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Dpp-iv resistant gip hybrid polypeptides with selectable properties

a hybrid polypeptide, selectable technology, applied in the field of peptide chemistry and pharmaceuticals, can solve the problems of lipid metabolism, no clear evidence of effect, and clinical use of gip that has not been significantly advanced, so as to reduce gastric emptying, increase insulin secretion, and reduce plasma glucos

Inactive Publication Date: 2013-10-24
LEVY ODILE ESTHER +15
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes methods for treating metabolic diseases and disorders such as diabetes and hypertension by administering a therapeutically effective amount of a GIP or GIP analog, alone or in combination with other agents such as GLP-1 or GLP-2. The methods can be used as monotherapy or adjunct therapy to existing treatments. The GIP or GIP analog can have enhanced properties such as increased resistance to proteases and reduced renal clearance. The patent also describes novel GIP-containing hybrid polypeptides with selectable properties that exhibit at least one hormonal activity. Overall, the patent provides new ways to develop effective treatments for metabolic diseases and disorders.

Problems solved by technology

However, in humans, there is no clear evidence for an effect of GIP on lipid metabolism.
Consequently, clinical use of GIP has not been significantly advanced.

Method used

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  • Dpp-iv resistant gip hybrid polypeptides with selectable properties
  • Dpp-iv resistant gip hybrid polypeptides with selectable properties
  • Dpp-iv resistant gip hybrid polypeptides with selectable properties

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of GIP Polypeptides

[0690]Peptides of the invention may be assembled on a Symphony peptide synthesizer (Protein Technologies, Inc.) using Rink amide resin (Novabiochem) with a loading of 0.43-0.49 mmol / g at 0.050-0.100 mmol or a pre-loaded Wang Resin (Fmoc-Tyr(tBu)-Wang resin) 0.63 mmol / g (Novabiochem). Fmoc amino acid (5.0 eq, 0.250-0.500 mmol) residues are dissolved at a concentration of 0.10 M in 1-methyl-2-pyrrolidinone. All other reagents (HBTU, 1-hydroxybenzotriazole hydrate and N,N-Diisopropylethylamine) are prepared as 0.55 M dimethylformamide solutions. The Fmoc protected amino acids are then coupled to the resin-bound amino acid using, HBTU (2.0 eq, 0.100-0.200 mmol), 1-hydroxybenzotriazole hydrate (1.8 eq, 0.090-0.18 mmol), N,N-diisopropylethylamine (2.4 eq, 0.120-0.240 mmol) for 2 hours. Following the last amino acid coupling, the peptide is deprotected using 20% (v / v) piperidine in dimethylformamide for 1 hour. Once peptide sequence is complete, the Symphony ...

example 2

Binding Assays

[0693]The GIP polypeptides of the invention may be tested in a variety of receptor, e.g. GIPR, GLP-1R, amylin receptor, binding assays using binding assay methodologies generally known to those skilled in the art. Such assays include those described herein.

[0694]GIP Receptor Binding Assay: To identify GIP analog peptides having affinity for the human GIP receptor the following assay was performed in a high throughput format. Cell membranes were prepared from confluent cultures of an HEK293 cell line stably expressing the human GIP receptor (HEK-GIPR), snap frozen, and stored at −80 degrees C. until use. At the time of assay, membranes were thawed on ice and diluted to 0.02 mg / mL in ice cold binding buffer (20 mM HEPES pH 7.4, 0.5% BSA, 5 mM MgCl2, 1 mM CaCl2, 170 μM Phosphoramidon, 1.5 mM Bestatin-HCL, and 70 mM Bacitracin). Heterologous binding assays were initiated by combining membranes with 30 μM 125I-GIP and 10 nM individual unlabeled GIP analogs diluted in assay ...

example 3

Mouse Food Intake Assay

[0706]The GIP hybrid polypeptides of the invention may be tested for appetite suppression in the mouse food intake assay and for their effect on body weight gain in diet-induced obesity (DIO) mice. The experimental protocols for the screens are described herein.

[0707]Female NIH / Swiss mice (8-24 weeks old) are group housed with a 12:12 hour light:dark cycle with lights on at 0600. Water and a standard pelleted mouse chow diet are available ad libitum, except as noted. Animals are fasted starting at approximately 1500 hrs, 1 day prior to experiment. The morning of the experiment, animals are divided into experimental groups. In a typical study, n=4 cages with 3 mice / cage.

[0708]At time=0 min, all animals are given an intraperitoneal injection of vehicle or compound, typically in an amount ranging from about 10 nmol / kg to 75 nmol / kg, and immediately given a pre-weighed amount (10-15 g) of the standard chow. Food is removed and weighed, typically at 30, 60, and 120...

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Abstract

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

Description

RELATED APPLICATIONS[0001]This application is a divisional of United State patent application Ser. No. 12 / 377,856, filed Feb. 22, 2012, which in turn is a §371 of PCT / US2007 / 018415, filed Aug. 17, 2007, which claims priority to commonly-owned U.S. patent application Ser. No. 11 / 507,081 filed Aug. 17, 2006, now abandoned, each of which is hereby incorporated by reference in its entirety.INCORPORATION BY REFERENCE OF MATERIAL SUBMITTED BY EFS[0002]The sequence listing in the present application was submitted by EFS entitled “92494-868234_ST25.txt,” 452,558 bytes in size, with date Mar. 26, 2013, the contents of which are hereby incorporated by reference.FIELD OF THE INVENTION[0003]The present invention relates to peptide chemistry and pharmaceuticals, and more particularly to novel gastric inhibitory peptide (“GIP”) analog and GIP-containing hybrid polypeptides with selectable properties. It further relates to the use of these and other GIP compounds either alone or in adjunct with ot...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K14/47
CPCC07K14/47A61K38/00C07K14/575C07K14/57563C07K14/605C07K2319/00A61P9/00A61P3/10
Inventor LEVY, ODILE ESTHERBARON, ALAIN D.D'SOUZA, LAWRENCE J.ERICKSON, MARYGHOSH, SOUMITRA S.HANLEY, MICHAEL R.JANSSEN, SAMUELJODKA, CAROLYN M.LEWIS, DIANA Y.MACK, CHRISTINE M.PARKES, DAVID G.PITTNER, RICHARD A.SOARES, CHRISTOPHER J.SRIVASTAVA, VEDYOUNG, ANDREW A.LE, THAO
Owner LEVY ODILE ESTHER
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