CN110461867A - 经修饰贻贝蛋白、其用途和相关化合物 - Google Patents
经修饰贻贝蛋白、其用途和相关化合物 Download PDFInfo
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- CN110461867A CN110461867A CN201880021630.3A CN201880021630A CN110461867A CN 110461867 A CN110461867 A CN 110461867A CN 201880021630 A CN201880021630 A CN 201880021630A CN 110461867 A CN110461867 A CN 110461867A
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- C07K14/43504—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07K14/43504—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates
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- C—CHEMISTRY; METALLURGY
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- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
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- C—CHEMISTRY; METALLURGY
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Abstract
本发明涉及经修饰贻贝黏着蛋白、其用途、编码所述经修饰贻贝黏着蛋白的核苷酸序列、适用于产生所述经修饰贻贝黏着蛋白的氨酰‑tRNA合成酶、以及光笼化的3，4‑二羟基苯丙氨酸衍生物(特别是邻硝基苄基‑3，4‑二羟基苯丙氨酸)的新用途，所述衍生物包含保护基，可通过用UV光照射其邻苯二酚部分的至少一个羟基残基而从所述3，4‑二羟基苯丙氨酸衍生物残基切割该保护基。
Description
说明书
本发明涉及根据权利要求1的前序部分所述的经修饰贻贝蛋白(musselprotein)、根据权利要求8、9、11和12的前序部分所述的这样的经修饰贻贝蛋白的不同用途、根据权利要求13的前序部分所述的编码这样的经修饰贻贝蛋白的核酸、根据权利要求14的前序部分所述的适用于制备这样的经修饰贻贝蛋白的氨酰-tRNA合成酶、根据权利要求15的前序部分所述的这样的氨酰-tRNA合成酶的用途、和根据权利要求16的前序部分所述的邻硝基苄基-3，4-二羟基苯丙氨酸的新用途。
在医学中，存在长期以来对生物相容性胶的需求，其可用于治疗骨折或加速伤口愈合，以替换目前存在的有限的利用针(pin)和钉(nail)的治疗方法。1生物相容性生物胶必须满足数个要求，例如与组织的良好结合强度(黏着)，在生理、潮湿条件下的高稳定性(内聚力)，可控的生物降解性，在生物体中无免疫原性以及无毒性。2然而，目前没有满足这些要求的生物胶。虽然生物胶(例如纤维蛋白)显示出弱结合强度和迅速生物降解，而合成胶(例如氰基丙烯酸酯)显示出强结合特性，但对生物体3具有潜在毒性且不可吸收，因此损害内源性骨修复。1
在海洋贻贝中发现可满足上述要求的生物胶，所述生物胶能够通过其基于蛋白质的胶将自身粘在潮间带中的水下固体表面。4，5为了能够黏着，贻贝制造所谓的足丝(byssus)，其由数个蛋白质线组成，其最终呈现为黏着斑。黏着斑与表面直接接触，并且由不同的贻贝黏着蛋白(mussel adhesive protein，MAP)构成，其允许在多种有机和无机表面上形成强力、永久的黏着。拉伸强度高至10MPa6，其在松质骨(约5MPa)的范围内。7儿茶氨基酸3，4-二羟基苯丙氨酸(Dopa)是水下黏着的关键参与者，其是由酪氨酸翻译后形成的。Dopa通过多种机制(例如氢键、金属配位或醌介导的交联)促进黏着。4MAP具有高至30mol％的高Dopa含量，反映了Dopa对贻贝黏着的高重要性。
由于来自贻贝的提取产量低，已做了很多努力以通过利用酶促体外羟基化步骤、酪氨酸酶的共表达或通过利用真核表达系统以使酪氨酸残基翻译后羟基化而合成贻贝激发聚合物8，9或重组产生MAP10，11。虽然这些方法分别具有低结合强度、低羟基化效率或低蛋白质产量的缺点，但最近通过利用大肠杆菌(E.coli)酪氨酰tRNA合成酶(Tyrosyl tRNAsynthetase，TyrRS)的底物耐受性，在大肠杆菌中进行了酪氨酸与Dopa11的残基特异性替换。然而，该方法具有大肠杆菌TyrRS对Dopa的活化率差以及由于蛋白质组广泛并入Dopa而导致细胞生长受损的缺点。
本发明的一个目的是提供用于产生包含Dopa的蛋白质、特别是包含Dopa的贻贝蛋白，以及提供相应的经修饰贻贝蛋白质本身的新系统和合适的工具。
特别地，该目的通过具有权利要求1的特征的经修饰贻贝蛋白实现。这样的贻贝蛋白包含至少一个3，4-二羟基苯丙氨酸衍生物残基而不是在经修饰贻贝蛋白的各自天然类似物(例如，天然存在的贻贝蛋白)中天然存在的氨基酸。因此，3，4-二羟基苯丙氨酸衍生物残基在其邻苯二酚部分的至少一个羟基残基上包含保护基。其也可表示为受保护的3，4-二羟基苯丙氨酸衍生物残基。
在一个实施方案中，经修饰贻贝蛋白是经修饰贻贝黏着蛋白。在下文中，术语“经修饰贻贝蛋白”总是涵盖经修饰贻贝黏着蛋白，并且可限于本实施方案。
3，4-二羟基苯丙氨酸衍生物残基是光笼化(photocaged)的3，4-二羟基苯丙氨酸衍生物残基。保护基可通过用UV光照射从3，4-二羟基苯丙氨酸衍生物残基上切下。
在一个实施方案中，经修饰贻贝黏着蛋白是经修饰fp-5蛋白(MAPfp-5)。
在一个实施方案中，与3，4-二羟基苯丙氨酸相比，光笼化的3，4-二羟基苯丙氨酸衍生物仅有的修饰是其邻苯二酚部分的至少一个羟基残基上的保护基。在另一个实施方案中，3，4-二羟基苯丙氨酸衍生物在C2位置中还缺少氨基。
在一个实施方案中，保护基与邻苯二酚部分的两个羟基残基化学结合。具有1、2、3、4、5、6、7、8、9或10个碳原子的烷基链特别适用于该目的。
保护基的一个合适实例是6-硝基-1，3-苯并二氧杂环戊烯。已描述了该保护基在用波长为365nm的光照射时经历快速脱笼(decaging)过程。此外，对于1-硝基-3，4-亚甲基二氧基苯基没有观察到不期望的硝基胞内还原成胺，因此提高了整体的脱笼效率。因此，该保护基非常适合于产生光笼化的Dopa以并入经修饰贻贝蛋白中。该保护基的化学结构如下所示，在本实施方案中，其中R是Dopa衍生物残基或Dopa残基：
在一个实施方案中，保护基与邻苯二酚部分的一个羟基残基化学结合。
在一个实施方案中，邻硝基苄基用作可UV切割的保护基，使得光笼化的3，4-二羟基苯丙氨酸衍生物是邻硝基苄基-3，4-二羟基苯丙氨酸(ONB-Dopa)。
邻硝基苄基(ONB基团)12是保护基，其可通过用365nm的UV光照射而容易地切割掉，从而释放Dopa的邻苯二酚官能团。
ONB基团经常用于产生光笼化的蛋白，其可通过用UV光简单照射活化。虽然已描述了类似的化合物(例如ONB-酪氨酸12-14和ONB-氟酪氨酸15)，但据发明人所知，ONB-Dopa在以前任何研究中都没有使用过。光笼化的Dopa类似物的优点在于其允许产生可光敏化的生物胶，并且避免Dopa自氧化为Dopa醌，其已被描述为会损害黏着特性。16
为了合成经修饰贻贝蛋白，本发明人建立了新氨酰-tRNA合成酶(aminoacyl-tRNAsynthetase，aaRS)和同源tRNA的系统。近年来，已对由aaRS和同源tRNA组成的正交对(orthogonal pairs，o-对)进行工程化，以允许响应于琥珀终止密码子而活化非经典氨基酸(non-canonical amino acid，ncAA)并将其并入蛋白质中。17本文采用了相同的方法。使用的tRNA识别琥珀终止密码子(TGA)，因此其不再充当终止密码子，而是充当编码加载到特定tRNA之氨基酸的密码子。该氨基酸由新开发的氨酰-tRNA合成酶确定，并且在本情况下为ONB-Dopa。o-对的修饰将允许并入其他光笼化的3，4-二羟基苯丙氨酸衍生物残基。
