/或(ii)所述多肽为非肽酶酰胺水解酶。
9.根据前述项目中任一项所述的多肽,其中所述多肽能够降解和/或水解非OTA(例如OTA无关的)霉菌毒素(例如单端孢霉烯霉菌毒素,诸如例如脱氧雪腐镰刀菌烯醇、雪腐镰刀菌烯醇、新茄镰孢菌醇、trichotecin、扁虫菌素(crotocin)、杆孢菌素(roridin)A、葡萄穗霉毒素H、二乙酰藨草镰刀烯醇、HT-2毒素或T-2毒素;黄曲霉毒素,诸如例如黄曲霉毒素B1、B2、G1或G2;烟曲霉毒素,诸如例如烟曲霉毒素B1、B2、B3或B4;多肽霉菌毒素,诸如例如白僵菌毒素或恩镰孢菌素;玉米赤霉烯酮;桔霉素;棒曲霉素;麦角生物碱,诸如例如麦角胺)和/或一种或多种植物或细菌衍生的毒素(例如内毒素等)。
10.一种编码和/或能够表达一种或多种根据前述项目中任一项所述的多肽的多核苷酸、核酸构建体或表达载体。
11.一种重组宿主细胞(例如分离的重组宿主细胞)、孢子、转基因植物、转基因种子或转基因花粉粒,其包含以下中的一种或多种:(i)一种或多种根据前述项目中任一项所述的多肽;(ii)一种或多种根据前述项目中任一项所述的多核苷酸;和/或(iii)一种或多种根据前述项目中任一项的核酸构建体和/或表达载体。
12.一种食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元、中间益生元和/或它们的混合物,其包含以下的一种或多种:一种或多种根据前述项目中任一项所述的多肽、多核苷酸、核酸构建体、表达载体、重组宿主细胞、孢子、转基因植物、转基因种子和/或转基因花粉粒。
13.一种组合物或试剂盒,其包含以下中的一种或多种:根据前述项目中任一项所述的多肽、多核苷酸、核酸构建体、表达载体、重组宿主细胞、孢子、转基因植物、转基因种子和/或转基因花粉粒、食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂、益生元、中间益生元和/或它们的混合物。
14.根据前述项目中任一项所述的组合物或试剂盒,其中所述组合物或试剂盒是以下中的一种或多种:无细胞的、非天然存在的和/或分级分离的组合物或试剂盒。
15.根据前述项目中任一项所述的组合物或试剂盒,其中所述组合物或试剂盒进一步包含以下中的一种或多种(例如表II):(i)能够使赭曲霉毒素A(OTA)和/或至少一种OTA衍生物(例如如本文所定义的,例如选自以下的化合物或物质:呋喃基丙烯酰基苯丙氨酸(也称为例如(2S)-2-[3-(呋喃-2-基)丙-2-烯酰氨基]-3-苯基丙酸),N-(3-(2-呋喃基)丙烯酰基)苯丙氨酸(也称为例如(2S)-2-[[(E)-3-(呋喃-2-基)丙-2-烯酰基]氨基]-3-苯基丙酸),L-苯基丙酸等,优选地所述至少一种OTA衍生物为赭曲霉毒素B和/或赭曲霉毒素C)解毒(例如修饰和/或水解)和/或结合所述赭曲霉毒素A(OTA)和/或至少一种OTA衍生物的一种或多种其它多肽,进一步优选地所述一种或多种其它多肽包含羧肽酶活性(例如羧肽酶A和/或B活性,例如分别具有EC 3.4.17.1和/或EC 3.4.17.2)和/或嗜热菌蛋白酶活性(例如具有EC 3.4.24.27);(ii)能够使一种或多种其它霉菌毒素(例如单端孢霉烯霉菌毒素,诸如例如脱氧雪腐镰刀菌烯醇、雪腐镰刀菌烯醇、新茄镰孢菌醇、trichotecin、扁虫菌素(crotocin)、杆孢菌素(roridin)A、葡萄穗霉毒素H、二乙酰藨草镰刀烯醇、HT-2毒素或T-2毒素;黄曲霉毒素,诸如例如黄曲霉毒素B1、B2、G1或G2;烟曲霉毒素,诸如例如烟曲霉毒素B1、B2、B3或B4;多肽霉菌毒素,诸如例如白僵菌毒素或恩镰孢菌素;玉米赤霉烯酮;桔霉素;棒曲霉素;麦角生物碱,诸如例如麦角胺)和/或一种或多种植物和/或细菌衍生的毒素(例如内毒素等)解毒的一种或多种其它多肽,特别是所述能够使一种或多种其它霉菌毒素和/或一种或多种植物和/或细菌衍生的毒素解毒的一种或多种其它多肽,例如伏马菌素酯酶(例如如WO 2016/134387 A1中公开)和/或玉米赤霉烯酮内酯酶(例如如WO 2020/025580A1中公开)和/或ergopeptine水解酶(例如如WO 2014/056006 A1中公开);(iii)一种或多种有机吸收剂(例如活的/失活的/冻干的/休眠的/死的全酵母或酵母衍生的产物,诸如例如酵母细胞壁,或酵母寡糖,诸如例如甘露聚糖)和/或无机吸收剂(例如硅藻土和/或粘土矿物,诸如例如高岭土或高岭石,绿土,诸如例如蒙脱石、伊利石或绿泥石;特别是膨润土);(iv)能够使一种或多种其它霉菌毒素(例如单端孢霉烯霉菌毒素,诸如例如脱氧雪腐镰刀菌烯醇、雪腐镰刀菌烯醇、新茄镰孢菌醇、trichotecin、扁虫菌素(crotocin)、杆孢菌素(roridin)A、葡萄穗霉毒素H、二乙酰藨草镰刀烯醇、HT-2毒素或T-2毒素;黄曲霉毒素,诸如例如黄曲霉毒素B1、B2、G1或G2;烟曲霉毒素,诸如例如烟曲霉毒素B1、B2、B3或B4;多肽霉菌毒素,诸如例如白僵菌毒素或恩镰孢菌素;玉米赤霉烯酮;桔霉素;棒曲霉素;麦角生物碱,诸如例如麦角胺)和/或一种或多种植物或细菌衍生的毒素(例如内毒素)解毒的一种或多种活的、灭活的、冻干的和/或休眠的微生物,特别地所述微生物是毛孢子菌属(Trichosporon)和Apriotrichum属(例如如WO 03/053161 A1中公开)或红蝽菌(Coriobacteriaceae)科(例如如EP 3 501 526 A1中公开)的成员;(v)一种或多种植物产品(例如海草,优选海草粉;和/或藻类,优选藻粉;和/或蓟,优选蓟种子;和/或甘草属植物制剂,优选甘草粉和/或甘草提取物,例如如WO 2018/121881 A1中公开);(vi)一种或多种调味化合物(例如植物提取物,例如来自牛至、百里香、冬青、香菜、墨角兰、薄荷、茴芹、橙、柠檬、茴香、八角、丁香、肉桂和/或大蒜;和/或精油,诸如例如D-柠檬烯、γ-萜品烯、对-伞花烃、2-蒈烯、芳樟醇氧化物、异薄荷酮、樟脑、芳樟醇、萜品烯-4-醇、2-异丙基-1-甲氧基-4-甲基苯、L-薄荷醇、乙胺、α-萜品醇、β-石竹烯、D-香芹酮、水杨酸甲酯、α-石竹烯、乙酸薰衣草酯、氧化石竹烯、丁子香酚、百里酚和/或香芹酚);(vii)一种或多种维生素(例如维生素A、D、E、K、C、B1、B2、B3、B4、B5、B6、B7、B8、B9、B12;特别是维生素E)。
16.根据前述项目中任一项所述的组合物或试剂盒,其中所述组合物或试剂盒是药物、兽医、诊断、解毒、监测和/或筛选组合物或试剂盒。
17.一种用于生产食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元、中间益生元和/或它们的混合物的方法,所述方法包括:
a)提供:(i)一种或多种根据前述项目中任一项所述的多肽;(ii)一种或多种根据前述项目中任一项所述的多核苷酸;(iii)一种或多种根据前述项目中任一项所述的核酸构建体和/或表达载体,和/或(iv)一种或多种根据前述项目中任一项所述的重组宿主细胞、孢子、转基因植物、转基因种子和/或转基因花粉粒;优选地,所述一种或多种多肽是一种或多种重组和/或分离的多肽;
b)将(a)应用于适用于生产食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元、中间益生元和/或它们的混合物的营养源或材料。
18.根据前述项目中任一项所述的方法,其中所述方法进一步包括:在适用于使赭曲霉毒素A(OTA)和/或至少一种赭曲霉毒素A衍生物解毒和/或改变OTA和/或OTA衍生物的毒性的条件下,将所述营养源或材料与(a)一起温育;优选地,所述方法进一步包括热处理和/或分级分离和/或干燥所述温育的产物。
19.一种通过根据前述项目中任一项所述的方法生产的食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元、中间益生元和/或它们的混合物。
20.一种用于使赭曲霉毒素A(OTA)解毒和/或改变OTA和/或至少一种OTA衍生物的毒性的方法,所述方法包括:
a)提供:(i)一种或多种根据前述项目中任一项所述的多肽;(ii)一种或多种根据前述项目中任一项所述的多核苷酸;(iii)一种或多种根据前述项目中任一项所述的核酸构建体和/或表达载体,和/或(iv)一种或多种根据前述项目中任一项所述的重组宿主细胞、孢子、转基因植物、转基因种子和/或转基因花粉粒;优选地,所述一种或多种多肽是一种或多种重组和/或分离的多肽;
b)将(a)应用于OTA和/或应用于至少一种OTA衍生物。
21.根据前述项目中任一项所述的多肽、多核苷酸、核酸构建体、表达载体、重组宿主细胞、孢子、转基因植物、转基因种子、转基因花粉粒、食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元、中间益生元或它们的混合物、组合物或试剂盒,其用于治疗、预防和/或作为药物(例如用于兽医用途)。
22.根据前述项目中任一项所述的多肽、多核苷酸、核酸构建体、表达载体、重组宿主细胞、孢子、转基因植物、转基因种子、转基因花粉粒、食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元、中间益生元或它们的混合物、组合物或试剂盒,其用于以下方法中的一种或多种:
(i)用于治疗、改善、预防和/或诊断霉菌毒素中毒、优选OTA霉菌毒素中毒的方法;
(ii)用于监测霉菌毒素中毒的发展和/或评估霉菌毒素中毒预防和/或治疗、优选OTA霉菌毒素中毒预防和/或治疗的功效的方法;
