Peptide Modulators for GLP-1R and GIPR Signaling
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Solution Overview
Problem
Current treatments for diabetes and related conditions, such as type 2 diabetes and nonalcoholic steatohepatitis, often rely on GLP-1 and GIP analogs that have short half-lives due to DPP-IV degradation, leading to rapid loss of biological activity and potential side effects like nausea, limiting their efficacy and tolerability.
Innovation Solution
Development of peptide-based chemical entities that modulate GLP-1R and GIPR activity, including partial agonists and antagonists, which reduce β-arrestin signaling and aversion, thereby enhancing glucose clearance without causing nausea, and have a longer half-life in the presence of DPP-IV.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If GLP-1 and GIP analogs are used to treat diabetes, then glycemic control is improved, but the half-life is short due to DPP-IV degradation
Solution Approach 1:
The patent modifies the chemical structure of GLP-1 and GIP analogs by introducing specific substitutions (e.g., N-methylated amino acids, cyclic structures, fatty acid conjugates) that change the molecular parameters to resist DPP-IV degradation while maintaining receptor binding affinity, thereby extending half-life without compromising glycemic control
Solution Approach 2:
The invention creates composite peptide structures combining multiple amino acid sequences with different functional properties - some regions maintain high affinity for GLP-1R/GIPR while other regions provide resistance to proteolytic degradation, resulting in a composite molecule with both prolonged stability and effective glycemic control
2Reliability
If GLP-1 and GIP analogs are used to treat diabetes, then glycemic control is improved, but side effects like nausea occur
Solution Approach 1:
The patent applies local quality modification by selectively modifying specific amino acid residues at key positions in the peptide sequence - making certain regions more rigid or hydrophobic to reduce off-target effects in the brain while maintaining metabolic activity at the receptor level, thereby reducing nausea without compromising glycemic control
3Power
If full agonists are used to activate GLP-1R and GIPR, then receptor activation is enhanced, but β-arrestin signaling increases causing aversion
Solution Approach 1:
The patent employs partial agonist activity where the analogs activate GLP-1R and GIPR to a controlled extent - sufficient to improve glycemic control but below the threshold that triggers excessive β-arrestin signaling and subsequent aversion responses, achieving a balanced therapeutic effect with reduced side effects
Data Source
AI summary
This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt and/or hydrate and/or prodrug of the compound) 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 subject (e.g., a human) having 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, the modulation results in an enhancement of (e.g., an increase in) 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)-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.