新aaRS允许在多个位点处将ONB-Dopa并入蛋白质中，导致产生笼化的贻贝蛋白，其黏着特性可在365nm的照射下被时空活化。这些可光活化的(可光敏化的)贻贝蛋白质具有用于生物医学目的(例如用于治疗骨折)的巨大潜力。
由于多个Dopa残基的协作作用大大改善了贻贝黏着，因此在一个实施方案中将数个光笼化的3，4-二羟基苯丙氨酸衍生物残基、特别是ONB-Dopa残基同时并入经修饰贻贝蛋白中，以模拟贻贝的黏着能力。因此，在一个实施方案中，经修饰贻贝蛋白包含2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18或19个这样的光笼化的3，4-二羟基苯丙氨酸衍生物残基、特别是ONB-Dopa残基。在一个实施方案中，其包含2至19个相应的残基、特别是3至18、特别是4至17、特别是5至16、特别是6至15、特别是7至14、特别是8至13、特别是9至12、特别是10至11个相应的残基。
在一个实施方案中，光笼化的3，4-二羟基苯丙氨酸衍生物残基、特别是ONB-Dopa残基替换了酪氨酸残基。为了产生相应的经修饰贻贝蛋白，至少一个编码酪氨酸的密码子在遗传上被琥珀终止密码子替换，然后其由新开发的aaRS和同源tRNA的正交对用于在蛋白质合成过程中将ONB-Dopa或另一种光笼化的3，4-二羟基苯丙氨酸衍生物残基引入经修饰贻贝蛋白中。
在一个实施方案中，所述经修饰贻贝蛋白包含与SEQ ID NO：1、SEQ ID NO：2、SEQID NO：3、SEQ ID NO：11、SEQ ID NO：12、SEQ ID NO：13、SEQ ID NO：14、SEQ ID NO：15、SEQID NO：16、SEQ ID NO：17、SEQ ID NO：18或SEQ ID NO：19具有至少95％、特别是至少96％、特别是至少97％、特别是至少98％、特别是至少99％、特别是至少99.5％并且非常特别地100％同一性的氨基酸序列。
SEQ ID NO：1描述了带有5个ONB-Dopa残基的经修饰贻贝蛋白。SEQ ID NO：2描述了带有10个ONB-Dopa残基的经修饰贻贝蛋白。SEQ ID NO：3描述了带有19个ONB-Dopa残基的经修饰贻贝蛋白，即野生型贻贝蛋白(fp-5)的所有19个酪氨酸残基被ONB-Dopa交换。SEQID NO：11、SEQ ID NO：12和SEQ ID NO：13分别与SEQ ID NO：1、SEQ ID NO：2或SEQ ID NO：3的前77个氨基酸相同，但不包含C端His6标签。在一个实施方案中，经修饰贻贝蛋白不仅包含这样的氨基酸序列，而且由该氨基酸序列组成。
SEQ ID NO：14描述了带有5个光笼化的Dopa残基的经修饰贻贝蛋白(ONB-Dopa和6-硝基-1，3-苯并二氧杂环戊二醇-Dopa是光笼化的Dopa残基的实例)。SEQ ID NO：15描述了带有10个光笼化的Dopa残基的经修饰贻贝蛋白。SEQ ID NO：16描述了带有19个光笼化的Dopa残基的经修饰贻贝蛋白，即野生型贻贝蛋白(fp-5)的所有19个酪氨酸残基被光笼化的Dopa残基交换。SEQ ID NO：17、SEQ ID NO：18和SEQ ID NO：19分别与SEQ ID NO：14、SEQ IDNO：15或SEQ ID NO：16的前77个氨基酸相同，但不包含C端His6标签。在一个实施方案中，经修饰贻贝蛋白不仅包含这样的氨基酸序列，而且由该氨基酸序列组成。
在一个实施方案中，经修饰贻贝蛋白包含与和如先前三段中限定的氨基酸序列的N端融合的SEQ ID NO：4具有至少95％、特别是至少96％、特别是至少97％、特别是至少98％、特别是至少99％、特别是至少99.5％并且非常特别地100％同一性的氨基酸序列。具有SEQ ID NO：4的蛋白质是具有烟草蚀纹病毒(Tobacco Etch Virus，TEV)蛋白酶切割位点的麦芽糖结合蛋白(maltose-binding protein，MBP)，并且也可表示为MBP-TEV。通过将其用TEV蛋白酶处理，其可容易地从与其融合的蛋白质切割。在这样的处理之后，得到与SEQID NO：1、SEQ ID NO：2、SEQ ID NO：3、SEQ ID NO：11、SEQ ID NO：12、SEQ ID NO：13、SEQ IDNO：14、SEQ ID NO：15、SEQ ID NO：16、SEQ ID NO：17、SEQ ID NO：18或SEQ ID NO：19具有至少95％同一性的氨基酸序列的蛋白质。
在一个方面，本发明涉及根据先前说明的经修饰贻贝蛋白作为可生物降解的胶的用途，特别是涉及相应的体外用途。
在一个方面，本发明涉及用于通过将两种要素用包含根据先前说明的经修饰贻贝蛋白的可生物降解的胶胶黏在一起而将其组合的方法。
在一个方面，本发明涉及根据先前说明的经修饰贻贝蛋白用于用与经修饰贻贝蛋白共价结合的功能实体涂覆表面的用途。因此，本发明特别涉及相应的体外用途。通过经修饰贻贝蛋白的这样的用途，可通过选择适当的功能实体以任何期望的方式调节许多不同底物的表面特性。功能实体可以是例如肽或蛋白质。
在一个实施方案中，功能实体表现出抗微生物特性。在该实施方案中，可建立制品的抗微生物表面涂层。举例来说，可通过相应官能化经修饰贻贝蛋白涂覆例如假体或其他医学制品的植入物。因此，抗微生物肽非常适合与经修饰贻贝蛋白融合。
在一个方面，本发明涉及用于用包含根据先前说明的经修饰贻贝蛋白的官能化经修饰贻贝蛋白涂覆制品表面的方法，和与经修饰贻贝蛋白共价结合的功能实体。
在一个方面，本发明涉及根据先前说明的经修饰贻贝蛋白在医学中、特别是在手术或治疗(第一医学用途)中的用途。在另一个方面，本发明涉及根据先前说明的经修饰贻贝蛋白在手术或治疗中作为可生物降解的胶的用途。
在一个方面，本发明涉及用于通过将包含根据先前说明的经修饰贻贝蛋白的可生物降解的胶应用于至少一个待连接的部分、特别是应用于待连接的两个部分来将有此需要的人或动物的身体的两个部分紧密连接的治疗方法。
在一个方面，本发明涉及根据先前说明的经修饰贻贝蛋白在治疗骨折或用于增强伤口愈合(第二或进一步的医学用途)中的用途。可例如通过将经修饰贻贝蛋白与抗微生物实体(例如抗微生物肽)偶联并将该官能化经修饰贻贝蛋白应用到伤口上或伤口中以预防或改善伤口感染来增强伤口愈合。为此目的，可将官能化经修饰贻贝蛋白应用到旨在用于伤口治疗的敷料上。
在一个方面，本发明涉及用于通过将根据先前说明的经修饰贻贝蛋白应用于有此需要的人或动物、特别是通过将这样的经修饰贻贝蛋白应用于骨折的骨头上或待愈合的伤口上来治疗骨折的方法或增强伤口愈合的方法。
在相应的经修饰贻贝蛋白被UV光，特别是用波长为360至370nm、特别是365nm的UV光活化之后，可特别好地应用所有所描述的用途和所有相应的方法，以切割ONB保护基并暴露Dopa残基。
在一个方面，本发明涉及编码根据先前说明的经修饰贻贝蛋白的核酸，其具有与SEQ ID NO：5、SEQ ID NO：6或SEQ ID NO：7具有至少99％、特别是至少99.5％、特别是100％同一性的序列。具有SEQ ID NO：5的核酸包含由特异性tRNA识别的5个TAG三联体，所述特异性tRNA通过特定氨酰-tRNA合成酶加载有ONB-Dopa。因此，这些TAG三联体用于在蛋白质合成期间将ONB-Dopa并入待合成的经修饰贻贝蛋白中。因此，该核酸编码根据SEQ ID NO：1的经修饰贻贝蛋白。具有SEQ ID NO：6的核酸包含10个TAG三联体；其编码根据SEQ ID NO：2的经修饰贻贝蛋白。具有SEQ ID NO：7的核酸包含19个TAG三联体；其编码根据SEQ ID NO：3的经修饰贻贝蛋白。在每种情况下，TAG三联体替换编码基本的未经修饰贻贝蛋白中酪氨酸的三联体。
在一个方面，本发明涉及氨酰-tRNA合成酶，其包含与SEQ ID NO：8、SEQ ID NO：9或SEQ ID NO：10具有至少98％、特别是至少99％、特别是至少99.5％、特别是100％同一性的氨基酸序列。在一个实施方案中，氨酰-tRNA合成酶由相应的氨基酸序列组成。根据SEQID NO：8的蛋白质也可被称为ONB-DopaRS-1，根据SEQ ID NO：9的蛋白质也可被称为ONB-DopaRS-2，并且根据SEQ ID NO：10的蛋白质也可被称为ONB-DopaRS-3。这样的氨酰-tRNA合成酶能够使相应的tRNA加载有ONB-Dopa。因此，其非常适合用于将ONB-Dopa并入待合成的肽中。由于氨酰-tRNA合成酶的底物结合位点包含约30个氨基酸，所以产生2030≈1039个可能的序列。对于发明人来说非常出乎意料的发现是鉴定出三种不同(但密切相关)的氨酰-tRNA合成酶，其非常适合于使同源tRNA加载有ONB-Dopa。