(iii)用于使赭曲霉毒素A(OTA)解毒和/或改变OTA和/或至少一种OTA衍生物的毒性的方法;
(iv)用于生产以下中的一种或多种的方法:食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元,中间益生元;药物、兽医、诊断、解毒、监测和/或筛选组合物或试剂盒;
(v)根据前述项目中任一项所述的方法;
(vi)根据(i)-(v)的方法的任何组合;
(vii)(i)-(vi)中任一项的方法,其中所述方法是体外、离体或体内方法。
23.根据前述项目中任一项所述的多肽、多核苷酸、核酸构建体、表达载体、重组宿主细胞、孢子、转基因植物、转基因种子、转基因花粉粒、食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元、中间益生元或它们的混合物、组合物或试剂盒中的一种或多种,其用于以下中的一种或多种/在以下中的一种或多种中的用途:
(i)霉菌毒素中毒、优选OTA霉菌毒素中毒的治疗、改善、预防和/或诊断;
(ii)监测霉菌毒素中毒的发展和/或评估霉菌毒素中毒预防和/或治疗、优选OTA霉菌毒素中毒预防和/或治疗的功效;
(iii)使赭曲霉毒素A(OTA)解毒和/或改变OTA和/或至少一种OTA衍生物的毒性;
(iv)生产以下中的一种或多种:食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元,中间益生元;药物、兽医、诊断、解毒、监测和/或筛选组合物或试剂盒;
(v)在根据前述项目中任一项所述的方法中;
(vi)根据(i)-(v)的任何组合;
(vii)(i)-(vi)中任一项的用途,其中所述用途是体外、离体或体内用途。
24.一种用于生产食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元、中间益生元和/或它们的混合物的方法,所述方法包括:
(a)提供:(i)一种或多种根据前述项目中任一项所述的多肽;(ii)一种或多种根据前述项目中任一项所述的多核苷酸;(iii)一种或多种根据前述项目中任一项所述的核酸构建体和/或表达载体和/或(iv)一种或多种根据前述项目中任一项所述的重组宿主细胞、孢子、转基因植物、转基因种子和/或转基因花粉粒;优选地,所述一种或多种多肽是一种或多种重组和/或分离的多肽;
(b)将(a)应用于适用于生产食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元、中间益生元和/或它们的混合物的营养源或材料。
25.根据前述项目中任一项所述的方法,所述方法包括:
a)提供:
(a’)一种或多种能够使赭曲霉毒素A(OTA)和/或至少一种OTA衍生物解毒的多肽,其中优选地所述OTA衍生物选自赭曲霉毒素B和赭曲霉毒素C,其中所述多肽为以下中的一种或多种:
(aa’)与选自SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4的氨基酸序列具有至少64%(例如至少69%或至少80%或至少85%或至少95%,优选至少69%)序列同一性的多肽;优选地,所述多肽具有选自SEQ ID NOs:1-3的氨基酸序列;进一步优选地,所述多肽具有SEQ ID NO:1;
(aaa’)包含以下氨基酸序列(例如保守基序)中的一个或多个的多肽:
i)GHACGHNLIA(SEQ ID NO:5);
ii)IGSPAEEGGGGK(SEQ ID NO:6);
iii)MAHP(SEQ ID NO:7);
iv)VNHT(SEQ ID NO:23);
v)KVAKGLA(SEQ ID NO:9);
vi)IGSPAEEGGGGKVIL(SEQ ID NO:10);
vii)AHAGAAPWLG(SEQ ID NO:11);
viii)PELGFHEVKA(SEQ ID NO:12);
ix)TNPTSLPTAFVAT(SEQ ID NO:13);
x)GGRTFGFNAEYDAL(SEQ ID NO:14);
xi)GHACGHNLIAIVAVASA(SEQ ID NO:15);
xii)IPGTIKVIGSPAEEGGGGKVILLNEG(SEQ ID NO:16);
xiii)DACVMAHPEGG(SEQ ID NO:17);
xiv)AHAGAAPWLGVNALDAAVQGY(SEQ ID NO:18);
xv)
GHACGHNLIAXXAVAXAXGXKAAXXXXXIXGTXKXIGSPAEEGGGGKXILXNEGXYDXXDACXMAHPXGG(SEQ ID NO:19),其中X为任何氨基酸;
xvi)(i)、(ii)、(iii)和(iv);和/或
xvii)AHAGAAPW(SEQ ID NO:8);
(b’)编码和/或能够表达一种或多种根据(a’)的多肽的一种或多种多核苷酸;
(c’)编码和/或能够表达一种或多种根据(a’)的多肽的一种或多种核酸构建体和/或表达载体;和/或
(d’)包含以下中的一种或多种的一种或多种重组宿主细胞、孢子、转基因植物、转基因种子和/或转基因花粉粒:(i)一种或多种根据(a’)的多肽;(ii)一种或多种根据(b’)的多核苷酸;和/或(iii)一种或多种根据(c’)的核酸构建体和/或表达载体;优选地,所述一种或多种多肽是一种或多种重组和/或分离的多肽;
b)将(a)应用于适用于生产食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元、中间益生元和/或它们的混合物的营养源或材料。
26.一种用于使赭曲霉毒素A(OTA)解毒和/或改变OTA和/或至少一种OTA衍生物的毒性的方法,所述方法包括:
a)提供:(i)一种或多种根据前述项目中任一项所述的多肽;(ii)一种或多种根据前述项目中任一项所述的多核苷酸;(iii)一种或多种根据前述项目中任一项所述的核酸构建体和/或表达载体和/或(iv)一种或多种根据前述项目中任一项所述的重组宿主细胞、孢子、转基因植物、转基因种子和/或转基因花粉粒;优选地,所述一种或多种多肽是一种或多种重组和/或分离的多肽;
b)将(a)应用于OTA和/或应用于至少一种OTA衍生物。
27.根据前述项目中任一项所述的方法,所述方法包括:
a)提供:
(a’)一种或多种能够使赭曲霉毒素A(OTA)和/或至少一种OTA衍生物解毒的多肽,其中优选地所述OTA衍生物选自赭曲霉毒素B和赭曲霉毒素C,其中所述多肽为以下中的一种或多种:
(aa’)与选自SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4的氨基酸序列具有至少64%(例如至少69%或至少80%或至少85%或至少95%,优选至少69%)序列同一性的多肽;优选地,所述多肽具有选自SEQ ID NOs:1-3的氨基酸序列;进一步优选地,所述多肽具有SEQ ID NO:1;
(aaa’)包含以下氨基酸序列(例如保守基序)中的一个或多个的多肽:
i)GHACGHNLIA(SEQ ID NO:5);
ii)IGSPAEEGGGGK(SEQ ID NO:6);
iii)MAHP(SEQ ID NO:7);
iv)VNHT(SEQ ID NO:23);
v)KVAKGLA(SEQ ID NO:9);
vi)IGSPAEEGGGGKVIL(SEQ ID NO:10);
vii)AHAGAAPWLG(SEQ ID NO:11);
viii)PELGFHEVKA(SEQ ID NO:12);
ix)TNPTSLPTAFVAT(SEQ ID NO:13);
x)GGRTFGFNAEYDAL(SEQ ID NO:14);
xi)GHACGHNLIAIVAVASA(SEQ ID NO:15);
xii)IPGTIKVIGSPAEEGGGGKVILLNEG(SEQ ID NO:16);
xiii)DACVMAHPEGG(SEQ ID NO:17);
xiv)AHAGAAPWLGVNALDAAVQGY(SEQ ID NO:18);
xv)
GHACGHNLIAXXAVAXAXGXKAAXXXXXIXGTXKXIGSPAEEGGGGKXILXNEGXYDXXDACXMAHPXGG(SEQ ID NO:19),其中X为任何氨基酸;
xvi)(i)、(ii)、(iii)和(iv);和/或
xvii)AHAGAAPW(SEQ ID NO:8);
(b’)编码和/或能够表达一种或多种根据(a’)的多肽的一种或多种多核苷酸;
(c’)编码和/或能够表达一种或多种根据(a’)的多肽的一种或多种核酸构建体和/或表达载体;和/或
(d’)包含以下中的一种或多种的一种或多种重组宿主细胞、孢子、转基因植物、转基因种子和/或转基因花粉粒:(i’)一种或多种根据(a’)的多肽;(ii’)一种或多种根据(b’)的多核苷酸;和/或(iii’)一种或多种根据(c’)的核酸构建体和/或表达载体;优选地,所述一种或多种多肽是一种或多种重组和/或分离的多肽;
b)将(a)应用于OTA和/或应用于所述至少一种OTA衍生物。
28.根据前述项目中任一项所述的方法,其中所述多肽、多核苷酸、核酸构建体、表达载体和/或重组宿主细胞、孢子、转基因植物、转基因种子和/或转基因花粉粒为根据前述项目中任一项所述。
通过以下实施例进一步阐述了本发明,然而本发明不限于所述实施例或受所述实施例的任何具体实施方案的限制。
本发明的实施例
实施例1:基因的克隆和重组多肽的生产
编码多肽序列SEQ ID NOs:1-4中任一个的基因由商业供应商TWIST Bioscience(https://www.twistbioscience.com/)合成,其密码子经优化用于在大肠杆菌中表达。最初设计基因以进一步编码C末端融合到多肽序列中任一个的六组氨酸标签,以便于随后的纯化。随后的多肽生产和酶表征也用未标记的酶进行,产生基本上相同的结果。
