Acylation of CGRP Peptides to Extend Half-Life

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Solution Overview

Problem

Native CGRP has a short half-life and vasodilatory effects that limit its pharmacological understanding and usefulness in treating metabolic syndrome, as its actions are contaminated by secondary vasoconstrictive effects, necessitating the development of CGRP analogues with prolonged action and improved pharmacokinetic and pharmacodynamic properties.

Innovation Solution

Development of acylated CGRP compounds with extended half-life and enhanced albumin binding affinity, which maintain the beneficial effects of CGRP while reducing vasodilatory side effects, including increased GLP-1 release, reduced food intake, weight loss, and improved insulin sensitivity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Duration of action of moving object

If native CGRP is administered to achieve pharmacological effects, then beneficial effects (AMPK activation, fat oxidation, reduced food intake) are obtained, but the short half-life and vasodilatory side effects limit its usefulness

Engineering Contradiction:

Improvehalf-lifeVSAvoidvasodilatory side effects

Core Design Contradiction:

Duration of action of moving objectVSObject-generated harmful factors

Solution Approach 1:

The patent applies parameter changes by modifying the chemical structure of CGRP through acylation at the N-terminus with various fatty acid chains. This structural modification changes the pharmacokinetic parameters (extending half-life from minutes to hours) and alters the pharmacodynamic profile (reducing vasodilatory effects while maintaining metabolic benefits).

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates composite peptide structures by combining CGRP with fatty acid moieties. The acylated CGRP compounds represent composite molecules that integrate the bioactive peptide sequence with hydrophobic fatty acid chains, enabling prolonged circulation and altered tissue distribution patterns.

Inventive Principle:

Principle #40Composite materials

2Duration of action of stationary object

If CGRP is administered at higher doses to overcome short duration of action, then prolonged exposure effects may be achieved, but vasodilatory effects become dose-limiting and contaminate study results

Engineering Contradiction:

Improveduration of pharmacological actionVSAvoidsecondary vasoconstrictive effects

Core Design Contradiction:

Duration of action of stationary objectVSObject-affected harmful factors

Solution Approach 1:

The acylation modification fundamentally changes the duration parameter of CGRP action, extending it from less than 30 minutes to several hours. This allows achievement of prolonged exposure effects at physiologically relevant doses without triggering dose-limiting vasodilatory responses.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If CGRP analogues with prolonged action are developed to maintain beneficial effects, then improved pharmacokinetic properties are achieved, but structural modifications may reduce binding affinity or activity

Engineering Contradiction:

Improvepharmacological usefulnessVSAvoidmolecular structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The acylation modification is applied locally at the N-terminus of the CGRP molecule, leaving the critical receptor-binding regions (C-terminal portion) unchanged. This localized modification approach preserves binding affinity and pharmacological activity while achieving the desired pharmacokinetic improvements.

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS8835379B2Derivatives of CGRP

Publication Date: 2014.09.16 EPOQE PHARMA APS

AI summary

Acylated CGRP compounds with a linker have prolonged action and are valuable as medicaments.