Bile Acid GPR39 Agonists Beyond Zinc Binding Sites
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Solution Overview
Problem
The ligand for GPR39, a G protein-coupled receptor, remains unknown, limiting the development of targeted therapeutic interventions for diseases associated with its activity.
Innovation Solution
Bile acids and their derivatives are used to activate GPR39 receptors, either independently of known zinc ion binding sites or through allosteric modulation with zinc ions, providing a basis for developing GPR39 agonists and drugs to treat related disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If zinc ions are used to activate GPR39 receptors, then receptor activation is achieved, but the mechanism is limited to known binding sites (H17 and H19)
Solution Approach 1:
The patent introduces bile acids as intermediary molecules that mediate GPR39 receptor activation through a novel mechanism independent of the traditional zinc ion binding sites. This intermediary approach bypasses the limitations of existing activation pathways while achieving the desired receptor activation effect
Solution Approach 2:
The invention changes the activation parameter from zinc ion-dependent binding at specific histidine residues to bile acid-mediated activation through alternative molecular interactions. This parameter change expands the versatility of receptor activation mechanisms beyond the constrained zinc ion pathway
2Reliability
If the ligand for GPR39 remains unknown, then research progress is limited, but developing targeted therapies becomes impossible
Solution Approach 1:
The patent employs a self-service approach where bile acids, which are naturally present in the body, spontaneously activate GPR39 receptors without requiring identification of a specific exogenous ligand. This allows therapeutic development to proceed using endogenous molecules that naturally interact with the receptor
Solution Approach 2:
The invention utilizes readily available bile acids as effective agonists, replacing the need for complex, expensive, or unidentified ligand molecules. This approach enables practical therapeutic development using simple, well-characterized endogenous compounds
3Adaptability or versatility
If bile acids activate GPR39 independent of zinc ion binding sites, then new activation pathways are discovered, but the mechanism diverges from established zinc ion activation
Solution Approach 1:
The patent segments the receptor activation process into distinct pathways: one mediated by zinc ions at traditional binding sites and another independently activated by bile acids. This segmentation allows both mechanisms to coexist without interfering with each other, maintaining stability in the overall system while adding versatility
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
Bile acids and derivatives effectively activate GPR39 receptors, inducing intracellular calcium signals and offering potential therapeutic benefits for gastrointestinal disorders and other conditions associated with GPR39 activity.
Implementation Method 1
GPR39 is a kind of G protein-coupled receptor belonging to the ghrelin/neurotensin subfamily of the rhodopsin family (class A)... Research has shown that zinc ions can activate GCP39 receptors by binding to histidines at positions 17 and 19 (H17&H19) in the N terminus of the extracellular domain
Implementation Method 2
Research has shown that zinc ions can activate GCP39 receptors by binding to histidines at positions 17 and 19 (H17&H19) in the N terminus of the extracellular domain
Data Source
AI summary
A use of the bile acids represented by Formula (1) and derivatives thereof in the preparation of a GPR39 agonist, as well as a drug composite which contains such bile acids and the derivatives thereof as the active ingredient, the drug composite being used to prevent, treat and/or relieve diseases associated with GPR39 activity.