使用本领域已知的在大肠杆菌中表达的常用工具将基因克隆到表达载体中。特别地,使用具有lac操纵子的T7启动子系统(Dubendorf和Studier Studier 1991,J.Mol.Biol.219,45-59)来调节基因表达。用所述表达载体转化大肠杆菌BL21(DE3)菌株。使用卡那霉素抗性标记以允许在含有50μg/mL卡那霉素的琼脂平板上选择转化体。
为了生产重组蛋白,将单个转化体菌落在terrific肉汤(TB)培养基(含有12g/L胰蛋白胨,24g/L酵母提取物,5g/L甘油,50mg/L卡那霉素)中于37℃下振荡培养过夜,以产生预培养物。培养后,将1mL该预培养物加入到50mL新鲜TB培养基中,并如前继续培养,直到OD600达到0.5-0.8。随后,加入异丙基-β-D-硫代半乳糖苷(IPTG)至400μM的终浓度以启动基因表达。通过在26-28℃下振荡进一步培养18-20小时进行基因表达。然后,通过离心收获细胞。弃去上清液,将细胞沉淀重悬于50mM Tris-HCl缓冲液,pH 7.5,然后在冰上使用超声处理系统(QSonica)破碎细胞。通过离心(18分钟,21,130×g,4℃)澄清粗裂解物。用Bio-Rad 12%mini-PROTEAN TGX无染色预制凝胶,通过SDS-PAGE(Laemmli 1970,Nature 227,680-685)验证裂解物的可溶级分中重组目标酶的存在。适用于在其它大肠杆菌菌株、其它细菌生产宿主(例如枯草芽孢杆菌(Bacillus subtilis)、谷氨酸棒杆菌(Corynebacteriumglutamicum)等)以及其它真核宿主(例如CHO细胞,酵母例如酿酒酵母(Saccharomycescerevisiae)、巴斯德毕赤酵母(Pichia pastoris)等,其它真菌宿主例如曲霉属(Aspergillus)菌株、木霉属(Trichoderma)菌株等)中实现重组蛋白生产的替代策略描述于现有技术中并且是技术人员熟知的。
为了通过亲和层析进一步纯化和分离六组氨酸标记的重组酶,使用HisGraviTrap TALON柱(GE Healthcare)。为此,将澄清的裂解物上样到柱上,然后用含有10mM咪唑、300mM NaCl的洗涤缓冲液洗涤,以除去非目标多肽。用含有150mM咪唑、300mM NaCl的洗脱缓冲液洗脱结合到柱上的重组目标蛋白。通过用50mM Tris-HCl缓冲液pH 7.5洗涤除去洗脱液中含有的咪唑,并使用VivaSpin 6离心柱(Sartorius)浓缩伴随的酶。使用软件GelAnalyzer(例如2010a版)通过SDS-PAGE再次分析纯化和浓缩的酶,以验证制备物的纯度并通过与已知浓度的牛血清白蛋白(BSA)标准物比较来估计蛋白质浓度。
实施例2:比活性的测定
为了测定例如如上文实施例1中所述生产的重组目标多肽的以单位/升(U/L)计的比活性,进行赭曲霉毒素A(OTA)水解活性测定。一个单位定义为当使用0.495μM的起始OTA浓度时,在1分钟内水解1μmol或OTA所需的酶量。
以200μL的反应混合物终体积设置OTA水解活性测定,该反应混合物含有在100mM磷酸钠缓冲液中的重组酶制备物(优选地稀释为产生1-10mU/L的体积活性(volumetricactivity))和200ng/mL OTA。
在pH 6.0和pH 7.5测定比活性。一旦反应混合物的所有组分都被混合,就通过跟踪在ex/em 390nm/450nm下荧光减少,在荧光分光光度计(BioTek Synergy H1 MFD多模式微板读数器)上于37℃下跟踪OTA水解。
为了计算比活性,使用记录的荧光减少曲线的初始线性部分。除了上述基于荧光的方法,还通过使用如Delafioria等2020,Toxins 12,258描述的HPLC-MS方法测定OTA水解,基本上证实了基于荧光的结果。具有SEQ ID NOs:1-4的氨基酸序列的多肽在不同pH的比活性示于表1中。
表1:在不同pH以U/g计的OTA水解比活性。
SEQ ID NO: | pH 6 | pH 7.5 |
1 | 0.11 | 1.20 |
2 | 3.53 | 11.01 |
3 | 0.63 | 1.44 |
4 | 1.57 | 1.43 |
实施例3:热稳定性的测定
为了测定所产生的酶对温度的动力学稳定性,进行热稳定性测定。为此,将纯化的蛋白质样品在20mM Tris-HCl缓冲液pH 7.5中稀释至0.1mg/mL的蛋白质浓度,并且将等分试样在热循环仪中在45、55、65、75或85℃下温育10分钟。在此温育之后,将等分试样储存在4℃下直至进一步分析。在整个温育过程中,将参比等分试样储存在4℃下。随后,用实施例2中所述的测定来测定所有等分试样的残留OTA水解活性。相对于参比等分试样计算残留酶活性。相对于参比等分试样测定在温育后丧失50%初始活性的温度范围。结果示于表2中。
表2:丧失50%初始活性的温度范围。
实施例4:饲喂试验
为了验证所产生的酶作为食品或饲料添加剂的适用性,进行了小猪饲喂试验。为此,通过在生物反应器中培养大肠杆菌转化体,产生足量的SEQ ID NO:1的多肽。将细胞培养液(broth)匀浆并离心。将上清液浓缩,通过冻干干燥并通过研磨配制成粉末。测定由此获得的冻干粉末的酶活性,并将粉末与饲料混合用于如下文所述的饲喂试验。
基于以下五个实验膳食设置研究五个小猪组:1)基础饲料;2)基础饲料+50ppbOTA;3)基础饲料+50ppb OTA+169mU SEQ ID NO:1的酶/kg饲料;4)基础饲料+500ppb OTA;5)基础饲料+500ppb OTA+169mU SEQ ID NO:1的酶/kg饲料。基础饲料本身不含任何可检测量的OTA。
每个试验组由四只重约7-8kg的小猪组成,它们刚断奶,并在喂以如上文所述的实验膳食之前适应固体膳食。饲喂试验的持续时间(即饲喂实验膳食的实际天数)为十四天。每个试验组共同消耗约15kg饲料。在整个饲养试验中没有小猪发生任何意外疾病。在第0天刚好在开始实验膳食之前和第14天收集尿液和血液样品。
从血浆和尿液样品中提取OTA,用于随后的HPLC-MS分析。将200μL样品与800μL萃取溶液(含有99%的乙酸乙酯和1%的85%磷酸)充分混合,然后在19000×g离心5分钟进行相分离。用50μL乙腈稀释50μL上层相,然后进行HPLC-MS分析。使用如Delafioria等2020,Toxins 12,258描述的HPLC-MS方法测定试验期间食用实验膳食时所取样品中OTA浓度的变化。使用如上文所述的膳食设置编号,结果示于表3中。值得注意的是,仅当重组酶是膳食设置的一部分时,才观察到血浆和尿液两者中OTA浓度的降低,证明本发明的酶在食品/饲料中用于OTA解毒的适用性。
表3:第0天和第14天血浆和血液样品中的OTA浓度。
本领域技术人员将容易地理解,本发明非常适于实现所述目的并获得所述结果和优点,以及其中固有的那些。此外,对于本领域技术人员来说显而易见的是,在不背离本发明的范围和精神的情况下,可以对本文所公开的发明进行各种替换和修改。本文所述的组合物、方法、程序、处理、分子和具体化合物目前代表了示例性的某些实施方案,并且不旨在作为对本发明范围的限制。本领域技术人员可以想到其中的变化和其它用途,这些变化和用途包含在由权利要求的范围限定的本发明的精神内。本说明书中对先前公开的文献的列举或讨论不应必然地被认为是承认该文献是现有技术的一部分或是公知常识。本发明在此已经被广泛和一般地描述。落入一般性公开的范围内的较窄种类和亚属分组中的每一个也形成本发明的一部分。这包括本发明的一般性描述,附带条件或负面限制从该属中除去任何主题,而不管所去除的材料是否在本文中具体叙述。本文所引用的所有文献,包括专利申请和科学出版物,均以引用方式并入本文用于所有目的。其它实施例在以下权利要求书内。另外,在本发明的特征或方面以马库什组的形式描述的情况下,本领域技术人员将认识到本发明也因此以马库什组的任何单独成员或成员的亚组的形式描述。
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<110> 艾尔柏股份公司
<120> 用于使赭曲霉毒素A解毒的工具和方法
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225 230 235 240
Leu Gly Tyr Asn Gly Val Ser Met Leu Arg Gln Gln Leu Glu Pro Thr
245 250 255
Val Arg Val His Gly Val Ile Arg Gly Pro Asn Asp Trp Val Asn Asn
260 265 270
Ile Ile Pro Ala Ser Ser His Val Glu Tyr Asp Val Arg Ala Pro Asp
275 280 285
Val Lys Gln Ala Met Ala Val Arg Asn Lys Ala Ile Ala Cys Phe Glu
290 295 300
Ser Ala Ala His Ala Thr Gly Cys Ser His Thr Thr Gln Ser Lys Asp
305 310 315 320
Lys Asp Ile Tyr Ala Glu Leu Arg Asn Ser Ile Arg Met Ala Gly Val
325 330 335
