Acylated GIP Agonist Compounds Proteolysis Resistance

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Solution Overview

Problem

Current GIP analogues have a short in vivo half-life due to susceptibility to proteolysis, leading to reduced stability and efficacy as therapeutic agents for metabolic disorders like diabetes and obesity, and they may produce antagonistic fragments that counteract their effects.

Innovation Solution

Development of GIP analogues with altered sequences, such as those represented by Formulas I, II, and III, which include specific residues and modifications to enhance terminal elimination half-life and maintain agonistic activity, thereby reducing susceptibility to proteolysis and increasing stability, including conjugation of a lipophilic substituent to the side chain of certain residues.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If GIP analogues are used as therapeutic agents, then they can treat metabolic disorders like diabetes and obesity, but they have short in vivo half-life due to susceptibility to proteolysis

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidin vivo half-life

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent applies parameter changes by systematically modifying the amino acid sequence of GIP analogues at specific positions (1, 2, 3, 8, 11, 12, 17, 18, 20, 21, 23, 24, 25, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42) to reduce susceptibility to proteolysis while maintaining agonist activity at the GIP receptor, thereby extending in vivo half-life

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs composite materials by combining modified amino acid residues with specific side chain configurations and lipophilic substituents to create GIP analogues that resist proteolytic degradation while maintaining biological activity, effectively creating a more stable therapeutic compound

Inventive Principle:

Principle #40Composite materials

2Reliability

If GIP analogues are administered therapeutically, then they can stimulate insulin secretion and improve glycemic control, but they produce antagonistic fragments that counteract their effects

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidantagonistic fragments

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent modifies specific amino acid positions in the GIP sequence to prevent cleavage at sites that would generate antagonistic fragments, thereby maintaining therapeutic efficacy while eliminating harmful byproducts

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent converts the potential harm of proteolytic cleavage into a benefit by strategically modifying the sequence to direct cleavage away from antagonistic fragment generation sites, or by making the analogues resistant to cleavage entirely, thus transforming a degradation pathway into a stability enhancement strategy

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Data Source

PatentUS20240209054A1GIP agonist compounds and methods

Publication Date: 2024.06.27 ZEALAND PHARMA AS

AI summary

The present invention relates to acylated GIP analogues which have GIP agonist activity, and their use in the treatment of metabolic disorders.