Biased GLP-1R GIPR Agonists for Glucose Clearance
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Solution Overview
Problem
Current treatments for diabetes and related conditions, such as type 2 diabetes and nonalcoholic steatohepatitis (NASH), often rely on incretin hormones like GLP-1 and GIP, which have limitations due to rapid degradation and side effects like nausea.
Innovation Solution
Development of peptide-based chemical entities that modulate GLP-1R and GIPR activities, including agonists, partial agonists, and antagonists, which also attenuate β-arrestin signaling to reduce side effects while maintaining glucose clearance efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If incretin hormones like GLP-1 and GIP are used to treat diabetes, then glucose clearance efficacy is improved, but the hormones undergo rapid degradation and cause side effects like nausea
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of incretin hormones to create analogues with altered properties. Specifically, the patent modifies peptide sequences and incorporates stable amino acid analogues to resist degradation by DPP-4 enzyme, thereby extending half-life and improving stability while maintaining or enhancing glucose clearance efficacy
Solution Approach 2:
The patent employs composite materials by creating hybrid molecules that combine natural amino acids with synthetic stable analogues. The incretin analogues incorporate both natural peptide structures for receptor binding and synthetic components for enhanced stability, resulting in a composite molecular structure that achieves both efficacy and durability
2Reliability
If incretin hormones like GLP-1 and GIP are used to treat diabetes, then glucose clearance efficacy is improved, but side effects like nausea occur
Solution Approach 1:
The patent applies local quality by selectively modifying specific regions of the incretin hormone molecules. The modifications are localized to particular amino acid positions that are critical for stability and receptor interaction, while leaving other regions unchanged to maintain natural biological activity patterns and minimize off-target effects that cause nausea
Solution Approach 2:
The patent changes molecular parameters such as peptide bond stability, hydrophobicity, and charge distribution at specific locations to optimize the balance between efficacy and tolerability. These parameter changes reduce activation of nausea-related pathways while preserving glucose-dependent insulin secretion
3Reliability
If native ligands are used to modulate GLP-1R and GIPR, then receptor signaling is activated, but β-arrestin signaling is also stimulated causing side effects
Solution Approach 1:
The patent applies inversion by designing biased agonists that activate the desired G-protein signaling pathway while specifically avoiding β-arrestin recruitment. This inverted selectivity approach reverses the typical pattern where full agonists activate all available pathways, instead selectively channeling activity through the therapeutic G-protein route while blocking β-arrestin-mediated side effects
Data Source
AI summary
This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt) that modulate (e.g., agonize or partially agonize or antagonize) glucagon-like peptide-1 receptor (“GLP-1R”) and/or the gastric inhibitory polypeptide receptor (“GIPR”). The chemical entities are useful, e.g., for treating a disease, disorder, or condition in which modulation (e.g., agonism, partial agonism or antagonism) of GLP-1R and/or GIPR activities is beneficial for the treatment or prevention of the underlying pathology and/or symptoms and/or progression of the disease, disorder, or condition. In some embodiments, modulation results in enhancement of (e.g., increases) existing levels (e.g., normal or below normal levels) of GLP-1R and/or GIPR activity (e.g., signaling). In some embodiments, the chemical entities described herein further modulate (e.g., attenuate, uncouple) β-arrestin signaling relative to what is observed with the native ligand. This disclosure also features compositions as well as other methods of using and making the said chemical entities.