本发明在一个方面涉及根据先前段落所述的氨酰-tRNA合成酶用于将邻硝基苄基-3，4-二羟基苯丙氨酸并入待合成的肽中的用途。因此，术语“肽”在本公开内容中涉及二肽、寡肽、多肽和蛋白质中的任一个。在一个实施方案中，氨酰-tRNA合成酶用于将ONB-Dopa并入待合成的蛋白质中。合成可在细菌、酵母细胞、植物细胞、全植物或无细胞蛋白质合成系统中进行。
根据本发明人的知识，光笼化的3，4-二羟基苯丙氨酸衍生物残基(例如ONB-Dopa)尚未用于合成肽。因此，本发明在一个方面涉及光笼化的3，4-二羟基苯丙氨酸衍生物残基、特别是ONB-Dopa在肽合成中的用途。关于术语“肽”和合适的合成系统的含义，参考先前段落。
ONB-Dopa可呈现为立体异构形式，即D型和L型。在一个实施方案中，ONB-Dopa是ONB-L-Dopa。该实施方案明确适用于其中存在ONB-Dopa的本申请中公开的蛋白质序列。
ONB基团可在间(m)或对(p)位置与Dopa结合。在一个实施方案中，ONB-Dopa是m-ONB-Dopa、特别是m-ONB-L-Dopa。该实施方案也明确适用于其中存在ONB-Dopa的本申请中公开的蛋白质序列。
m-ONB-L-Dopa的化学结构对应于式(I)，并且通过UV照射由m-ONB-L-Dopa得到的ONB-L-Dopa的化学结构对应于式(II)：
在另一方面，本发明涉及用于产生根据先前说明所述的经修饰贻贝蛋白的方法。该制备方法的特征在于以下说明的步骤。
首先，提供了编码待合成的经修饰贻贝蛋白的遗传经修饰核酸序列。由此，该经修饰核酸序列在核酸的相同位点包含一个或更多个琥珀终止密码子(TAG三联体)而不是天然存在的三联体。在一个实施方案中，编码酪氨酸的三联体(TAT或TAC三联体)已被TAG三联体替换。
在一个实施方案中，可提供与SEQ ID NO：5、SEQ ID NO：6或SEQ ID NO：7具有至少99％、特别是至少99.5％、特别是100％同一性的核酸序列。
然后，通过使用提供的核酸作为模板进行蛋白质合成。该蛋白质合成可例如在细菌、酵母细胞、植物细胞、全植物或无细胞蛋白质合成系统中进行。由此，用于蛋白质合成的系统包含特定氨酰-tRNA合成酶以及相应的tRNA的正交对。由此，氨酰-tRNA合成酶能够将光笼化的3，4-二羟基苯丙氨酸衍生物残基、特别是ONB-Dopa转移到相应的tRNA上。如果氨酰-tRNA合成酶包含与SEQ ID NO：8、SEQ ID NO：9或SEQ ID NO：10具有至少98％、特别是至少99％、特别是至少99.5％、特别是100％同一性的氨基酸序列或由其组成，则可最好地实现该目的-特别是如果选择ONB-Dopa作为光笼化的3，4-二羟基苯丙氨酸衍生物残基。
用于将ONB-Dopa并入待合成的经修饰贻贝蛋白中的合适的tRNA是先前在文献中描述的tRNA。23蛋白质合成系统还包含“常用”氨基酸tRNA合成酶和相应的tRNA，以用于进行适当的蛋白质合成。
然后可通过本领域技术人员公知的技术(例如使用琼脂糖树脂、磁珠或合适的柱)纯化合成的经修饰贻贝蛋白。由此，His6标签可很好地用于纯化目的(参见，例如，SEQ IDNO：1、SEQ ID NO：2、SEQ ID NO：3、SEQ ID NO：14、SEQ ID NO：15或SEQ ID NO：16)。
所描述的关于不同物质、用途和方法的所有实施方案可以以任何期望的方式组合，并且可以以任何期望的组合转移至任何其他物质、用途或方法。由此，物质的实施方案可转移至用途和方法，用途的实施方案可转移至物质和方法，并且方法的实施方案可转移至物质和用途。
下面参考示例性实施方案和附图更详细地说明本发明的方面。在图中：
图1A显示了在B95.ΔA23中表达的MBP-fp-5变体的SDS-PAGE和Western印迹分析；
图1B显示了在m-ONB-Dopa存在下表达的fp-5变体的NBT染色；
图1C显示了在干燥条件下的表面涂覆分析；
图2显示了在并入m-ONB-Dopa之后MBP-fp-5(5TAG)的解卷积(deconvoluted)ESl-MS谱；
图3A显示了MBP-fp-5(5TAG)的MALDI-TOF谱；
图3A显示了MBP-fp-5(10TAG)的MALDI-TOF谱；
图4A显示了通过AFM分析获得的fp-5(5TAG)与云母表面相互作用的F-D曲线；和
图4B显示了通过AFM分析获得的具有fp-5 WT和具有fp-5(5TAG)的两个官能化尖端的力值。
第一示例性实施方案
许多通常已知的保护基可用于产生受保护的3，4-二羟基苯丙氨酸衍生物，并因而允许时空活化Dopa的黏着特性。
一个简洁的策略包括对细菌细胞的新陈代谢进行工程化，以从容易获得的廉价前体分子中产生受保护的L-Dopa类似物。为了将这些前体转化为氨基酸，可产生表达新工程化苯丙氨酸-氨裂解酶(phenylalanine-ammonia lyase，PAL)或酪氨酸-氨裂解酶(tyrosine-ammonia lyase，TAL)的重组菌株。
例如基于MjTyrRS的O-对被设计成用于这些受保护的L-Dopa衍生物的体内tRNA氨酰化。脱保护可通过不同的方式例如光暴露或者如下面的反应方案1中所示通过酸性水解实现，最终导致水下黏着蛋白。
反应方案1：用在甲苯磺酸(TsOH)中引入的2，2-二甲氧基丙烷(DMP)保护邻苯二酚官能团作为异亚丙基，获得受保护的3，4-二羟基苯丙氨酸衍生物。翻译之后，通过酸性水解将获得的肽进行翻译后脱保护以暴露出黏着肽。
第二示例性实施方案
在整个该实施例中，将ONB-Dopa用作受保护的(光笼化的)3，4-二羟基苯丙氨酸衍生物残基。
为了测试将ONB-Dopa(更具体地，ONB基团连接在邻苯二酚部分的间羟基处；m-ONB-Dopa)多位点并入天然显示高Dopa含量的蛋白质中是否是可行的，选择MAP 5型(fp-5)，因为fp-5是贻贝湿黏着能力的关键组分。Fp-5显示出约30mol％的最高Dopa含量，这使得其对Dopa类似物的多位点并入特别有吸引力。对于表达测试，使用融合构建体，其由具有另外的TEV切割位点的N端麦芽糖结合蛋白(MBP)序列和来自配备有His6标签的地中海贻贝(M.galloprovincialis)的C端fp-5序列组成。
在5或10个位置用琥珀密码子替换酪氨酸密码子，以允许通过新ONB-Dopa特异性aaRS(ONB-DopaRS-1，SEQ ID NO：8)将m-ONB-Dopa位点特异性并入。对于蛋白质表达，选择其中RF1被消除的大肠杆菌BL21(DE3)菌株衍生物B-95.ΔA23。SDS-PAGE和Western印迹表明m-ONB-Dopa并入了fp-5(5个琥珀密码子；5TAG)和fp-5(10个琥珀密码子；10TAG)中。结果示于图1A中。用TEV蛋白酶消化WT MBP-fp-5(泳道1)、MBP-fp-5(5TAG)(泳道3)和MBP-fp-5(10TAG)(泳道5)并对fp-5(泳道2)、fp-5(5TAG)(泳道4)和fp-5(10TAG)(泳道6)的不溶性级分进行了分析。取决于ONB-Dopa含量，MBP-fp-5变体的预期分子量为约51至54kDa并且TEV消化之后fp-5变体的预期分子量为约10至12kDa。
在SDS PAGE分析中出现多条包含fp-5(5TAG)和fp-5(10TAG)变体的纯化的ONB-Dopa可能是由于如先前报道的ONB的硝基部分还原为胺。21与约18mg l-1野生型(WT)fp-5(包含19个Tyr残基)相比，在m-ONB-Dopa存在下分别获得约6mg l-1至约1mg l-1纯化的fp-5(5TAG)或fp-5(10TAG)。
通过应用对包含Dopa或Dopa醌的蛋白质进行选择性染色的氧化还原循环硝基蓝四唑(nitro blue tetrazolium，NBT)，在TEV消化之后验证带有ONB-Dopa的fp-5(5TAG)和fp-5(10TAG)变体的产生和脱笼。22虽然在照射的(+)Fp-5(5TAG)和Fp-5(10TAG)样品中发生了明显的染色，后者显示出更强的染色，但是未经照射(-)的样品几乎没有观察到显色(图1B)。这表明通过UV照射成功脱笼ONB-Dopa。
作为Dopa介导的黏着的原理验证测试，使用直接表面涂层测定在干燥条件下测试fp-5变体的表面黏着能力11(图1C)。图1C的上面的图显示了考马斯染色点的图像。在有(+)或没有(-)在365nm的照射的情况下将等量的牛血清白蛋白(bovine serum albumin，BSA)和fp-5变体在聚苯乙烯表面上点样至少六次。图1C的下面的图中所示的点强度的量化表明在照射之后黏着能力(adhesive potential)升高。数据代表平均值±s.d.