Tyr Ala Asp Ile Met Glu Glu Val Phe Asp Gln His Ile Gln Arg Asp
340 345 350
Gly Met Thr Thr Ala Ser Thr Asp Phe Gly Asn Ile Thr Ile Ser Ala
355 360 365
Cys Pro Ala Val His Pro Met Tyr Leu Ile Glu Thr Asp Gly Val Asn
370 375 380
His Thr Pro Glu Phe Thr Ala Gly Ala Ala Thr Met Asp Ser His Glu
385 390 395 400
Arg Ser Ile Lys Val Ala Lys Gly Leu Ala Leu Leu Gly Phe Lys Val
405 410 415
Leu Thr Asp Asp Val Phe Ala Lys Lys Ile Lys Asp Glu Phe Glu Glu
420 425 430
Gln Lys Lys Arg Leu Gly Ala
435
<210> 5
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 保守基序
<400> 5
Gly His Ala Cys Gly His Asn Leu Ile Ala
1 5 10
<210> 6
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 保守基序
<400> 6
Ile Gly Ser Pro Ala Glu Glu Gly Gly Gly Gly Lys
1 5 10
<210> 7
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 保守基序
<400> 7
Met Ala His Pro
1
<210> 8
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 保守基序
<400> 8
Ala His Ala Gly Ala Ala Pro Trp
1 5
<210> 9
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 保守基序
<400> 9
Lys Val Ala Lys Gly Leu Ala
1 5
<210> 10
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 保守基序
<400> 10
Ile Gly Ser Pro Ala Glu Glu Gly Gly Gly Gly Lys Val Ile Leu
1 5 10 15
<210> 11
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 保守基序
<400> 11
Ile Gly Ser Pro Ala Glu Glu Gly Gly Gly Gly Lys Val Ile Leu
1 5 10 15
<210> 12
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 保守基序
<400> 12
Pro Glu Leu Gly Phe His Glu Val Lys Ala
1 5 10
<210> 13
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 保守基序
<400> 13
Thr Asn Pro Thr Ser Leu Pro Thr Ala Phe Val Ala Thr
1 5 10
<210> 14
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 保守基序
<400> 14
Gly Gly Arg Thr Phe Gly Phe Asn Ala Glu Tyr Asp Ala Leu
1 5 10
<210> 15
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 保守基序
<400> 15
Gly His Ala Cys Gly His Asn Leu Ile Ala Ile Val Ala Val Ala Ser
1 5 10 15
Ala
<210> 16
<211> 26
<212> PRT
<213> 人工序列
<220>
<223> 保守基序
<400> 16
Ile Pro Gly Thr Ile Lys Val Ile Gly Ser Pro Ala Glu Glu Gly Gly
1 5 10 15
Gly Gly Lys Val Ile Leu Leu Asn Glu Gly
20 25
<210> 17
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 保守基序
<400> 17
Asp Ala Cys Val Met Ala His Pro Glu Gly Gly
1 5 10
<210> 18
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 保守基序
<400> 18
Ala His Ala Gly Ala Ala Pro Trp Leu Gly Val Asn Ala Leu Asp Ala
1 5 10 15
Ala Val Gln Gly Tyr
20
<210> 19
<211> 70
<212> PRT
<213> 人工序列
<220>
<223> 保守基序
<220>
<221> misc_feature
<222> (11)..(12)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> misc_feature
<222> (16)..(16)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> misc_feature
<222> (18)..(18)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> misc_feature
<222> (24)..(28)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> misc_feature
<222> (30)..(30)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> misc_feature
<222> (33)..(33)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> misc_feature
<222> (35)..(35)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> misc_feature
<222> (48)..(48)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> misc_feature
<222> (51)..(51)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> misc_feature
<222> (55)..(55)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> misc_feature
<222> (58)..(59)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> misc_feature
<222> (63)..(63)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> misc_feature
<222> (68)..(68)
<223> Xaa可以是任何天然存在的氨基酸
<400> 19
Gly His Ala Cys Gly His Asn Leu Ile Ala Xaa Xaa Ala Val Ala Xaa
1 5 10 15
Ala Xaa Gly Xaa Lys Ala Ala Xaa Xaa Xaa Xaa Xaa Ile Xaa Gly Thr
20 25 30
Xaa Lys Xaa Ile Gly Ser Pro Ala Glu Glu Gly Gly Gly Gly Lys Xaa
35 40 45
Ile Leu Xaa Asn Glu Gly Xaa Tyr Asp Xaa Xaa Asp Ala Cys Xaa Met
50 55 60
Ala His Pro Xaa Gly Gly
65 70
<210> 20
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> M20肽酶氨基酰化酶1-样蛋白2-样酰胺水解酶亚家族保守基序
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa可以是Lys或His
<400> 20
Cys His Glu His Xaa
1 5
<210> 21
<211> 38
<212> PRT
<213> 人工序列
<220>
