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Isoform-specific insulin analogues

A technology for insulin analogs and analogs, which can be applied in the directions of microorganisms, drug combinations, biochemical equipment and methods, etc., and can solve problems such as non-enhanced binding to IGFR

Inactive Publication Date: 2011-05-18
CASE WESTERN RESERVE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] Without regard to theory, we have found that single-chain analogs of human insulin can be designed to preferentially bind IR-A with an affinity equal to or higher than that of wild-type insulin, but without enhanced binding to IGFR

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  • Isoform-specific insulin analogues
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  • Isoform-specific insulin analogues

Examples

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Embodiment Construction

[0041] The present invention is directed to recombinant single-chain insulin analogs that provide isoform-specific binding of the analog to the insulin receptor A isoform (IR-A) while simultaneously binding to the B isoform (IR-B) Reduced by at least 6 times. To this end, the insulin analog provided by the present invention comprises a variant insulin A chain polypeptide and a variant insulin B chain polypeptide, and the two are linked by a truncated linker polypeptide. In one embodiment, the linker polypeptide may be less than 15 amino acids in length. In other embodiments, the linker polypeptide may be 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids in length.

[0042] The single chain insulin analogs of the invention may also contain other modifications. As used in the specification and claims, various substituted analogs of insulin may be labeled according to convention, indicating the substituted amino acid followed by the position of that amino acid, optionally indicat...

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Abstract

A method treating a mammal by administering a physiologically effective amount of an insulin analogue or a physiologically acceptable salt thereof where the insulin analogue displays more than twofold greater binding affinity to insulin receptor isoform A (IR-A) than insulin receptor isoform B (IR-B). The insulin analogue may be a single-chain insulin analogue or a physiologically acceptable salt thereof, containing an insulin A-chain sequence or an analogue thereof and an insulin B-chain sequence or an analogue thereof connected by a polypeptide of 4-13 amino acids. A single-chain insulin analogue may display greater in vitro insulin receptor binding to IR-A but lower binding to IR-B than normal insulin while displaying less than or equal binding to IGFR than normal insulin.

Description

[0001] This invention was made with government support under cooperative agreements provided by the National Institutes of Health, Contract Nos. NIH R01DK069764, R01-DK74176, and R01-DK065890. The United States Government may have certain rights in this invention. Background of the invention [0002] Administration of insulin has long been established as a treatment for diabetes. Insulin is the product of a single-chain precursor, proinsulin, in which a linking region (35 residues) connects the C-terminal residue of the B chain (residue B30) to the N-terminal residue of the A chain ( Figure 1A ). Although the structure of proinsulin has not been determined, there are multiple indications that it consists of an insulin-like core with disordered connecting peptides ( Figure 1B ). Three specific disulfide bonds (A6-A11, A7-B7, and A20-B19; Figure 1B ) formation is believed to be related to the oxidative folding of proinsulin in the rough endoplasmic reticulum (ER). Proinsu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/28C12N5/06C12N5/16
CPCA61K38/28A61P3/10A61K38/08
Inventor M·维斯J·惠特克
Owner CASE WESTERN RESERVE UNIV
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