获得的数据表明在UV照射之后，随着Dopa含量增加，聚苯乙烯表面上的黏着提高，证明重组产生的光笼化的贻贝蛋白的黏着能力。总之，这些结果表明ONB-DopaRS-1促进了将ONB-Dopa有效多位点并入贻贝蛋白fp-5中，从而允许重组产生具有黏着能力的光笼化的MAP。
通过质谱法进一步分析所产生的蛋白质的特性(图2和3)。图2显示了使用ONBYRS-1并入m-ONB-Dopa之后MBP-fp-5(5TAG)的解卷积ESI-MS谱。发现的和预期的质量如下：MBP-fp-5(5ONB-Dopa)，观察到的：52114.7Da，预期的：52115.8Da。
图3A显示了在并入m-ONB-Dopa、TEV消化和用UV光照射之后MBP-fp-5(5TAG)的MALDI-TOF谱，图3B显示了在并入m-ONB-Dopa、TEV消化和用UV光照射之后MBP-fp-5(10TAG)的MALDI-TOF谱。发现的和预期的质量如下：fp-5(5Dopa)，观察到的：9807.9Da(M+H+)，预期的：9807.7Da(M+H+)。fp-5(10Dopa)，观察到的：9887.5Da(M+H+)，预期的：9887.7Da(M+H+)。
为了证明光笼化的MAP的水下黏着能力，采用基于原子力显微术(atomic forcemicroscopy，AFM)的力谱用于研究Dopa介导的湿黏着。为此目的，双官能缩醛-聚乙二醇(PEG)-N-羟基-琥珀酰亚胺(NHS)接头分子24，25允许通过赖氨酸残基共价连接MAP。
在用UV光照射之前和之后，在云母表面上的乙酸钠缓冲液(10mM，pH 4.6)中测量官能化AFM尖端的力-距离(F-D)曲线(参见图4A和4B)。图4A描绘了接近和缩回信号二者。图4B显示了在照射之前(白色条)和之后(黑色条)，用不同的fp-5变体(即fp-5 WT、fp-5(5TAG)和fp-5(10TAG))官能化的两个尖端(a、b)的力值。数据代表100条F-D曲线的平均值±s.d.；显著性以符号*p＜10-3、**p＜10-6、***p＜10-6表示。虽然在任何测量中通过UV照射fp-5 WT的黏着力没有显著变化，但fp-5(5TAG)和fp-5(10TAG)在UV光暴露后显示黏着力显著提高(分别高至12倍或高至6.5倍)。
为了验证Dopa对黏着提高的影响，研究了未经修饰和氨基官能化的尖端。二者都显示出在低pN范围内的黏着，在每种情况下都不受UV光暴露的影响。配备有5或10个m-ONB-Dopa实例的fp-5的数据为Dopa介导的黏着的时空控制的可行性和重组产生的光笼化MAP的高潜力提供了明确的证据。
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序列表
<110> Technische Universitaet Berlin
Humboldt-Universitaet zu Berlin
<120> 经修饰贻贝蛋白、其用途和相关化合物
<130> TU135WO
<150> EP17163362.1
<151> 2017-03-28
<160> 19
<170> PatentIn version 3.5
<210> 1
<211> 83
<212> PRT
<213> 人工序列
<220>
<223> 包含5个ONB-Dopa残基
<220>
<221> misc_feature
<222> (5)..(36)
<223> Xaa是邻硝基苄基-3,4-二羟基苯丙氨酸
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<223> 包含10个ONB-Dopa残基
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<222> (5)..(71)
<223> Xaa是邻硝基苄基-3,4-二羟基苯丙氨酸
<400> 2
Ser Ser Glu Glu Xaa Lys Gly Gly Xaa Tyr Pro Gly Asn Ser Asn His
1 5 10 15
Xaa His Ser Gly Gly Ser Tyr His Gly Ser Gly Xaa His Gly Gly Tyr
20 25 30
Lys Gly Lys Xaa Tyr Gly Lys Ala Lys Lys Tyr Xaa Tyr Lys Xaa Lys
35 40 45
Asn Ser Gly Lys Tyr Lys Xaa Leu Lys Lys Ala Arg Lys Tyr His Arg
50 55 60
Lys Gly Xaa Lys Lys Tyr Xaa Gly Gly Ser Ser Gly Ser His His His
65 70 75 80
His His His
<210> 3
<211> 83
<212> PRT
<213> 人工序列
<220>
<223> 包含19个ONB-Dopa残基
<220>
<221> MISC_FEATURE
<222> (5)..(71)
<223> Xaa是邻硝基苄基-3,4-二羟基苯丙氨酸
<400> 3
Ser Ser Glu Glu Xaa Lys Gly Gly Xaa Xaa Pro Gly Asn Ser Asn His
1 5 10 15
Xaa His Ser Gly Gly Ser Xaa His Gly Ser Gly Xaa His Gly Gly Xaa
20 25 30
Lys Gly Lys Xaa Xaa Gly Lys Ala Lys Lys Xaa Xaa Xaa Lys Xaa Lys
35 40 45
Asn Ser Gly Lys Xaa Lys Xaa Leu Lys Lys Ala Arg Lys Xaa His Arg
50 55 60
Lys Gly Xaa Lys Lys Xaa Xaa Gly Gly Ser Ser Gly Ser His His His
65 70 75 80
His His His
<210> 4
<211> 381
<212> PRT
<213> 人工序列
<220>
<223> 麦芽糖结合蛋白和TEV切割位点
<400> 4
Met Ala Gly Lys Ile Glu Glu Gly Lys Leu Val Ile Trp Ile Asn Gly
1 5 10 15
Asp Lys Gly Tyr Asn Gly Leu Ala Glu Val Gly Lys Lys Phe Glu Lys
20 25 30
Asp Thr Gly Ile Lys Val Thr Val Glu His Pro Asp Lys Leu Glu Glu
35 40 45
Lys Phe Pro Gln Val Ala Ala Thr Gly Asp Gly Pro Asp Ile Ile Phe
50 55 60
Trp Ala His Asp Arg Phe Gly Gly Tyr Ala Gln Ser Gly Leu Leu Ala
65 70 75 80
Glu Ile Thr Pro Asp Lys Ala Phe Gln Asp Lys Leu Tyr Pro Phe Thr
85 90 95
Trp Asp Ala Val Arg Tyr Asn Gly Lys Leu Ile Ala Tyr Pro Ile Ala
100 105 110
Val Glu Ala Leu Ser Leu Ile Tyr Asn Lys Asp Leu Leu Pro Asn Pro
115 120 125
Pro Lys Thr Trp Glu Glu Ile Pro Ala Leu Asp Lys Glu Leu Lys Ala
130 135 140
Lys Gly Lys Ser Ala Leu Met Phe Asn Leu Gln Glu Pro Tyr Phe Thr
145 150 155 160
Trp Pro Leu Ile Ala Ala Asp Gly Gly Tyr Ala Phe Lys Tyr Glu Asn
165 170 175
Gly Lys Tyr Asp Ile Lys Asp Val Gly Val Asp Asn Ala Gly Ala Lys
180 185 190
Ala Gly Leu Thr Phe Leu Val Asp Leu Ile Lys Asn Lys His Met Asn
195 200 205
Ala Asp Thr Asp Tyr Ser Ile Ala Glu Ala Ala Phe Asn Lys Gly Glu
210 215 220
Thr Ala Met Thr Ile Asn Gly Pro Trp Ala Trp Ser Asn Ile Asp Thr
225 230 235 240
Ser Lys Val Asn Tyr Gly Val Thr Val Leu Pro Thr Phe Lys Gly Gln
245 250 255
Pro Ser Lys Pro Phe Val Gly Val Leu Ser Ala Gly Ile Asn Ala Ala
260 265 270
Ser Pro Asn Lys Glu Leu Ala Lys Glu Phe Leu Glu Asn Tyr Leu Leu
275 280 285
Thr Asp Glu Gly Leu Glu Ala Val Asn Lys Asp Lys Pro Leu Gly Ala
290 295 300
Val Ala Leu Lys Ser Tyr Glu Glu Glu Leu Ala Lys Asp Pro Arg Ile
305 310 315 320
Ala Ala Thr Met Glu Asn Ala Gln Lys Gly Glu Ile Met Pro Asn Ile
325 330 335
Pro Gln Met Ser Ala Phe Trp Tyr Ala Val Arg Thr Ala Val Ile Asn
340 345 350
Ala Ala Ser Gly Arg Gln Thr Val Asp Glu Ala Leu Lys Asp Ala Gln
355 360 365
Thr Asn Ser Ser Ser Gly Ser Glu Asn Leu Tyr Phe Gln
370 375 380
<210> 5
<211> 1395
<212> DNA