<223> M20肽酶氨基酰化酶1-样蛋白2-样酰胺水解酶亚家族保守基序
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> misc_feature
<222> (4)..(37)
<223> Xaa可以是任何天然存在的氨基酸
<400> 21
Cys Xaa His Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5 10 15
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
20 25 30
Xaa Xaa Xaa Xaa Xaa Glu
35
<210> 22
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> M20肽酶氨基酰化酶1-样蛋白2-样酰胺水解酶亚家族保守基序
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa可以是Lys或His
<400> 22
Cys His Glu Glu His Xaa
1 5
<210> 23
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 保守基序
<400> 23
Val Asn His Thr
1
Claims (15)
1.一种用于生产食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元、中间益生元和/或它们的混合物的方法,所述方法包括:
a)提供:
(a’)一种或多种能够使赭曲霉毒素A(OTA)和/或至少一种OTA衍生物解毒的多肽,其中优选地所述OTA衍生物选自赭曲霉毒素B和赭曲霉毒素C,其中所述多肽为以下中的一种或多种:
(aa’)与选自SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4的氨基酸序列具有至少64%(例如至少69%或至少80%或至少85%或至少95%,优选至少69%)序列同一性的多肽;优选地,所述多肽具有选自SEQ ID NOs:1-3的氨基酸序列;进一步优选地,所述多肽具有SEQ ID NO:1;
(aaa’)包含以下氨基酸序列(例如保守基序)中的一个或多个的多肽:
i)GHACGHNLIA(SEQ ID NO:5);
ii)IGSPAEEGGGGK(SEQ ID NO:6);
iii)MAHP(SEQ ID NO:7);
iv)VNHT(SEQ ID NO:23);
v)KVAKGLA(SEQ ID NO:9);
vi)IGSPAEEGGGGKVIL(SEQ ID NO:10);
vii)AHAGAAPWLG(SEQ ID NO:11);
viii)PELGFHEVKA(SEQ ID NO:12);
ix)TNPTSLPTAFVAT(SEQ ID NO:13);
x)GGRTFGFNAEYDAL(SEQ ID NO:14);
xi)GHACGHNLIAIVAVASA(SEQ ID NO:15);
xii)IPGTIKVIGSPAEEGGGGKVILLNEG(SEQ ID NO:16);
xiii)DACVMAHPEGG(SEQ ID NO:17);
xiv)AHAGAAPWLGVNALDAAVQGY(SEQ ID NO:18);
xv)GHACGHNLIAXXAVAXAXGXKAAXXXXXIXGTXKXIGSPAEEGGGGKXILXNEGXYDXXDACXMAHPXGG(SEQ ID NO:19),其中X为任何氨基酸;
xvi)(i)、(ii)、(iii)和(iv);和/或
xvii)AHAGAAPW(SEQ ID NO:8);
(b’)编码和/或能够表达一种或多种根据(a’)的多肽的一种或多种多核苷酸;
(c’)编码和/或能够表达一种或多种根据(a’)的多肽的一种或多种核酸构建体和/或表达载体;和/或
(d’)包含以下中的一种或多种的一种或多种重组宿主细胞、孢子、转基因植物、转基因种子和/或转基因花粉粒:(i)一种或多种根据(a’)的多肽;(ii)一种或多种根据(b’)的多核苷酸;和/或(iii)一种或多种根据(c’)的核酸构建体和/或表达载体;优选地,所述一种或多种多肽是一种或多种重组和/或分离的多肽;
b)将(a)应用于适用于生产食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元、中间益生元和/或它们的混合物的营养源或材料。
2.一种用于使赭曲霉毒素A(OTA)解毒和/或改变OTA和/或至少一种OTA衍生物的毒性的方法,其中优选地所述OTA衍生物选自赭曲霉毒素B和赭曲霉毒素C,所述方法包括:
a)提供:
(a’)一种或多种能够使赭曲霉毒素A(OTA)和/或至少一种OTA衍生物解毒的多肽,其中优选地所述OTA衍生物选自赭曲霉毒素B和赭曲霉毒素C,其中所述多肽为以下中的一种或多种:
(aa’)与选自SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4的氨基酸序列具有至少64%(例如至少69%或至少80%或至少85%或至少95%,优选至少69%)序列同一性的多肽;优选地,所述多肽具有选自SEQ ID NOs:1-3的氨基酸序列;进一步优选地,所述多肽具有SEQ ID NO:1;
(aaa’)包含以下氨基酸序列(例如保守基序)中的一个或多个的多肽:
i)GHACGHNLIA(SEQ ID NO:5);
ii)IGSPAEEGGGGK(SEQ ID NO:6);
iii)MAHP(SEQ ID NO:7);
iv)VNHT(SEQ ID NO:23);
v)KVAKGLA(SEQ ID NO:9);
vi)IGSPAEEGGGGKVIL(SEQ ID NO:10);
vii)AHAGAAPWLG(SEQ ID NO:11);
viii)PELGFHEVKA(SEQ ID NO:12);
ix)TNPTSLPTAFVAT(SEQ ID NO:13);
x)GGRTFGFNAEYDAL(SEQ ID NO:14);
xi)GHACGHNLIAIVAVASA(SEQ ID NO:15);
xii)IPGTIKVIGSPAEEGGGGKVILLNEG(SEQ ID NO:16);
xiii)DACVMAHPEGG(SEQ ID NO:17);
xiv)AHAGAAPWLGVNALDAAVQGY(SEQ ID NO:18);
xv)GHACGHNLIAXXAVAXAXGXKAAXXXXXIXGTXKXIGSPAEEGGGGKXILXNEGXYDXXDACXMAHPXGG(SEQ ID NO:19),其中X为任何氨基酸;
xvi)(i)、(ii)、(iii)和(iv);和/或
xvii)AHAGAAPW(SEQ ID NO:8);
(b’)编码和/或能够表达一种或多种根据(a’)的多肽的一种或多种多核苷酸;
(c’)编码和/或能够表达一种或多种根据(a’)的多肽的一种或多种核酸构建体和/或表达载体;和/或
(d’)包含以下中的一种或多种的一种或多种重组宿主细胞、孢子、转基因植物、转基因种子和/或转基因花粉粒:(i)一种或多种根据(a’)的多肽;(ii)一种或多种根据(b’)的多核苷酸;和/或(iii)一种或多种根据(c’)的核酸构建体和/或表达载体;优选地,所述一种或多种多肽是一种或多种重组和/或分离的多肽;
b)将(a)应用于OTA和/或应用于所述至少一种OTA衍生物。
3.一种能够使赭曲霉毒素A(OTA)和/或至少一种OTA衍生物解毒的多肽,其中优选地所述OTA衍生物选自赭曲霉毒素B和赭曲霉毒素C,其中所述多肽是以下中的一种或多种:
a)与选自SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3的氨基酸序列具有至少64%(例如至少69%或至少80%或至少85%或至少95%,优选至少69%)序列同一性的多肽;优选地,所述多肽具有选自SEQ ID NOs:1-3的氨基酸序列;进一步优选地,所述多肽具有SEQ IDNO:1;
b)包含以下氨基酸序列(例如保守基序)中的一个或多个的多肽:
i)GHACGHNLIA(SEQ ID NO:5);
ii)IGSPAEEGGGGK(SEQ ID NO:6);
iii)MAHP(SEQ ID NO:7);
iv)VNHT(SEQ ID NO:23);
v)KVAKGLA(SEQ ID NO:9);
vi)IGSPAEEGGGGKVIL(SEQ ID NO:10);
vii)AHAGAAPWLG(SEQ ID NO:11);
viii)PELGFHEVKA(SEQ ID NO:12);
ix)TNPTSLPTAFVAT(SEQ ID NO:13);
x)GGRTFGFNAEYDAL(SEQ ID NO:14);
xi)GHACGHNLIAIVAVASA(SEQ ID NO:15);
xii)IPGTIKVIGSPAEEGGGGKVILLNEG(SEQ ID NO:16);
xiii)DACVMAHPEGG(SEQ ID NO:17);
xiv)AHAGAAPWLGVNALDAAVQGY(SEQ ID NO:18);
xv)GHACGHNLIAXXAVAXAXGXKAAXXXXXIXGTXKXIGSPAEEGGGGKXILXNEGXYDXXDACXMAHPXGG(SEQ ID NO:19),其中X为任何氨基酸;
xvi)(i)、(ii)、(iii)和(iv);和/或
xvii)xvii)AHAGAAPW(SEQ ID NO:8)。
