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1. 发明申请

WO2009083549A1 SEMI-RECOMBINANT PREPARATION OF GLP-1 ANALOGUES 审中-公开
标题翻译： GLP-1类似物的半重复制备
公开(公告)号：WO2009083549A1
公开(公告)日：2009-07-09
申请号：PCT/EP2008/068211
申请日：2008-12-22
申请人： NOVO NORDISK A/S , LAU, Jesper Færgeman , ANDERSEN, Asser Sloth , BLOCH, Paw , LAU, Jesper , GARIBAY, Patrick William , KRUSE, Thomas , NØRBY, Inga Sig Nielsen , JESSEN, Claus Ulrich , CHRISTENSEN, Caspar , NORRILD, Jens Christian
发明人： LAU, Jesper Færgeman , ANDERSEN, Asser Sloth , BLOCH, Paw , LAU, Jesper , GARIBAY, Patrick William , KRUSE, Thomas , NØRBY, Inga Sig Nielsen , JESSEN, Claus Ulrich , CHRISTENSEN, Caspar , NORRILD, Jens Christian
IPC分类号： C07K1/10 , C07K14/605
CPC分类号： C07K14/605 , C07K1/006 , C07K1/02 , C07K1/061 , C07K1/107 , C07K1/1077
摘要： A semi-recombinant method for the production of GLP-1 analogues and derivatives with non-proteogenic amino acids in the N-terminal part combining the use of recombinant expression techniques and chemical peptide synthesis.
摘要翻译：在重组表达技术和化学肽合成的N末端部分中用于生产具有非蛋白质氨基酸的GLP-1类似物和衍生物的半重组方法。

2. 发明申请

WO2014191455A1 METHODS FOR PRODUCING PEPTIDES USING ENGINEERED INTEINS 审中-公开
标题翻译：使用工程化产品生产胶囊的方法
公开(公告)号：WO2014191455A1
公开(公告)日：2014-12-04
申请号：PCT/EP2014/061048
申请日：2014-05-28
申请人： NOVO NORDISK A/S
发明人： SHAW, Allan Christian , NORRILD, Jens Christian , ALBERTSEN, Louise
IPC分类号： A61K38/22 , C07K14/575 , C07K7/00 , C12N15/09 , C12N15/62
CPC分类号： C07K14/47 , C07K1/006 , C07K7/00 , C07K14/575 , C07K2319/00 , C07K2319/92 , C12N9/90 , C12N15/09 , C12N15/625
摘要： The present invention provides a method for producing peptides by recombinant means. The peptides are expressed as part of a fusion protein comprising the target peptide and an engineered intein. The invention also provides the engineered inteins, fusion proteins comprising these, and DNA constructs coding for these fusion proteins. Upon thiol-induced cleavage of the fusion protein the carboxy-terminal a-thioester of the target peptide is obtained. The carboxy-terminal α-thioester can in principle react with any nucleophile and the strategy therefore allows a wider range of carboxy-terminal modifications such as chemical ligation, bioconjugation, or amidation. The engineered inteins of the present invention are minimized in size and has a cysteine mutation in the position corresponding by alignment to position 3 of Mxe GyrA intein (SEQ ID NO:1 ) leading to increased expression levels of the fusion protein and higher yields of the isolated target peptide, thus making the method of the invention suitable for production scale.
摘要翻译：本发明提供了通过重组方法制备肽的方法。肽被表达为包含靶肽和工程化内含肽的融合蛋白的一部分。本发明还提供了工程化的内含肽，包含它们的融合蛋白以及编码这些融合蛋白的DNA构建体。在硫醇诱导的融合蛋白切割时，获得了靶肽的羧基末端α-硫酯。羧基末端α-硫酯可以原则上与任何亲核试剂反应，因此该策略允许更广泛的羧基末端修饰，如化学连接，生物共轭或酰胺化。本发明的工程化内含子在尺寸上最小化，并且在对应于Mxe GyrA内含肽（SEQ ID NO：1）的位置3的对应位置处具有半胱氨酸突变，导致融合蛋白的表达水平升高，并且更高的产量分离的靶肽，从而使本发明的方法适合于生产规模。

