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Insulin analogues containing a glucose-regulated conformational switch

An insulin analog and insulin technology, which can be applied to insulin, peptides containing affinity tags, and medical preparations containing active ingredients, etc., and can solve the problems of decreased and increased activity.

Inactive Publication Date: 2018-01-02
CASE WESTERN RESERVE UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The formulation of insulin analogues of the above classes also ignores the significant reduction in activity, regardless of the possibility that the free glucose concentration may be affected by the substitution of residues A2 or A3 (Ile A2 or Val A3 ); these analogs are expected to have negligible biological activity and are therefore not as useful as long known in the art

Method used

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  • Insulin analogues containing a glucose-regulated conformational switch
  • Insulin analogues containing a glucose-regulated conformational switch
  • Insulin analogues containing a glucose-regulated conformational switch

Examples

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Embodiment Construction

[0037] The present invention relates to an insulin analog that provides enhanced insulin resistance through a glucose-dependent rate of disassembly of insulin hexamers in subcutaneous depots and / or glucose-dependent binding to insulin receptors in the bloodstream and at target tissues. Blood sugar control in the body. Six novel insulin analogs, listed in Table 2, were prepared. Each employs fluoro-phenylboronic acid as the glucose sensing element. Fluoro-PBA moieties and Gly A1 The chemical bonds between the α-amino groups such as Figure 7 shown in; in Phe B1 The corresponding bond (not shown) is employed in the analogue with the fluoro-PBA adduct at the α-amino group of .

[0038]Two analogs contained one such adduct (α-amino group at the A chain; Table 2A), and three analogs contained two such adducts (α-amino group at both the A and B chains). amino group; Table 2B). A protocol for the derivatization of insulin fragments by the active agent FPA reagent is provided be...

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Abstract

A two-chain insulin analogue contains an A chain modified by (i) a monomeric glucose-binding element at or near its N terminus and (ii) a B chain modified by at or near its C terminus by an element that reversibly binds to the monomeric glucose-binding element such that this linkage is displaceable by glucose. The monomeric glucose-binding element may be phenylboronic acid derivative (optionally halogenated). The B chain may be modified by a diol-containing element derived from a monosaccharide, disaccharide or oligosaccharide, a non-saccharide diol-containing moiety or a [Alpha]-hydroxycarboxylate-containing moiety. The analogue can be manufactured by trypsin-mediated semi-synthesis. Formulations can be at strengths U-10 to U-1000 in soluble solutions at pH 7.0-8.0 with or without zinc ions at a molar ratio of 0.0-3.0 ions per insulin analogue monomer. A patient with diabetes mellitus may be treated with subcutaneous, intraperitoneal, or oral administration of a physiologically effective amount of the insulin analogue.

Description

[0001] Statement Regarding Federally Sponsored Research or Development [0002] This invention was made with government support under a collaborative agreement awarded by the National Institutes of Health, grant number DK040949. The US Government has certain rights in this invention. Background of the invention [0003] The present invention relates to polypeptide hormone analogs which contain a glucose-conformational switch and thus exhibit a glucose-responsive rate of hormone disassembly or glucose-responsive binding to cognate cellular receptors. The use of insulin for the treatment of patients with type 1 or type 2 diabetes mellitus and non-human mammals by subcutaneous, intraperitoneal or intravenous injection is described. The insulin analogs of the invention may also exhibit other enhanced pharmaceutical properties, such as increased thermodynamic stability, enhanced resistance to thermofibrillation above room temperature, reduced mitogenicity and / or altered pharmacoki...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/28C07K14/62
CPCC07K14/622C07K2319/20C07K2319/70A61K38/00C07K14/62A61P3/10Y02A50/30
Inventor M.维斯
Owner CASE WESTERN RESERVE UNIV
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