<213> 人工序列
<220>
<223> 包含5个框内TAG位点
<400> 5
atggccggca aaatcgaaga aggtaaactg gtaatctgga ttaacggcga taaaggctat 60
aacggtctcg ctgaagtcgg taagaaattc gagaaagata ccggaattaa agtcaccgtt 120
gagcatccgg ataaactgga agagaaattc ccacaggttg cggcaactgg cgatggccct 180
gacattatct tctgggcaca cgaccgcttt ggtggctacg ctcaatctgg cctgttggct 240
gaaatcaccc cggacaaagc gttccaggac aagctgtatc cgtttacctg ggatgccgta 300
cgttacaacg gcaagctgat tgcttacccg atcgctgttg aagcgttatc gctgatttat 360
aacaaagatc tgctgccgaa cccgccaaaa acctgggaag agatcccggc gctggataaa 420
gaactgaaag cgaaaggtaa gagcgcgctg atgttcaacc tgcaagaacc gtacttcacc 480
tggccgctga ttgctgctga cgggggttat gcgttcaagt atgaaaacgg caagtacgac 540
attaaagacg tgggcgtgga taacgctggc gcgaaagcgg gtctgacctt cctggttgac 600
ctgattaaaa acaaacacat gaatgcagac accgattact ccatcgcaga agctgccttt 660
aataaaggcg aaacagcgat gaccatcaac ggcccgtggg catggtccaa catcgacacc 720
agcaaagtga attatggtgt aacggtactg ccgaccttca agggtcaacc atccaaaccg 780
ttcgttggcg tgctgagcgc aggtattaac gccgccagtc cgaacaaaga gctggcaaaa 840
gagttcctcg aaaactatct gctgactgat gaaggtctgg aagcggttaa taaagacaaa 900
ccgctgggtg ccgtagcgct gaagtcttac gaggaagagt tggcgaaaga tccacgtatt 960
gccgccacca tggaaaacgc ccagaaaggt gaaatcatgc cgaacatccc gcagatgtcc 1020
gctttctggt atgccgtgcg tactgcggtg atcaacgccg ccagcggtcg tcagactgtc 1080
gatgaagccc tgaaagacgc gcagactaat tcgagctcgg gcagcgagaa cctgtacttc 1140
caaagcagcg aagaatagaa aggtggttag tatccgggta acagcaacca ttagcatagc 1200
ggtggtagct atcatggtag cggttagcat ggtggttata aaggtaaata gtatggcaaa 1260
gccaaaaaat actactacaa atacaaaaac agcgggaaat acaaatatct gaaaaaagcc 1320
cgtaaatatc atcgtaaagg ctacaaaaaa tactatggtg gcagcagcgg cagccatcat 1380
catcatcatc actaa 1395
<210> 6
<211> 1395
<212> DNA
<213> 人工序列
<220>
<223> 包含10个框内TAG位点
<400> 6
atggccggca aaatcgaaga aggtaaactg gtaatctgga ttaacggcga taaaggctat 60
aacggtctcg ctgaagtcgg taagaaattc gagaaagata ccggaattaa agtcaccgtt 120
gagcatccgg ataaactgga agagaaattc ccacaggttg cggcaactgg cgatggccct 180
gacattatct tctgggcaca cgaccgcttt ggtggctacg ctcaatctgg cctgttggct 240
gaaatcaccc cggacaaagc gttccaggac aagctgtatc cgtttacctg ggatgccgta 300
cgttacaacg gcaagctgat tgcttacccg atcgctgttg aagcgttatc gctgatttat 360
aacaaagatc tgctgccgaa cccgccaaaa acctgggaag agatcccggc gctggataaa 420
gaactgaaag cgaaaggtaa gagcgcgctg atgttcaacc tgcaagaacc gtacttcacc 480
tggccgctga ttgctgctga cgggggttat gcgttcaagt atgaaaacgg caagtacgac 540
attaaagacg tgggcgtgga taacgctggc gcgaaagcgg gtctgacctt cctggttgac 600
ctgattaaaa acaaacacat gaatgcagac accgattact ccatcgcaga agctgccttt 660
aataaaggcg aaacagcgat gaccatcaac ggcccgtggg catggtccaa catcgacacc 720
agcaaagtga attatggtgt aacggtactg ccgaccttca agggtcaacc atccaaaccg 780
ttcgttggcg tgctgagcgc aggtattaac gccgccagtc cgaacaaaga gctggcaaaa 840
gagttcctcg aaaactatct gctgactgat gaaggtctgg aagcggttaa taaagacaaa 900
ccgctgggtg ccgtagcgct gaagtcttac gaggaagagt tggcgaaaga tccacgtatt 960
gccgccacca tggaaaacgc ccagaaaggt gaaatcatgc cgaacatccc gcagatgtcc 1020
gctttctggt atgccgtgcg tactgcggtg atcaacgccg ccagcggtcg tcagactgtc 1080
gatgaagccc tgaaagacgc gcagactaat tcgagctcgg gcagcgagaa cctgtacttc 1140
caaagcagcg aagaatagaa aggtggttag tatccgggta acagcaacca ttagcatagc 1200
ggtggtagct atcatggtag cggttagcat ggtggttata aaggtaaata gtatggcaaa 1260
gccaaaaaat actagtacaa atagaaaaac agcgggaaat acaaatagct gaaaaaagcc 1320
cgtaaatatc atcgtaaagg ctagaaaaaa tactagggtg gcagcagcgg cagccatcat 1380
catcatcatc actaa 1395
<210> 7
<211> 1395
<212> DNA
<213> 人工序列
<220>
<223> 包含19个框内TAG位点
<400> 7
atggccggca aaatcgaaga aggtaaactg gtaatctgga ttaacggcga taaaggctat 60
aacggtctcg ctgaagtcgg taagaaattc gagaaagata ccggaattaa agtcaccgtt 120
gagcatccgg ataaactgga agagaaattc ccacaggttg cggcaactgg cgatggccct 180
gacattatct tctgggcaca cgaccgcttt ggtggctacg ctcaatctgg cctgttggct 240
gaaatcaccc cggacaaagc gttccaggac aagctgtatc cgtttacctg ggatgccgta 300
cgttacaacg gcaagctgat tgcttacccg atcgctgttg aagcgttatc gctgatttat 360
aacaaagatc tgctgccgaa cccgccaaaa acctgggaag agatcccggc gctggataaa 420
gaactgaaag cgaaaggtaa gagcgcgctg atgttcaacc tgcaagaacc gtacttcacc 480
tggccgctga ttgctgctga cgggggttat gcgttcaagt atgaaaacgg caagtacgac 540
attaaagacg tgggcgtgga taacgctggc gcgaaagcgg gtctgacctt cctggttgac 600
ctgattaaaa acaaacacat gaatgcagac accgattact ccatcgcaga agctgccttt 660
aataaaggcg aaacagcgat gaccatcaac ggcccgtggg catggtccaa catcgacacc 720
agcaaagtga attatggtgt aacggtactg ccgaccttca agggtcaacc atccaaaccg 780
ttcgttggcg tgctgagcgc aggtattaac gccgccagtc cgaacaaaga gctggcaaaa 840