4.根据前述权利要求中任一项所述的多肽,其中所述多肽包含以下氨基酸序列(例如保守基序)中的一个或多个:
i)GHACGHNLIA(SEQ ID NO:5);
ii)IGSPAEEGGGGK(SEQ ID NO:6);
iii)MAHP(SEQ ID NO:7);
iv)VNHT(SEQ ID NO:23);
v)KVAKGLA(SEQ ID NO:9);
vi)IGSPAEEGGGGKVIL(SEQ ID NO:10);
vii)AHAGAAPWLG(SEQ ID NO:11);
viii)PELGFHEVKA(SEQ ID NO:12);
ix)TNPTSLPTAFVAT(SEQ ID NO:13);
x)GGRTFGFNAEYDAL(SEQ ID NO:14);
xi)GHACGHNLIAIVAVASA(SEQ ID NO:15);
xii)IPGTIKVIGSPAEEGGGGKVILLNEG(SEQ ID NO:16);
xiii)DACVMAHPEGG(SEQ ID NO:17);
xiv)AHAGAAPWLGVNALDAAVQGY(SEQ ID NO:18);
xv)GHACGHNLIAXXAVAXAXGXKAAXXXXXIXGTXKXIGSPAEEGGGGKXILXNEGXYDXXDACXMAHPXGG(SEQ ID NO:19),其中X为任何氨基酸;
xvi)AHAGAAPW(SEQ ID NO:8);
xvii)与选自(i)-(xvi)的氨基酸序列具有至少70%序列同一性(例如至少70%、74%、80%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、100%)的多肽;
xviii)与(xv)的氨基酸序列具有至少70%同一性的多肽;和/或与(viii)-(xiv)中的任一个具有至少80%同一性的多肽;和/或与(vi)和/或(vii)具有至少90%同一性的多肽;
xix)具有氨基酸序列(i)、(ii)、(iii)、(iv)、(v)、(vi)、(vii)、(viii)、(ix)、(x)、(xi)、(xii)、(xiii)或(xiv)的多肽的变体,其中所述变体在一个或多个位置处包含取代、缺失和/或插入;
xx)包含氨基酸序列:(i)、(ii)、(iii)和(iv)的多肽。
5.根据前述权利要求中任一项所述的多肽,其中所述使赭曲霉毒素A(OTA)解毒包含水解OTA的酰胺键或由水解OTA的酰胺键组成。
6.根据前述权利要求中任一项所述的多肽,其中所述多肽具有酰胺水解酶活性(例如EC 3.5.1.14)。
7.根据前述权利要求中任一项所述的多肽,其中所述多肽是以下中的一种或多种:
a)所述多肽属于M20肽酶氨基酰化酶1样蛋白2样酰胺水解酶亚家族(例如M20肽酶ACY1L2酰胺水解酶亚家族,例如具有根据保守域数据库(Conserved Domain Database)的标识符cd05672),优选地所述M20肽酶ACY1L2酰胺水解酶亚家族的特征在于具有金属(例如Zn)结合位点,进一步优选地所述金属结合位点包含氨基酸序列基序:CXHXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXE(SEQ ID NO:21);和/或
b)所述多肽包含:在对应于SEQ ID NO:1的位置123的位置处的氨基酸C或等同氨基酸;在对应于SEQ ID NO:1的位置125的位置处的氨基酸H或等同氨基酸;在对应于SEQ ID NO:1的位置160和/或161的位置处、优选在对应于SEQ ID NO:1的位置161的位置处的氨基酸E或等同氨基酸;在对应于SEQ ID NO:1的位置185的位置处的氨基酸H或等同氨基酸;和在SEQID NO:1的位置383处的氨基酸H或K(优选H)或等同氨基酸;优选地,使用SEQ ID NO:1的编号。
8.一种编码和/或能够表达一种或多种根据前述权利要求中任一项所述的多肽的多核苷酸、核酸构建体或表达载体。
9.一种重组宿主细胞(例如分离的重组宿主细胞)、孢子、转基因植物、转基因种子或转基因花粉粒,其包含以下中的一种或多种:
(a’)一种或多种能够使赭曲霉毒素A(OTA)和/或至少一种OTA衍生物解毒的多肽,其中优选地所述OTA衍生物选自赭曲霉毒素B和赭曲霉毒素C,其中所述多肽为以下中的一种或多种:
(aa’)与选自SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4的氨基酸序列具有至少64%(例如至少69%或至少80%或至少85%或至少95%,优选至少69%)序列同一性的多肽;优选地,所述多肽具有选自SEQ ID NOs:1-3的氨基酸序列;进一步优选地,所述多肽具有SEQ ID NO:1;
(aaa’)包含以下氨基酸序列(例如保守基序)中的一个或多个的多肽:
i)GHACGHNLIA(SEQ ID NO:5);
ii)IGSPAEEGGGGK(SEQ ID NO:6);
iii)MAHP(SEQ ID NO:7);
iv)VNHT(SEQ ID NO:23);
v)KVAKGLA(SEQ ID NO:9);
vi)IGSPAEEGGGGKVIL(SEQ ID NO:10);
vii)AHAGAAPWLG(SEQ ID NO:11);
viii)PELGFHEVKA(SEQ ID NO:12);
ix)TNPTSLPTAFVAT(SEQ ID NO:13);
x)GGRTFGFNAEYDAL(SEQ ID NO:14);
xi)GHACGHNLIAIVAVASA(SEQ ID NO:15);
xii)IPGTIKVIGSPAEEGGGGKVILLNEG(SEQ ID NO:16);
xiii)DACVMAHPEGG(SEQ ID NO:17);
xiv)AHAGAAPWLGVNALDAAVQGY(SEQ ID NO:18);
xv)GHACGHNLIAXXAVAXAXGXKAAXXXXXIXGTXKXIGSPAEEGGGGKXILXNEGXYDXXDACXMAHPXGG(SEQ ID NO:19),其中X为任何氨基酸;
xvi)(i)、(ii)、(iii)和(iv);和/或
xvii)AHAGAAPW(SEQ ID NO:8);
(b’)编码和/或能够表达一种或多种根据(a’)的多肽的一种或多种多核苷酸;
(c’)编码和/或能够表达一种或多种根据(a’)的多肽的一种或多种核酸构建体和/或表达载体。
10.一种食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元、中间益生元和/或它们的混合物,其包含以下的一种或多种:
(a’)一种或多种能够使赭曲霉毒素A(OTA)和/或至少一种OTA衍生物解毒的多肽,其中优选地所述OTA衍生物选自赭曲霉毒素B和赭曲霉毒素C,其中所述多肽为以下中的一种或多种:
(aa’)与选自SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4的氨基酸序列具有至少64%(例如至少69%或至少80%或至少85%或至少95%,优选至少69%)序列同一性的多肽;优选地,所述多肽具有选自SEQ ID NOs:1-3的氨基酸序列;进一步优选地,所述多肽具有SEQ ID NO:1;
(aaa’)包含以下氨基酸序列(例如保守基序)中的一个或多个的多肽:
i)GHACGHNLIA(SEQ ID NO:5);
ii)IGSPAEEGGGGK(SEQ ID NO:6);
iii)MAHP(SEQ ID NO:7);
iv)VNHT(SEQ ID NO:23);
v)KVAKGLA(SEQ ID NO:9);
vi)IGSPAEEGGGGKVIL(SEQ ID NO:10);
vii)AHAGAAPWLG(SEQ ID NO:11);
viii)PELGFHEVKA(SEQ ID NO:12);
ix)TNPTSLPTAFVAT(SEQ ID NO:13);
x)GGRTFGFNAEYDAL(SEQ ID NO:14);
xi)GHACGHNLIAIVAVASA(SEQ ID NO:15);
xii)IPGTIKVIGSPAEEGGGGKVILLNEG(SEQ ID NO:16);
xiii)DACVMAHPEGG(SEQ ID NO:17);
xiv)AHAGAAPWLGVNALDAAVQGY(SEQ ID NO:18);
xv)GHACGHNLIAXXAVAXAXGXKAAXXXXXIXGTXKXIGSPAEEGGGGKXILXNEGXYDXXDACXMAHPXGG(SEQ ID NO:19),其中X为任何氨基酸;
xvi)(i)、(ii)、(iii)和(iv);和/或
xvii)AHAGAAPW(SEQ ID NO:8);
(b’)编码和/或能够表达一种或多种根据(a’)的多肽的一种或多种多核苷酸;
(c’)编码和/或能够表达一种或多种根据(a’)的多肽的一种或多种核酸构建体和/或表达载体;和/或
(d’)包含以下中的一种或多种的一种或多种重组宿主细胞、孢子、转基因植物、转基因种子和/或转基因花粉粒:(i’)一种或多种根据(a’)的多肽;(ii’)一种或多种根据(b’)的多核苷酸;和/或(iii’)一种或多种根据(c’)的核酸构建体和/或表达载体;优选地,所述一种或多种多肽是一种或多种重组和/或分离的多肽。
11.一种组合物或试剂盒,其包含根据前述权利要求中任一项所述的以下中的一种或多种:
(a’)能够使赭曲霉毒素A(OTA)和/或至少一种OTA衍生物解毒的多肽,其中优选地所述OTA衍生物选自赭曲霉毒素B和赭曲霉毒素C,其中所述多肽为以下中的一种或多种:
