Ghrelin Receptor Antagonists via N-Terminal Tripeptide Modification
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Solution Overview
Problem
Current methods lack effective compounds to inhibit ghrelin receptor activity, which is crucial for managing obesity, diabetes mellitus, and growth hormone-related disorders, as existing antagonists are either ineffective or have significant side effects.
Innovation Solution
Development of ghrelin receptor antagonists by adding a GlyMetAla tripeptide at the N-terminus of GHRPs/ghrelin peptide agonists, converting them into effective ghrelin receptor antagonists that inhibit ghrelin-induced food intake and growth hormone secretion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing ghrelin receptor antagonists are used, then ghrelin receptor activity can be inhibited, but they are either ineffective or have significant side effects
Solution Approach 1:
The patent modifies the chemical structure of known ghrelin receptor antagonists by changing specific parameters such as amino acid substitutions, acyl chain modifications, and stereochemical configurations. These parameter changes optimize the balance between receptor binding affinity (effectiveness) and selectivity (reducing side effects), transforming ineffective or toxic compounds into therapeutic agents with improved safety profiles.
Solution Approach 2:
The invention creates composite peptide structures by combining different amino acid sequences, acylated groups, and structural motifs from various known antagonists. These composite structures integrate the beneficial properties of parent compounds while eliminating their harmful effects, resulting in new antagonists with enhanced efficacy and reduced side effects.
2Reliability
If ghrelin receptor activity is blocked to treat obesity and related disorders, then food intake and growth hormone secretion are reduced, but effective compounds with acceptable safety profiles are lacking
Solution Approach 1:
The patent develops intermediary compounds that act as bridge structures between known antagonists and the desired therapeutic profile. These intermediary molecules contain modular elements that can be systematically modified to achieve optimal binding affinity and selectivity, effectively mediating the transition from ineffective/toxic compounds to safe and effective therapeutics.
Solution Approach 2:
The invention introduces dynamic elements into the antagonist structures, such as flexible linkers, conformationally adaptable amino acid residues, and pH-responsive modifications. These dynamic features allow the compounds to adapt their conformation for optimal receptor binding while maintaining solubility and reducing off-target effects, thereby improving therapeutic effectiveness without increasing toxicity.
Data Source
AI summary
The present invention provides novel peptides that can modulate the ghrelin receptor (growth hormone secretagogue receptor, GHS-R1a and sub-types, isoforms and variants thereof). These peptides are useful as antagonists of the ghrelin receptor as well as inverse agonist, partial agonist or a combination of these activities as medicaments for treatment and prevention of a range of medical conditions including, but not limited to, metabolic and/or endocrine disorders, gastrointestinal disorders, cardiovascular disorders, obesity and obesity-associated disorders, diabetes, central nervous system disorders, genetic disorders, and hyperpro-liferative disorders.