gagttcctcg aaaactatct gctgactgat gaaggtctgg aagcggttaa taaagacaaa 900
ccgctgggtg ccgtagcgct gaagtcttac gaggaagagt tggcgaaaga tccacgtatt 960
gccgccacca tggaaaacgc ccagaaaggt gaaatcatgc cgaacatccc gcagatgtcc 1020
gctttctggt atgccgtgcg tactgcggtg atcaacgccg ccagcggtcg tcagactgtc 1080
gatgaagccc tgaaagacgc gcagactaat tcgagctcgg gcagcgagaa cctgtacttc 1140
caaagcagcg aagaatagaa aggtggttag tagccgggta acagcaacca ttagcatagc 1200
ggtggtagct agcatggtag cggttagcat ggtggttaga aaggtaaata gtagggcaaa 1260
gccaaaaaat agtagtagaa atagaaaaac agcgggaaat agaaatagct gaaaaaagcc 1320
cgtaaatagc atcgtaaagg ctagaaaaaa tagtagggtg gcagcagcgg cagccatcat 1380
catcatcatc actaa 1395
<210> 8
<211> 306
<212> PRT
<213> 人工序列
<220>
<223> ONB-Dopa 氨酰-tRNA合成酶1
<400> 8
Met Asp Glu Phe Glu Met Ile Lys Arg Asn Thr Ser Glu Ile Ile Ser
1 5 10 15
Glu Glu Glu Leu Arg Glu Val Leu Lys Lys Asp Glu Lys Ser Ala Ala
20 25 30
Ile Gly Phe Glu Pro Ser Gly Lys Ile His Leu Gly His Tyr Leu Gln
35 40 45
Ile Lys Lys Met Ile Asp Leu Gln Asn Ala Gly Phe Asp Ile Ile Ile
50 55 60
Ile Leu Ala Asp Leu Ala Ala Tyr Leu Asn Gln Lys Gly Glu Leu Asp
65 70 75 80
Glu Ile Arg Lys Ile Gly Asp Tyr Asn Lys Lys Val Phe Glu Ala Met
85 90 95
Gly Leu Lys Ala Lys Tyr Val Tyr Gly Ser Glu Phe Ala Leu Asp Lys
100 105 110
Asp Tyr Thr Leu Asn Val Tyr Arg Leu Ala Leu Lys Thr Thr Leu Lys
115 120 125
Arg Ala Arg Arg Ser Met Glu Leu Ile Ala Arg Glu Asp Glu Asn Pro
130 135 140
Lys Val Ala Glu Val Ile Tyr Pro Ile Met Gln Val Asn Ala Ala His
145 150 155 160
Tyr Met Gly Val Asp Val Asn Val Gly Gly Met Glu Gln Arg Lys Ile
165 170 175
His Met Leu Gln Arg Glu Leu Leu Pro Lys Lys Val Val Cys Ile His
180 185 190
Asn Pro Val Leu Thr Gly Leu Asp Gly Glu Gly Lys Met Ser Ser Ser
195 200 205
Lys Gly Asn Phe Ile Ala Val Asp Asp Ser Pro Glu Glu Ile Arg Ala
210 215 220
Lys Ile Lys Lys Ala Tyr Cys Pro Ala Gly Val Val Glu Gly Asn Pro
225 230 235 240
Ile Met Glu Ile Ala Lys Tyr Phe Leu Glu Tyr Pro Leu Thr Ile Lys
245 250 255
Arg Pro Glu Lys Phe Gly Gly Asp Leu Thr Val Asn Ser Tyr Glu Glu
260 265 270
Leu Glu Ser Leu Phe Lys Asn Lys Glu Leu His Pro Met Arg Leu Lys
275 280 285
Asn Ala Val Ala Glu Glu Leu Ile Lys Ile Leu Glu Pro Ile Arg Lys
290 295 300
Arg Leu
305
<210> 9
<211> 306
<212> PRT
<213> 人工序列
<220>
<223> ONB-Dopa 氨酰-tRNA合成酶2
<400> 9
Met Asp Glu Phe Glu Met Ile Lys Arg Asn Thr Ser Glu Ile Ile Ser
1 5 10 15
Glu Glu Glu Leu Arg Glu Val Leu Lys Lys Asp Glu Lys Ser Ala Ser
20 25 30
Ile Gly Phe Glu Pro Ser Gly Lys Ile His Leu Gly His Tyr Leu Gln
35 40 45
Ile Lys Lys Met Ile Asp Leu Gln Asn Ala Gly Phe Asp Ile Ile Ile
50 55 60
Ile Leu Ala Asp Leu Ala Ala Tyr Leu Asn Gln Lys Gly Glu Leu Asp
65 70 75 80
Glu Ile Arg Lys Ile Gly Asp Tyr Asn Lys Lys Val Phe Glu Ala Met
85 90 95
Gly Leu Lys Ala Lys Tyr Val Tyr Gly Ser Glu Phe Ala Leu Asp Lys
100 105 110
Asp Tyr Thr Leu Asn Val Tyr Arg Leu Ala Leu Lys Thr Thr Leu Lys
115 120 125
Arg Ala Arg Arg Ser Met Glu Leu Ile Ala Arg Glu Asp Glu Asn Pro
130 135 140
Lys Val Ala Glu Val Ile Tyr Pro Ile Met Gln Val Asn Ala Gly His
145 150 155 160
Tyr Met Gly Ala Asp Val Asn Val Gly Gly Met Glu Gln Arg Lys Ile
165 170 175
His Met Leu Gln Arg Glu Leu Leu Pro Lys Lys Val Val Cys Ile His
180 185 190
Asn Pro Val Leu Thr Gly Leu Asp Gly Glu Gly Lys Met Ser Ser Ser
195 200 205
Lys Gly Asn Phe Ile Ala Val Asp Asp Ser Pro Glu Glu Ile Arg Ala
210 215 220
Lys Ile Lys Lys Ala Tyr Cys Pro Ala Gly Val Val Glu Gly Asn Pro
225 230 235 240
Ile Met Glu Ile Ala Lys Tyr Phe Leu Glu Tyr Pro Leu Thr Ile Lys
245 250 255
Arg Pro Glu Lys Phe Gly Gly Asp Leu Thr Val Asn Ser Tyr Glu Glu
260 265 270
Leu Glu Ser Leu Phe Lys Asn Lys Glu Leu His Pro Met Arg Leu Lys
275 280 285
Asn Ala Val Ala Glu Glu Leu Ile Lys Ile Leu Glu Pro Ile Arg Lys
290 295 300
Arg Leu
305
<210> 10
<211> 306
<212> PRT
<213> 人工序列
<220>
<223> ONB-Dopa 氨酰-tRNA合成酶3
<400> 10
Met Asp Glu Phe Glu Met Ile Lys Arg Asn Thr Ser Glu Ile Ile Ser
1 5 10 15
Glu Glu Glu Leu Arg Glu Val Leu Lys Lys Asp Glu Lys Ser Ala Ser
20 25 30
Ile Gly Phe Glu Pro Ser Gly Lys Ile His Leu Gly His Tyr Leu Gln
35 40 45
Ile Lys Lys Met Ile Asp Leu Gln Asn Ala Gly Phe Asp Ile Ile Ile
50 55 60
Ile Leu Ala Asp Leu Ala Ala Tyr Leu Asn Gln Lys Gly Glu Leu Asp
65 70 75 80
Glu Ile Arg Lys Ile Gly Asp Tyr Asn Lys Lys Val Phe Glu Ala Met
85 90 95
Gly Leu Lys Ala Lys Tyr Val Tyr Gly Ser Glu Phe Ala Leu Asp Lys
100 105 110
Asp Tyr Thr Leu Asn Val Tyr Arg Leu Ala Leu Lys Thr Thr Leu Lys
115 120 125
Arg Ala Arg Arg Ser Met Glu Leu Ile Ala Arg Glu Asp Glu Asn Pro
130 135 140
Lys Val Ala Glu Val Ile Tyr Pro Ile Met Gln Val Asn Ala Gly His
