Peptide analogues of GIP for treatment of diabetes, insulin resistance and obesity

a peptide and insulin resistance technology, applied in the field of insulin release and blood glucose concentration control, can solve the problems of affecting the therapeutic role of incretin hormones, impairing oral glucose tolerance and glycemic response to nutrient ingestion, and debilitating diabetic complications and premature death, so as to enhance the capacity to stimulate insulin secretion, delay glucose absorption, and enhance glucose disposal

Inactive Publication Date: 2005-12-08
UUTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0028] Analogues of GIP(1-42) may have an enhanced capacity to stimulate insulin secretion, enhance glucose disposal, delay glucose absorption or may exhibit enhanced stability in plasma as compared to native GIP. They also may have enhanced resistance to degradation.
[0029] Any of these properties will enhance the potency of the analogue as a therapeutic agent.

Problems solved by technology

Obesity and diabetes are predicted to reach epidemic proportions throughout the world in the next 20 years and current treatments do not restore normal insulin sensitivity or glucose homeostasis, therein resulting in debilitating diabetic complications and premature death.
Since GIP functions as a potent and natural stimulator of insulin secretion released from the intestine by feeding, it is widely expected that antagonists opposing GIP action will block the insulin-releasing actions of GIP and impair both oral glucose tolerance and the glycemic response to nutrient ingestion.
However, the current goal of a possible therapeutic role of incretin hormones, particularly tGLP-1 in non-insulin dependent diabetes (NIDDM) therapy is frustrated by a number of factors in addition to finding a convenient route of administration.
However, these structural modifications seem to impair receptor binding and insulinotrophic activity thereby compromising part of the benefits of protection from proteolytic degradation.
In recent studies using His7-glucitol tGLP-1, resistance to DPP IV and serum degradation was accompanied by severe loss of insulin releasing activity.

Method used

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  • Peptide analogues of GIP for treatment of diabetes, insulin resistance and obesity
  • Peptide analogues of GIP for treatment of diabetes, insulin resistance and obesity
  • Peptide analogues of GIP for treatment of diabetes, insulin resistance and obesity

Examples

Experimental program
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Effect test

example 1

Preparation of N-Terminally Modified GIP and Analogues Thereof

[0173] The N-terminal modification of GIP is essentially a three step process. Firstly, GIP is synthesized from its C-terminal (starting from a Fmoc-Gln (Trt)-Wang resin (Calbiochem Novabiochem, Beeston, Nottingham, UK) up to the penultimate N-terminal amino-acid (Ala2) on an automated peptide synthesizer (Applied Biosystems, California, USA). The synthesis-follows standard Fmoc peptide chemistry protocols. Secondly, the N-terminal amino acid of native GIP (Tyr) is added to a manual bubbler system as a Fmoc-protected Tyr(tBu)-Wang resin. This amino acid is deprotected at its N-terminus (piperidine in DMF (20% v / v)) and allowed to react with a high concentration of glucose (glycation, under reducing conditions with sodium cyanoborohydride), acetic anhydride (acetylation), pyroglutamic acid (pyroglutamyl) etc. for up to 24 hours as necessary to allow the reaction to go to completion. The completeness of reaction is monitor...

example 2

Preparation of Tyr1-Glucitol GIP and its Properties In Vivo

[0174] The following example investigates preparation of Tyr1 glucitol GIP together with evaluation of its antihyperglycemic and insulin-releasing properties in vivo. The results clearly demonstrate that this novel GIP analogue exhibits a substantial resistance to aminopeptidase degradation and increased glucose lowering activity compared with the native GIP.

Research Design and Methods

[0175] Materials. Human GIP was purchased from the American Peptide Company (Sunnyvale, Calif., USA). HPLC grade acetonitrile was obtained from Rathburn (Walkersburn, Scotland). Sequencing grade trifluoroacetic acid (TFA) was obtained from Aldrich (Poole, Dorset, UK). All other chemicals purchased including dextran T-70, activated charcoal, sodium cyanoborohydride and bovine serum albumin fraction V were from Sigma (Poole, Dorset, UK). Diprotin A (DPA) was purchased from Calbiochem-Novabiochem (UK) Ltd. (Beeston, Nottingham, UK) and rat ins...

example 3

Additional N-Terminal Structural Modifications of GIP

[0190] This example further looked at the ability of additional N-terminal structural modifications of GIP in preventing inactivation by DPP and in plasma and their associated increase in both the insulin-releasing potency and potential therapeutic value. Native human GIP, glycated GIP, acetylated GIP and a number of GIP analogues with N-terminal amino acid substitutions were tested.

[0191] Materials and Methods. High-performance liquid chromatography (HPLC) grade acetonitrile was obtained from Rathburn (Walkersburn, Scotland). Sequencing grade trifluoroacetic acid (TFA) was obtained from Aldrich (Poole, Dorset, UK). Dipeptidyl peptidase IV was purchased from Sigma (Poole, Dorset, UK), and Diprotin A was purchased from Calbiochem Novabiochem (Beeston, Nottingham, UK). RPMI 1640 tissue culture medium, foetal calf serum, penicillin and streptomycin were all purchased from Gibco (Paisley, Strathclyde, UK). All water used in these ex...

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Abstract

The present invention provides peptide analogues which are antagonists of gastric inhibitory peptide (GIP). The peptides, based on GIP 1-42 include substitutions and / or modifications which have enhanced resistance to degradation by the enzyme dipeptidyl peptidase IV (DPP IV). The invention also provides a process of N terminally modifying GIP and the use of the peptide analogues for treatment of diabetes.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation-in-part application of International Application No. PCT / GB2005 / 000710, which was filed on Feb. 25, 2005, designated the United States and was published in English, which claims benefit of U.K. Application No. GB 0404124.0, filed on Feb. 25, 2004. The present application is also a continuation-in-part of U.S. application Ser. No. 09 / 937,687, filed Jan. 8, 2002, which is the U.S. National Phase Application of International Application No. PCT / GB00 / 01089, which is designated the United States and was filed on Mar. 29, 2000 and published in English, which in turn claims the benefit of GB9907216.7, filed on Mar. 29, 1999, and GB9917565.5, filed Jul. 27, 1999. The entire teachings of the above applications are incorporated herein by reference.FIELD OF THE INVENTION [0002] The present invention relates to the release of insulin and the control of blood glucose concentration. More particularly the invention r...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/00A61K38/22C07K14/575
CPCA61K38/00C07K14/575Y10T29/4935
Inventor GAULT, VICTORO'HARTE, FINBARRIRWIN, NIGELHARRIOTT, PATRICKFLATT, PETER
Owner UUTECH
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