3. 发明申请

WO2013127779A1 GLP-1 PRODRUGS 审中-公开
公开(公告)号：WO2013127779A1
公开(公告)日：2013-09-06
申请号：PCT/EP2013/053796
申请日：2013-02-26
申请人： NOVO NORDISK A/S
发明人： NORRILD, Jens Christian
IPC分类号： C07K14/605 , A61K38/26
CPC分类号： A61K47/48269 , A61K38/00 , A61K38/26 , A61K47/642 , C07K14/575 , C07K14/605
摘要： The invention relates to a GLP-1 prodrug of the general formula I: R1-(NHXaa1)- Xaa2-(OHis)-(GLP-1peptide) (Formula I), wherein GLP-1 peptide is GLP-1(8-37) (SEQ ID NO: 1) or an analogue thereof having a maximum of nineamino acid changes as compared to GLP-1(8-37), R1 is lower alkyl, (NHXaa1) is an amino acid, Xaa2 is an amino acid, and (OHis) is a radical of imidazole-lactic acid; or a pharmaceutically acceptable salt, amide, or ester of the prodrug. The invention also relates to specific GLP-1 parent drugs of the general formula II: (HOHis)-(GLP-1peptide) (Formula II), as well as specific intermediate products. The invention furthermore relates to a method of achieving release in vivo of an active and stabilised GLP-1 parent drug of the general formula II: (HOHis)-(GLP-1 peptide), by administering a GLP-1 prodrug; as well as to such GLP-1 prodrug, and such GLP-1 parent drug, respectively, for use as a medicament, in particular for use in the treatment and/or prevention of all forms of diabetes and related diseases. The prodrug may be used to alter the PK and/or absorption profile of the drug, for example to a desirable bell-shaped curve. The parent drug has a good biological activity, and is stabilised against degradation by DPP- IV.
摘要翻译：本发明涉及通式Ⅰ的GLP-1前药：R1-（NHXaa1）-Xaa2-（OHis） - （GLP-1肽）（式I），其中GLP-1肽是GLP-1（8-37 ）（SEQ ID NO：1）或其与GLP-1（8-37）相比具有最多9个氨基酸变化的类似物，R1为低级烷基，（NHXaa1）为氨基酸，Xaa2为氨基酸，和（OHis）是咪唑 - 乳酸的基团; 或前药的药学上可接受的盐，酰胺或酯。本发明还涉及通式II（HOHis） - （GLP-1肽）（式II）的具体GLP-1亲本药物以及具体的中间产物。本发明还涉及通过施用GLP-1前药，实现通式II：（HOHis） - （GLP-1肽）的活性和稳定的GLP-1母体药物体内释放的方法; 以及这样的GLP-1前药以及这样的GLP-1亲本药物，分别用作药物，特别是用于治疗和/或预防所有形式的糖尿病和相关疾病。前药可用于改变药物的PK和/或吸收曲线，例如改变为期望的钟形曲线。母体药物具有良好的生物活性，并且通过DPP-IV稳定化降解。

4. 发明申请

WO2013098191A1 DIPEPTIDE COMPRISING A NON-PROTEOGENIC AMINO ACID 审中-公开
标题翻译：含非氨基酸氨基酸的肽
公开(公告)号：WO2013098191A1
公开(公告)日：2013-07-04
申请号：PCT/EP2012/076408
申请日：2012-12-20
申请人： NOVO NORDISK A/S
发明人： CHRISTENSEN, Caspar , RAUNKJÆR, Michael , SEVERINSEN, Rune , NORRILD, Jens Christian
IPC分类号： C07K1/107 , C07K5/06 , C07K14/605
CPC分类号： C07K5/06147 , C07K1/107 , C07K4/00 , C07K5/06 , C07K14/001 , C07K14/605
摘要： Described is a dipeptide comprising a non-proteogenic amino acid, methods of making such and methods of using said dipeptide in a process of making a polypeptide or protein comprising one or more non-proteogenic amino acids.
摘要翻译：描述了包含非蛋白原性氨基酸的二肽，制备方法以及在制备包含一种或多种非蛋白原性氨基酸的多肽或蛋白质的方法中使用所述二肽的方法。

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