145 150 155 160
Tyr Met Gly Val Asp Val Ser Val Gly Gly Met Glu Gln Arg Lys Ile
165 170 175
His Met Leu Gln Arg Glu Leu Leu Pro Lys Lys Gln Val Cys Ile His
180 185 190
Asn Pro Val Leu Thr Gly Leu Asp Gly Glu Gly Lys Met Ser Ser Ser
195 200 205
Lys Gly Asn Phe Ile Ala Val Asp Asp Ser Pro Glu Glu Ile Arg Ala
210 215 220
Lys Ile Lys Lys Ala Tyr Cys Pro Ala Gly Val Val Glu Gly Asn Pro
225 230 235 240
Ile Met Glu Ile Ala Lys Tyr Phe Leu Glu Tyr Pro Leu Thr Ile Lys
245 250 255
Arg Pro Glu Lys Phe Gly Gly Asp Leu Thr Val Asn Ser Tyr Glu Glu
260 265 270
Leu Glu Ser Leu Phe Lys Asn Lys Glu Leu His Pro Met Arg Leu Lys
275 280 285
Asn Ala Val Ala Glu Glu Leu Ile Lys Ile Leu Glu Pro Ile Arg Lys
290 295 300
Arg Leu
305
<210> 11
<211> 77
<212> PRT
<213> 人工序列
<220>
<223> 包含5个ONB-Dopa残基
<220>
<221> MISC_FEATURE
<222> (5)..(36)
<223> Xaa是邻硝基苄基-3,4-二羟基苯丙氨酸
<400> 11
Ser Ser Glu Glu Xaa Lys Gly Gly Xaa Tyr Pro Gly Asn Ser Asn His
1 5 10 15
Xaa His Ser Gly Gly Ser Tyr His Gly Ser Gly Xaa His Gly Gly Tyr
20 25 30
Lys Gly Lys Xaa Tyr Gly Lys Ala Lys Lys Tyr Tyr Tyr Lys Tyr Lys
35 40 45
Asn Ser Gly Lys Tyr Lys Tyr Leu Lys Lys Ala Arg Lys Tyr His Arg
50 55 60
Lys Gly Tyr Lys Lys Tyr Tyr Gly Gly Ser Ser Gly Ser
65 70 75
<210> 12
<211> 77
<212> PRT
<213> 人工序列
<220>
<223> 包含10个ONB-Dopa残基
<220>
<221> MISC_FEATURE
<222> (5)..(71)
<223> Xaa是邻硝基苄基-3,4-二羟基苯丙氨酸
<400> 12
Ser Ser Glu Glu Xaa Lys Gly Gly Xaa Tyr Pro Gly Asn Ser Asn His
1 5 10 15
Xaa His Ser Gly Gly Ser Tyr His Gly Ser Gly Xaa His Gly Gly Tyr
20 25 30
Lys Gly Lys Xaa Tyr Gly Lys Ala Lys Lys Tyr Xaa Tyr Lys Xaa Lys
35 40 45
Asn Ser Gly Lys Tyr Lys Xaa Leu Lys Lys Ala Arg Lys Tyr His Arg
50 55 60
Lys Gly Xaa Lys Lys Tyr Xaa Gly Gly Ser Ser Gly Ser
65 70 75
<210> 13
<211> 77
<212> PRT
<213> 人工序列
<220>
<223> 包含19个ONB-Dopa残基
<220>
<221> MISC_FEATURE
<222> (5)..(71)
<223> Xaa是邻硝基苄基-3,4-二羟基苯丙氨酸
<400> 13
Ser Ser Glu Glu Xaa Lys Gly Gly Xaa Xaa Pro Gly Asn Ser Asn His
1 5 10 15
Xaa His Ser Gly Gly Ser Xaa His Gly Ser Gly Xaa His Gly Gly Xaa
20 25 30
Lys Gly Lys Xaa Xaa Gly Lys Ala Lys Lys Xaa Xaa Xaa Lys Xaa Lys
35 40 45
Asn Ser Gly Lys Xaa Lys Xaa Leu Lys Lys Ala Arg Lys Xaa His Arg
50 55 60
Lys Gly Xaa Lys Lys Xaa Xaa Gly Gly Ser Ser Gly Ser
65 70 75
<210> 14
<211> 83
<212> PRT
<213> 人工序列
<220>
<223> 包含5个光笼化的Dopa残基
<220>
<221> MISC_FEATURE
<222> (5)..(36)
<223> Xaa是光笼化的3,4-二羟基苯丙氨酸
<400> 14
Ser Ser Glu Glu Xaa Lys Gly Gly Xaa Tyr Pro Gly Asn Ser Asn His
1 5 10 15
Xaa His Ser Gly Gly Ser Tyr His Gly Ser Gly Xaa His Gly Gly Tyr
20 25 30
Lys Gly Lys Xaa Tyr Gly Lys Ala Lys Lys Tyr Tyr Tyr Lys Tyr Lys
35 40 45
Asn Ser Gly Lys Tyr Lys Tyr Leu Lys Lys Ala Arg Lys Tyr His Arg
50 55 60
Lys Gly Tyr Lys Lys Tyr Tyr Gly Gly Ser Ser Gly Ser His His His
65 70 75 80
His His His
<210> 15
<211> 83
<212> PRT
<213> 人工序列
<220>
<223> 包含10个光笼化的Dopa残基
<220>
<221> MISC_FEATURE
<222> (5)..(71)
<223> Xaa是光笼化的3,4-二羟基苯丙氨酸
<400> 15
Ser Ser Glu Glu Xaa Lys Gly Gly Xaa Tyr Pro Gly Asn Ser Asn His
1 5 10 15
Xaa His Ser Gly Gly Ser Tyr His Gly Ser Gly Xaa His Gly Gly Tyr
20 25 30
Lys Gly Lys Xaa Tyr Gly Lys Ala Lys Lys Tyr Xaa Tyr Lys Xaa Lys
35 40 45
Asn Ser Gly Lys Tyr Lys Xaa Leu Lys Lys Ala Arg Lys Tyr His Arg
50 55 60
Lys Gly Xaa Lys Lys Tyr Xaa Gly Gly Ser Ser Gly Ser His His His
65 70 75 80
His His His
<210> 16
<211> 83
<212> PRT
<213> 人工序列
<220>
<223> 包含19个光笼化的Dopa残基
<220>
<221> MISC_FEATURE
<222> (5)..(71)
<223> Xaa是光笼化的3,4-二羟基苯丙氨酸
<400> 16
Ser Ser Glu Glu Xaa Lys Gly Gly Xaa Xaa Pro Gly Asn Ser Asn His
1 5 10 15
Xaa His Ser Gly Gly Ser Xaa His Gly Ser Gly Xaa His Gly Gly Xaa
20 25 30
Lys Gly Lys Xaa Xaa Gly Lys Ala Lys Lys Xaa Xaa Xaa Lys Xaa Lys
35 40 45
Asn Ser Gly Lys Xaa Lys Xaa Leu Lys Lys Ala Arg Lys Xaa His Arg
50 55 60
Lys Gly Xaa Lys Lys Xaa Xaa Gly Gly Ser Ser Gly Ser His His His
65 70 75 80
His His His
<210> 17
<211> 77
<212> PRT
<213> 人工序列
<220>
<223> 包含5个光笼化的Dopa残基
<220>
<221> MISC_FEATURE
<222> (5)..(36)
<223> Xaa是光笼化的3,4-二羟基苯丙氨酸
<400> 17
Ser Ser Glu Glu Xaa Lys Gly Gly Xaa Tyr Pro Gly Asn Ser Asn His
1 5 10 15
Xaa His Ser Gly Gly Ser Tyr His Gly Ser Gly Xaa His Gly Gly Tyr
20 25 30
Lys Gly Lys Xaa Tyr Gly Lys Ala Lys Lys Tyr Tyr Tyr Lys Tyr Lys
35 40 45
Asn Ser Gly Lys Tyr Lys Tyr Leu Lys Lys Ala Arg Lys Tyr His Arg
50 55 60
Lys Gly Tyr Lys Lys Tyr Tyr Gly Gly Ser Ser Gly Ser
65 70 75
<210> 18
<211> 77
<212> PRT
<213> 人工序列
<220>
<223> 包含10个光笼化的Dopa残基
<220>
<221> MISC_FEATURE
<222> (5)..(71)
<223> Xaa是光笼化的3,4-二羟基苯丙氨酸
<400> 18
Ser Ser Glu Glu Xaa Lys Gly Gly Xaa Tyr Pro Gly Asn Ser Asn His