(aa’)与选自SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4的氨基酸序列具有至少64%(例如至少69%或至少80%或至少85%或至少95%,优选至少69%)序列同一性的多肽;优选地,所述多肽具有选自SEQ ID NOs:1-3的氨基酸序列;进一步优选地,所述多肽具有SEQ ID NO:1;
(aaa’)包含以下氨基酸序列(例如保守基序)中的一个或多个的多肽:
i)GHACGHNLIA(SEQ ID NO:5);
ii)IGSPAEEGGGGK(SEQ ID NO:6);
iii)MAHP(SEQ ID NO:7);
iv)VNHT(SEQ ID NO:23);
v)KVAKGLA(SEQ ID NO:9);
vi)IGSPAEEGGGGKVIL(SEQ ID NO:10);
vii)AHAGAAPWLG(SEQ ID NO:11);
viii)PELGFHEVKA(SEQ ID NO:12);
ix)TNPTSLPTAFVAT(SEQ ID NO:13);
x)GGRTFGFNAEYDAL(SEQ ID NO:14);
xi)GHACGHNLIAIVAVASA(SEQ ID NO:15);
xii)IPGTIKVIGSPAEEGGGGKVILLNEG(SEQ ID NO:16);
xiii)DACVMAHPEGG(SEQ ID NO:17);
xiv)AHAGAAPWLGVNALDAAVQGY(SEQ ID NO:18);
xv)GHACGHNLIAXXAVAXAXGXKAAXXXXXIXGTXKXIGSPAEEGGGGKXILXNEGXYDXXDACXMAHPXGG(SEQ ID NO:19),其中X为任何氨基酸;
xvi)(i)、(ii)、(iii)和(iv);和/或
xvii)AHAGAAPW(SEQ ID NO:8);
(b’)编码和/或能够表达一种或多种根据(a’)的多肽的多核苷酸;
(c’)编码和/或能够表达一种或多种根据(a’)的多肽的核酸构建体和/或表达载体;和/或
(d’)重组宿主细胞、孢子、转基因植物、转基因种子和/或转基因花粉粒、食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂、益生元、中间益生元和/或它们的混合物。
12.一种通过根据前述权利要求中任一项所述的方法生产的食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元、中间益生元和/或它们的混合物,其中所述食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元、中间益生元和/或它们的混合物包含以下的一种或多种:
(a’)一种或多种能够使赭曲霉毒素A(OTA)和/或至少一种OTA衍生物解毒的多肽,其中优选地所述OTA衍生物选自赭曲霉毒素B和赭曲霉毒素C,其中所述多肽为以下中的一种或多种:
(aa’)与选自SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4的氨基酸序列具有至少64%(例如至少69%或至少80%或至少85%或至少95%,优选至少69%)序列同一性的多肽;优选地,所述多肽具有选自SEQ ID NOs:1-3的氨基酸序列;进一步优选地,所述多肽具有SEQ ID NO:1;
(aaa’)包含以下氨基酸序列(例如保守基序)中的一个或多个的多肽:
i)GHACGHNLIA(SEQ ID NO:5);
ii)IGSPAEEGGGGK(SEQ ID NO:6);
iii)MAHP(SEQ ID NO:7);
iv)VNHT(SEQ ID NO:23);
v)KVAKGLA(SEQ ID NO:9);
vi)IGSPAEEGGGGKVIL(SEQ ID NO:10);
vii)AHAGAAPWLG(SEQ ID NO:11);
viii)PELGFHEVKA(SEQ ID NO:12);
ix)TNPTSLPTAFVAT(SEQ ID NO:13);
x)GGRTFGFNAEYDAL(SEQ ID NO:14);
xi)GHACGHNLIAIVAVASA(SEQ ID NO:15);
xii)IPGTIKVIGSPAEEGGGGKVILLNEG(SEQ ID NO:16);
xiii)DACVMAHPEGG(SEQ ID NO:17);
xiv)AHAGAAPWLGVNALDAAVQGY(SEQ ID NO:18);
xv)GHACGHNLIAXXAVAXAXGXKAAXXXXXIXGTXKXIGSPAEEGGGGKXILXNEGXYDXXDACXMAHPXGG(SEQ ID NO:19),其中X为任何氨基酸;
xvi)(i)、(ii)、(iii)和(iv);和/或
xvii)AHAGAAPW(SEQ ID NO:8);
(b’)编码和/或能够表达一种或多种根据(a’)的多肽的一种或多种多核苷酸;
(c’)编码和/或能够表达一种或多种根据(a’)的多肽的一种或多种核酸构建体和/或表达载体;和/或
(d’)包含以下中的一种或多种的一种或多种重组宿主细胞、孢子、转基因植物、转基因种子和/或转基因花粉粒:(i’)一种或多种根据(a’)的多肽;(ii’)一种或多种根据(b’)的多核苷酸;和/或(iii’)一种或多种根据(c’)的核酸构建体和/或表达载体;优选地,所述一种或多种多肽是一种或多种重组和/或分离的多肽。
13.根据前述权利要求中任一项所述的多肽(a’),其中所述多肽能够使赭曲霉毒素A(OTA)和/或至少一种OTA衍生物解毒,其中优选地所述OTA衍生物选自赭曲霉毒素B和赭曲霉毒素C,其中所述多肽为以下中的一种或多种:
(aa’)与选自SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4的氨基酸序列具有至少64%(例如至少69%或至少80%或至少85%或至少95%,优选至少69%)序列同一性的多肽;优选地,所述多肽具有选自SEQ ID NOs:1-3的氨基酸序列;进一步优选地,所述多肽具有SEQ ID NO:1;
(aaa’)包含以下氨基酸序列(例如保守基序)中的一个或多个的多肽:
i)GHACGHNLIA(SEQ ID NO:5);
ii)IGSPAEEGGGGK(SEQ ID NO:6);
iii)MAHP(SEQ ID NO:7);
iv)VNHT(SEQ ID NO:23);
v)KVAKGLA(SEQ ID NO:9);
vi)IGSPAEEGGGGKVIL(SEQ ID NO:10);
vii)AHAGAAPWLG(SEQ ID NO:11);
viii)PELGFHEVKA(SEQ ID NO:12);
ix)TNPTSLPTAFVAT(SEQ ID NO:13);
x)GGRTFGFNAEYDAL(SEQ ID NO:14);
xi)GHACGHNLIAIVAVASA(SEQ ID NO:15);
xii)IPGTIKVIGSPAEEGGGGKVILLNEG(SEQ ID NO:16);
xiii)DACVMAHPEGG(SEQ ID NO:17);
xiv)AHAGAAPWLGVNALDAAVQGY(SEQ ID NO:18);
xv)GHACGHNLIAXXAVAXAXGXKAAXXXXXIXGTXKXIGSPAEEGGGGKXILXNEGXYDXXDACXMAHPXGG(SEQ ID NO:19),其中X为任何氨基酸;
xvi)(i)、(ii)、(iii)和(iv);和/或
xvii)AHAGAAPW(SEQ ID NO:8);
编码和/或能够表达所述根据(a’)的多肽的多核苷酸,编码和/或能够表达一种或多种根据(a’)的多肽的核酸构建体、表达载体;
重组宿主细胞、孢子、转基因植物、转基因种子、转基因花粉粒、食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元、中间益生元或它们的混合物、组合物或试剂盒;
其用于治疗、预防和/或作为药物(例如用于兽医用途)。
14.根据前述权利要求中任一项所述的多肽(a’),其中所述多肽能够使赭曲霉毒素A(OTA)和/或至少一种OTA衍生物解毒,其中优选地所述OTA衍生物选自赭曲霉毒素B和赭曲霉毒素C,其中所述多肽为以下中的一种或多种:
(aa’)与选自SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4的氨基酸序列具有至少64%(例如至少69%或至少80%或至少85%或至少95%,优选至少69%)序列同一性的多肽;优选地,所述多肽具有选自SEQ ID NOs:1-3的氨基酸序列;进一步优选地,所述多肽具有SEQ ID NO:1;
(aaa’)包含以下氨基酸序列(例如保守基序)中的一个或多个的多肽:
i)GHACGHNLIA(SEQ ID NO:5);
ii)IGSPAEEGGGGK(SEQ ID NO:6);
iii)MAHP(SEQ ID NO:7);
iv)VNHT(SEQ ID NO:23);
v)KVAKGLA(SEQ ID NO:9);
vi)IGSPAEEGGGGKVIL(SEQ ID NO:10);
vii)AHAGAAPWLG(SEQ ID NO:11);
viii)PELGFHEVKA(SEQ ID NO:12);
ix)TNPTSLPTAFVAT(SEQ ID NO:13);
x)GGRTFGFNAEYDAL(SEQ ID NO:14);
xi)GHACGHNLIAIVAVASA(SEQ ID NO:15);
