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Methods for treatment of diabetes using peptide analogues of insulin

An analog, diabetes technology, applied in the field of diabetes treatment, can solve problems such as short half-life of insulin and difficult dosage

Inactive Publication Date: 2001-05-09
NEUROCRINE BIOSCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although administration of insulin is beneficial for diabetics, maintaining proper doses is difficult because insulin has a short serum half-life
Insulin use also leads to various hypoglycemic side effects and the production of neutralizing antibodies

Method used

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  • Methods for treatment of diabetes using peptide analogues of insulin
  • Methods for treatment of diabetes using peptide analogues of insulin
  • Methods for treatment of diabetes using peptide analogues of insulin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Preparation of peptides

[0051] This example illustrates the synthesis of representative peptide analogs.

[0052] The peptides were synthesized on a peptide synthesizer (Beckman Model 990) by solid phase method. A p-methylbenzylamine resin (MBHA resin) was used to prepare peptides with amidated carboxyl ends; for peptides with free carboxyl ends, a Merrifield resin coupled with appropriately protected amino acids was used. These two resins were purchased from Bachem Fine Chemicals (Torrance, CA). Unless otherwise specified, the derivatized amino acids (Bachem Fine Chemicals) used in the synthesis are all in the L-configuration, and the N-α-amino function is protected with tert-butoxycarbonyl without exception. The side chain functional groups are protected as follows: benzyl protects serine and threonine; cyclohexyl protects glutamic acid and aspartic acid; p-toluenesulfonyl protects histidine and arginine; 2-chlorobenzyloxycarbonyl protects lys Amino...

Embodiment 2

[0054] Long-term T cell line

[0055] This example illustrates the preparation of an insulin-specific long-term NOD T cell line.

[0056] When there are diffuse NOD splenocytes as antigen-presenting cells and cytokines, they are stimulated in vitro with 25μg / ml porcine insulin or diffused NOD islet cells, and the lymphocytes isolated from the islet infiltration population are cultured to establish insulin-specific NOD T cell line. In order to obtain the infiltrated lymphocytes, the following operations (see Wegmann et al., European Journal of Immunology 24: 1853, 1994): digest the pancreas of NOD mice with collagenase and manually separate individual islets. Then the islets are gently digested by trypsin to obtain infiltrated lymphocytes. When NOD spleen cells, porcine insulin and lymphokines are present, a series of stimulations are performed to proliferate insulin-specific T cell lines or clones. These clones were obtained by limiting dilution of a T cell line specifi...

Embodiment 3

[0058] Effect of peptide analogs on the clonal proliferation of insulin-specific NOD T cells

[0059] This example illustrates the effect of representative peptide analogs on T cell proliferation.

[0060] As described in Example 2, a mouse (NOD) T cell clone specific for insulin B chain (9-23) (SEQ ID NO: 2) was isolated from the infiltrated islets. The peptide analogs containing single alanine substitution were prepared as described in Example 1. The effects of each analogue on T cell proliferation were then evaluated using tests performed in 96-well flat-bottomed microtiter plates (see Daniel et al., European Journal of Immunology, 25: 1056, 1995). Simply put, in the presence of 50μg / ml insulin B chain 9-23 peptide or any of the alanine substituted peptides listed below, culture three 25,000 T cell clones and one million diffuse NOD splenocytes . At 7% CO 2 Incubate the titer plate in an atmosphere for a total of 72 hours, and pulse with 1μCi / well of tritiated thymidine for ...

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Abstract

The present invention is directed toward peptide analogues of insulin (B) chain that are generally derived from peptides comprising residues (9 to 23) of the native (B) chain sequence. The analogues are altered from the native sequence at position (12, 13, 15) and / or (16), and may be additionally altered at position (19) and / or other positions. Pharmaceutical compositions containing these peptide analogues are provided. The peptide analogues are useful for treating and inhibiting the development of diabetes.

Description

Technical field [0001] The present invention relates generally to peptide analogs of insulin, and more specifically to a method of treating diabetes using peptide analogs derived from residues 9-23 of the human insulin B chain. Background of the invention [0002] Insulin-dependent diabetes mellitus (IDDM) is an organ-specific autoimmune disease that affects about one million Americans of different ages. This disease is characterized by extensive destruction of insulin-producing pancreatic beta cells and dysregulation of glucose metabolism leading to symptomatic diabetes. The distinguishing feature of IDDM is the infiltration of lymphocytes in the pancreatic islets. Among infecting cells, T cells seem to be a major mediator of autoimmune damage. [0003] Type I diabetes is also characterized by increased levels of antibodies against various islet-associated antigens including insulin, GAD65, GAD67, and ICA512. These antibodies can be detected well before the disease emerges, and ...

Claims

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Application Information

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IPC IPC(8): A61K38/28A61K38/00A61P3/10C07K14/62
CPCC07K14/62A61K38/00A61P5/50A61P3/10
Inventor A·高尔N·凌P·J·康伦
Owner NEUROCRINE BIOSCI INC
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