Gip analog and hybrid polypeptides with selectable properties

An analogue and hybrid technology, applied in the field of hybrid polypeptides containing GIP, can solve the problems that GIP has not made significant progress in clinical application

Inactive Publication Date: 2008-04-02
AMYLIN PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

As a result, the clinical application o

Method used

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  • Gip analog and hybrid polypeptides with selectable properties
  • Gip analog and hybrid polypeptides with selectable properties
  • Gip analog and hybrid polypeptides with selectable properties

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0314] Implementation options include:

[0315] SEQ ID

NO.:

sequence

YAEGTFISDYSIAMDKIRQQDFVNWLLAQK-connector-

KCNTATCVLGKLSQELHRLQTYPRTNTGSNTY

YAEGTFISDYSIAMDKIRQQDFVNWLLAQK-connector-

KCNTATCVLGRLS QELHRLQTLPRTNTGSNTY

YAEGTFISDYSIAMDKIRQQDFVNWLLAQK-connector-

KCNTATCVLGRLS QELHRLQTYPPTNTGSNTY

YAEGTFISDYSIAMDKIRQQDFVNWLLAQK-connector-

KCNTATCVLGRLSQELHRLQTYPRTNVGSNTY

YAEGTFISDYSIAMDKIRQQDFVNWLLAQK-connector-

KCNTATCVLGRLSQELHRLQTLPPTNVGSNTY

YAEGTFISDYSIAMDKIRQQDFVNWLLAQK-connector-

KCNTATCVLGRLANFLHRLQTYPRTNTGSNTY

YAEGTFISDYSIAMDKIRQQDFVNWLLAQK-connector-

ACNTATCVLGRLSQELHRLQTYPRTNTGSNTY

YAEGTFISDYSIAMDKIRQQDFVNWLLAQK-connector-

KCNAATCVLGRLSQELHRLQTYPRTNTGSNTY

YAEGTFISDYSIAMDKIRQQDFVNWLLAQK-connector-

KCNTAACVLGRLSQELHRLQTYPRTNTGSNTY

YAEGTFISDYSIAMDKIRQQDFVNWLLAQK-connector-

CANLSTCVLGRLSQELHRLQTYPRTNTGSNTY ...

Embodiment 1

[0763] The preparation of embodiment 1.GIP polypeptide

[0764] Rink amide resin (Novabiochem) at 0.43-0.49 mmol / g loaded at 0.050-0.100 mmol, or 0.63 mmol / g preloaded Wang resin (Fmoc-Tyr(tBu)-Wang resin) (Novabiochem) can be used at The peptides of the present invention were assembled on a Symphony peptide synthesizer (Protein Technologies, Inc.). Fmoc amino acid (5.0 equivalents, 0.250-0.500 mmol) residues were dissolved in 1-methyl-2-pyrrolidone at a concentration of 0.10M. All other reagents (HBTU, 1-hydroxybenzotriazole hydrate and N,N-diisopropylethylamine) were prepared as 0.55M solutions in dimethylformamide. Then use HBTU (2.0 equivalents, 0.100-0.200mmol), 1-hydroxybenzotriazole hydrate (1.8 equivalents, 0.090-0.18mmol), N,N-diisopropylethylamine (2.4 equivalents, 0.120-0.240mmol ), the Fmoc-protected amino acid was coupled to the resin-bound amino acid for 2 hours. After the final amino acid coupling, the peptide was deprotected for 1 hour using 20% ​​(v / v) pi...

Embodiment 2

[0767] Embodiment 2. Binding experiment

[0768] GIP polypeptides of the invention can be tested in various receptor (eg GIPR, GLP-1R, amylin receptor) binding assays using binding assay methods well known to those skilled in the art. Such experiments include those described below.

[0769] Amylin binding assay : Binding of certain exemplary compounds of the invention to amylin receptors can be assessed in nucleus accumbens membranes prepared from rat brain as follows. Male Sprague-Dawley(R) rats (200-250 g) were sacrificed by decapitation. Brains were removed and placed in cold phosphate buffered saline (PBS). Starting on the ventral side, an incision was made from the mouth to the hypothalamus, laterally bounded by the olfactory tracts, and extended from these tracts at a 45° angle to the midline. This basal forebrain tissue, including the nucleus accumbens and surrounding area, was weighed and homogenized in ice-cold 20 mM HEPES buffer (20 mM HEPES acid, pH adjusted ...

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PUM

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Abstract

The present invention generally relates to novel GIP analogs and GIP hybrid polypeptides with selectable properties, which are useful as agents for the treatment and prevention of metabolic diseases and disorders, such as by controlling blood glucose levels, insulin levels and/or insulin secretion, inotropic effects, reduction of catabolic effects, slowing of gastric emptying to alleviate those. Such conditions and disorders include, but are not limited to, hypertension, dyslipidemia, cardiovascular disease, eating disorders, critical care, insulin resistance, obesity, and diabetes of any kind, including type 1, type 2, and gestational diabetes.

Description

[0001] related application [0002] This application claims priority to the following commonly owned and pending U.S. Provisional Applications: U.S. Provisional Application No. 60 / 652,662, filed February 11, 2005, and U.S. Provisional Application No. 60 / 653,433, filed February 15, 2005 , U.S. Provisional Application No. 60 / 651,647, filed February 11, 2005, U.S. Provisional Application No. 60 / 707,244, filed August 11, 2005, U.S. Provisional Application No. 60 / 707,369, filed August 11, 2005, 2005 US Provisional Application No. 60 / 709,320, filed August 17, 2005, and US Provisional Application No. 60 / 709,316, filed August 17, 2005, each of which is hereby incorporated by reference in its entirety. This application is hereby incorporated by reference in its entirety the following commonly owned applications: PCT / US05 / 04178, filed February 11, 2005, published as WO2005 / 077072; PCT / US2005 / 004351, filed February 11, 2005; PCT / US2005 / 004631, filed February 11, 2005; PCT / US2005 / 045471, f...

Claims

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Application Information

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IPC IPC(8): C07K14/575
Inventor O·E·莱维M·R·汉利C·M·乔卡D·Y·路易斯C·J·索尔斯S·S·高希L·J·德索扎D·G·帕克斯C·M·麦克V·斯里瓦斯塔瓦S·詹森A·D·巴伦A·A·杨R·A·皮特纳M·埃里克森
Owner AMYLIN PHARMA INC
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