Dual GLP-1R GIPR Polypeptide Derivative for Enhanced Stability
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Solution Overview
Problem
Current polypeptide drugs targeting both GLP-1R and GIPR for diabetes and weight management have limited therapeutic potential due to instability, rapid degradation, and varying pharmacological effects and adverse reactions, necessitating a more potent and long-acting dual agonist with improved clinical value.
Innovation Solution
A polypeptide derivative with dual GLP-1R and GIPR targeting agonism, specifically structured with a branched chain linked by an amide bond, offering enhanced stability and potency through a novel synthesis method involving solid-phase or liquid-phase peptide synthesis, resulting in a compound with a significantly longer half-life and stronger pharmacodynamic effects compared to existing dual-targeting agents like Tirzepatide.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If naturally occurring GLP-1 and GIP are used as dual-targeting agents, then they can activate both GLP-1R and GIPR receptors, but they are unstable in vivo and susceptible to rapid degradation by DPP-IV
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of the polypeptide, specifically replacing certain amino acids with chemically stable analogs (e.g., D-amino acids, aminoethylisobutyric acid) and introducing cyclic structures to resist DPP-IV degradation while maintaining receptor binding capability
Solution Approach 2:
The patent creates a composite polypeptide structure combining GLP-1 and GIP sequences with modified amino acid residues, forming a chimeric molecule that integrates functions of both incretins while gaining enhanced stability through structural hybridization
2Adaptability or versatility
If existing dual GLP-1R and GIPR targeting agonists are used, then they can provide both insulinotropic and metabolic effects, but they have limited half-life and varying pharmacological effects
Solution Approach 1:
The patent optimizes pharmacokinetic parameters by introducing fatty acid amide modifications at the C-terminus and adjusting amino acid composition to achieve extended half-life through reduced renal clearance and enhanced protein binding
Solution Approach 2:
The patent employs selective amino acid substitutions at specific positions to achieve optimal balance between receptor affinity and metabolic stability, using partial modifications rather than complete sequence replacement to maintain biological activity while improving durability
3Adaptability or versatility
If polypeptide drugs with dual GLP-1R and GIPR targeting are developed, then they can treat diabetes and obesity, but they require complex synthesis methods and have varying manufacturing precision
Solution Approach 1:
The patent divides the polypeptide synthesis into protected fragment assembly steps, allowing modular construction of the complex molecule with controlled purification at each stage, reducing overall manufacturing complexity
Solution Approach 2:
The patent performs preliminary protection of amino acid side chains and strategic placement of cleavage sites before final assembly, enabling simplified deprotection and purification steps that reduce manufacturing complexity
Data Source
AI summary
The present invention discloses a polypeptide derivative with dual GLP-1R and GIPR targeting agonism, and a preparation method and use thereof. The polypeptide derivative is set forth in the formula (I). The formula (II) is a branched-chain modification structure of a peptide chain. The groups are defined in this specification. The polypeptide derivative and a pharmaceutically acceptable salt thereof that are provided in the present invention can be used in the fields of treatment of diabetes, weight loss, metabolism-related diseases such as NASH, and neurodegenerative disorders.Tyr-Aib-Asp-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-Xaa13-Leu-Asp-Lys-Ile-Ala-Gln-Xaa20-Glu-Phe-Val-Gln-Trp-Leu-Leu-Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2