xii)IPGTIKVIGSPAEEGGGGKVILLNEG(SEQ ID NO:16);
xiii)DACVMAHPEGG(SEQ ID NO:17);
xiv)AHAGAAPWLGVNALDAAVQGY(SEQ ID NO:18);
xv)GHACGHNLIAXXAVAXAXGXKAAXXXXXIXGTXKXIGSPAEEGGGGKXILXNEGXYDXXDACXMAHPXGG(SEQ ID NO:19),其中X为任何氨基酸;
xvi)(i)、(ii)、(iii)和(iv);和/或
xvii)AHAGAAPW(SEQ ID NO:8);
编码和/或能够表达所述根据(a’)的多肽的多核苷酸,编码和/或能够表达所述根据(a’)的多肽的核酸构建体、表达载体;
重组宿主细胞、孢子、转基因植物、转基因种子、转基因花粉粒、食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元、中间益生元或它们的混合物、组合物或试剂盒;
其用于以下方法中的一种或多种:
(i)用于治疗、改善、预防和/或诊断霉菌毒素中毒、优选OTA霉菌毒素中毒的方法;
(ii)用于监测霉菌毒素中毒的发展和/或评估霉菌毒素中毒预防和/或治疗、优选OTA霉菌毒素中毒预防和/或治疗的功效的方法;
(iii)用于使赭曲霉毒素A(OTA)解毒和/或改变OTA和/或至少一种OTA衍生物的毒性的方法,其中优选地所述OTA衍生物选自赭曲霉毒素B和赭曲霉毒素C;
(iv)生产以下中的一种或多种的方法:食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元,中间益生元;药物、兽医、诊断、解毒、监测和/或筛选组合物或试剂盒;
(v)根据前述权利要求中任一项所述的方法;
(vi)根据(i)-(v)的方法的任何组合;
(vii)(i)-(vi)中任一项的方法,其中所述方法是体外、离体或体内方法。
15.根据前述权利要求中任一项所述的以下中的一种或多种:
(a’)多肽,所述多肽能够使赭曲霉毒素A(OTA)和/或至少一种OTA衍生物解毒,其中优选地所述OTA衍生物选自赭曲霉毒素B和赭曲霉毒素C,其中所述多肽为以下中的一种或多种:
(aa’)与选自SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4的氨基酸序列具有至少64%(例如至少69%或至少80%或至少85%或至少95%,优选至少69%)序列同一性的多肽;优选地,所述多肽具有选自SEQ ID NOs:1-3的氨基酸序列;进一步优选地,所述多肽具有SEQ ID NO:1;
(aaa’)包含以下氨基酸序列(例如保守基序)中的一个或多个的多肽:
i)GHACGHNLIA(SEQ ID NO:5);
ii)IGSPAEEGGGGK(SEQ ID NO:6);
iii)MAHP(SEQ ID NO:7);
iv)VNHT(SEQ ID NO:23);
v)KVAKGLA(SEQ ID NO:9);
vi)IGSPAEEGGGGKVIL(SEQ ID NO:10);
vii)AHAGAAPWLG(SEQ ID NO:11);
viii)PELGFHEVKA(SEQ ID NO:12);
ix)TNPTSLPTAFVAT(SEQ ID NO:13);
x)GGRTFGFNAEYDAL(SEQ ID NO:14);
xi)GHACGHNLIAIVAVASA(SEQ ID NO:15);
xii)IPGTIKVIGSPAEEGGGGKVILLNEG(SEQ ID NO:16);
xiii)DACVMAHPEGG(SEQ ID NO:17);
xiv)AHAGAAPWLGVNALDAAVQGY(SEQ ID NO:18);
xv)GHACGHNLIAXXAVAXAXGXKAAXXXXXIXGTXKXIGSPAEEGGGGKXILXNEGXYDXXDACXMAHPXGG(SEQ ID NO:19),其中X为任何氨基酸;
xvi)(i)、(ii)、(iii)和(iv);和/或
xvii)AHAGAAPW(SEQ ID NO:8);
(b’)编码和/或能够表达所述根据(a’)的多肽的多核苷酸或者编码和/或能够表达所述根据(a’)的多肽的核酸构建体或表达载体,
(d’)重组宿主细胞、孢子、转基因植物、转基因种子、转基因花粉粒、食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元、中间益生元或它们的混合物、组合物或试剂盒;
其用于以下中的一种或多种/在以下中的一种或多种中的用途:
(i)霉菌毒素中毒、优选OTA霉菌毒素中毒的治疗、改善、预防和/或诊断;
(ii)监测霉菌毒素中毒的发展和/或评估霉菌毒素中毒预防和/或治疗、优选OTA霉菌毒素中毒预防和/或治疗的功效;
(iii)使赭曲霉毒素A(OTA)解毒和/或改变OTA和/或至少一种OTA衍生物的毒性,其中优选地所述OTA衍生物选自赭曲霉毒素B和赭曲霉毒素C;
(iv)生产以下中的一种或多种:食物、中间食物;草料、中间草料;饲料、中间饲料;添加剂(例如食物、草料或饲料添加剂)、中间添加剂(例如食物、草料或饲料中间添加剂);解毒剂、中间解毒剂;营养补充剂、中间营养补充剂;益生元,中间益生元;药物、兽医、诊断、解毒、监测和/或筛选组合物或试剂盒;
(v)在根据前述权利要求中任一项所述的方法中;
(vi)根据(i)-(v)的任何组合;
(vii)(i)-(vi)中任一项的用途,其中所述用途是体外、离体或体内用途。
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EP1620539A4 (en) | 2003-05-05 | 2007-09-26 | Monsanto Technology Llc | TRANSGENIC PLANTS WITH INCREASED GLYCIN BETAIN |
US9113649B2 (en) * | 2010-09-06 | 2015-08-25 | Dupont Nutrition Biosciences Aps | Food additive comprising an amidase for detoxifying ochratoxin |
AT513473B1 (de) | 2012-10-09 | 2016-01-15 | Erber Ag | Enzyme zur Transformation von Ergopeptinen sowie Verfahren hierfür |
PT3262163T (pt) | 2015-02-24 | 2019-10-08 | Erber Ag | Toxinas de fusarium - clivagem de variantes de polipeptídeos aditivo para clivagem das toxinas com o mesmo aditivo e o mesmo procedimento |
DK179660B1 (en) | 2016-04-08 | 2019-03-13 | Novozymes A/S | Stabilized Alpha-Amylase Variants and use of the same |
EP3342416A1 (de) | 2016-12-28 | 2018-07-04 | Erber Aktiengesellschaft | Verwendung von wenigstens einem glycyrrhiza-pflanzenpräparats, eines antidos davon sowie verwendung des antidots |
CN108120791A (zh) | 2017-12-08 | 2018-06-05 | 广东出入境检验检疫局检验检疫技术中心 | 一种同时快速测定样品中三种赭曲霉毒素总量的方法 |
EP3501526B1 (en) | 2017-12-22 | 2022-11-02 | DSM Austria GmbH | Use of coriobacteriia to promote gut health |
WO2020025580A1 (en) | 2018-07-31 | 2020-02-06 | Erber Aktiengesellschaft | Means and methods for cleavage of zearalenone |
-
2021
- 2021-12-17 US US18/268,189 patent/US20240067950A1/en active Pending
- 2021-12-17 WO PCT/EP2021/086480 patent/WO2022129517A2/en unknown
- 2021-12-17 EP EP21839993.9A patent/EP4263826A2/en active Pending
- 2021-12-17 CN CN202111558833.6A patent/CN114645037A/zh active Pending
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WO2022129517A3 (en) | 2022-07-28 |
US20240067950A1 (en) | 2024-02-29 |
WO2022129517A2 (en) | 2022-06-23 |
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