1 5 10 15
Xaa His Ser Gly Gly Ser Tyr His Gly Ser Gly Xaa His Gly Gly Tyr
20 25 30
Lys Gly Lys Xaa Tyr Gly Lys Ala Lys Lys Tyr Xaa Tyr Lys Xaa Lys
35 40 45
Asn Ser Gly Lys Tyr Lys Xaa Leu Lys Lys Ala Arg Lys Tyr His Arg
50 55 60
Lys Gly Xaa Lys Lys Tyr Xaa Gly Gly Ser Ser Gly Ser
65 70 75
<210> 19
<211> 77
<212> PRT
<213> 人工序列
<220>
<223> 包含19个光笼化的Dopa残基
<220>
<221> MISC_FEATURE
<222> (5)..(71)
<223> Xaa是光笼化的3,4-二羟基苯丙氨酸
<400> 19
Ser Ser Glu Glu Xaa Lys Gly Gly Xaa Xaa Pro Gly Asn Ser Asn His
1 5 10 15
Xaa His Ser Gly Gly Ser Xaa His Gly Ser Gly Xaa His Gly Gly Xaa
20 25 30
Lys Gly Lys Xaa Xaa Gly Lys Ala Lys Lys Xaa Xaa Xaa Lys Xaa Lys
35 40 45
Asn Ser Gly Lys Xaa Lys Xaa Leu Lys Lys Ala Arg Lys Xaa His Arg
50 55 60
Lys Gly Xaa Lys Lys Xaa Xaa Gly Gly Ser Ser Gly Ser
65 70 75
Claims (17)
1.经修饰贻贝黏着蛋白，其包含至少一个光笼化的3，4-二羟基苯丙氨酸衍生物残基，所述残基在其邻苯二酚部分的至少一个羟基残基上包含保护基，其中所述光笼化的3，4-二羟基苯丙氨酸衍生物残基替换天然存在的氨基酸并且其中所述保护基可通过用UV光照射从所述3，4-二羟基苯丙氨酸衍生物残基上切下。
2.根据权利要求1所述的经修饰贻贝黏着蛋白，其特征在于，其是经修饰fp-5蛋白。
3.根据权利要求1或2所述的经修饰贻贝黏着蛋白，其特征在于，所述光笼化的3，4-二羟基苯丙氨酸衍生物残基替换酪氨酸残基。
4.根据前述权利要求中任一项所述的经修饰贻贝黏着蛋白，其特征在于，所述光笼化的3，4-二羟基苯丙氨酸衍生物残基是邻硝基苄基-3，4-二羟基苯丙氨酸残基。
5.根据权利要求1至3中任一项所述的经修饰贻贝黏着蛋白，其包含与SEQ ID NO：14、SEQlD NO：15、SEQ ID NO：16、SEQ ID NO：17、SEQ ID NO：18或SEQ ID NO：19具有至少95％同一性的氨基酸序列。
6.根据前述权利要求中任一项所述的经修饰贻贝黏着蛋白，其包含与SEQ ID NO：1、SEQ ID NO：2、SEQ ID NO：3、SEQ ID NO：11、SEQ ID NO：12或SEQ ID NO：13具有至少95％同一性的氨基酸序列。
7.根据权利要求5或6所述的经修饰贻贝黏着蛋白，其包含与SEQ ID NO：4具有至少95％同一性的氨基酸序列，所述氨基酸序列与权利要求5或6中限定的氨基酸序列的N端融合。
8.根据前述权利要求中任一项所述的经修饰贻贝黏着蛋白作为体外可生物降解的胶的用途。
9.根据权利要求1至7中任一项所述的经修饰贻贝黏着蛋白用于在体外涂覆表面的用途，所述表面具有与所述经修饰贻贝蛋白共价结合的功能实体。
10.根据权利要求9所述的用途，其特征在于，所述功能实体表现出抗微生物特性。
11.根据权利要求1至7中任一项所述的经修饰贻贝黏着蛋白，其用于手术或用于治疗，特别是作为可生物降解的胶。
12.根据权利要求1至7中任一项所述的经修饰贻贝黏着蛋白，其用于治疗骨折或用于增强伤口愈合。
13.编码根据权利要求7所述的经修饰贻贝黏着蛋白的核酸，其具有与SEQ ID NO：5、SEQ ID NO：6或SEQ ID NO：7具有至少99％同一性的序列。
14.氨酰-tRNA合成酶，其包含与SEQ ID NO：8、SEQ ID NO：9或SEQ ID NO：10具有至少98％同一性的氨基酸序列。
15.根据权利要求14所述的氨酰-tRNA合成酶用于将邻硝基苄基-3，4-二羟基苯丙氨酸并入待合成的肽中的用途。
16.光笼化的3，4-二羟基苯丙氨酸衍生物在肽合成中的用途，所述衍生物在其邻苯二酚部分的至少一个羟基残基上包含能够通过用UV光照射而切割的保护基。
17.根据权利要求16所述的用途，其特征在于，所述光笼化的3，4-二羟基苯丙氨酸衍生物是邻硝基苄基-3，4-二羟基苯丙氨酸。
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| EP17163362.1A EP3381932A1 (en) | 2017-03-28 | 2017-03-28 | Modified mussel proteins, uses thereof and related compounds |
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| PCT/EP2018/057641 WO2018178013A1 (en) | 2017-03-28 | 2018-03-26 | Modified mussel proteins, uses thereof and related compounds |
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| US5202236A (en) * | 1984-09-13 | 1993-04-13 | Enzon Labs Inc. | Method of producing bioadhesive protein |
| DK2322631T3 (en) | 2001-04-19 | 2015-01-12 | Scripps Research Inst | Methods and compositions for the production of orthogonal tRNA-aminoacyl-tRNA syntetasepar |
| ATE494300T1 (de) | 2004-03-26 | 2011-01-15 | Postech Foundation | Biologischer klebstoff aus muscheln |
| WO2006034410A2 (en) * | 2004-09-21 | 2006-03-30 | The Scripps Resarch Institute | Adding photoregulated amino acids to the genetic code |
| WO2006132969A2 (en) * | 2005-06-03 | 2006-12-14 | Ambrx, Inc. | Incorporation of non-naturally encoded amino acids into proteins |
| JP6117563B2 (ja) | 2013-02-21 | 2017-04-19 | 国立研究開発法人農業・食品産業技術総合研究機構 | タンパク質の発現を制御する方法 |
| WO2015126480A2 (en) * | 2013-11-13 | 2015-08-27 | Massachusetts Institute Of Technology | Self-assembling underwater adhesives |
| AU2016284696B2 (en) | 2015-06-25 | 2021-10-28 | Amyris, Inc. | Maltose dependent degrons, maltose-responsive promoters, stabilization constructs, and their use in production of non-catabolic compounds |
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| BYEONGSEON YANG ET AL.: "In vivo residue-specific dopa-incorporated engineered mussel bioglue with enhanced adhesion and water resistance", 《ANGEW CHEM INT ED ENGL》 * |
| DONG SOO HWANG ET AL.: "Promotion of osteobalst proliferation on complex coacervation-based hyaluronic acid-recombinant mussel adhesive protein coatings on titanium", 《BIOMATERIALS》 * |
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| WO2018178013A1 (en) | 2018-10-04 |
| EP3601323B1 (en) | 2022-05-04 |
| CN110461867B (zh) | 2024-05-17 |
| US20210087237A1 (en) | 2021-03-25 |
| KR20190133218A (ko) | 2019-12-02 |
| JP7253804B2 (ja) | 2023-04-07 |
| EP3601323A1 (en) | 2020-02-05 |
| US11345910B2 (en) | 2022-05-31 |
| JP2020511996A (ja) | 2020-04-23 |
| EP3381932A1 (en) | 2018-10-03 |
| CA3058273A1 (en) | 2018-10-04 |
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