Fluoropeptide Analogs for GPCR Signaling Stability
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Solution Overview
Problem
Naturally occurring peptides used for targeting G-protein coupled receptors (GPCRs) face challenges due to poor chemical and physical stability and short circulating half-life, limiting their therapeutic potential for CNS and cardiovascular diseases.
Innovation Solution
Development of fluorocarbon conjugates that create metabolically stable, non-immunogenic, and completely hydrosoluble peptide analogs by covalently linking a fluorocarbon group to peptides like apelin, angiotensin, or oxytocin, either directly or through a linker, enhancing their stability and solubility without increasing immunogenicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If naturally occurring peptides are used to target GPCRs, then they provide selective and efficacious signaling, but they exhibit poor chemical and physical stability and short circulating half-life
Solution Approach 1:
The patent creates composite structures by conjugating fluorocarbon groups to peptide backbones, forming hybrid molecules that combine the biological activity of peptides with the metabolic stability of fluorocarbons. This composite approach allows the fluoropeptides to maintain GPCR binding affinity while resisting enzymatic degradation, thus resolving the contradiction between signaling efficacy and chemical stability
Solution Approach 2:
The invention modifies the chemical parameters of the peptide by replacing certain amino acid residues with fluorocarbon-containing analogs. This parameter change in the molecular structure increases the peptide's resistance to proteolytic enzymes and improves overall chemical stability without significantly altering the biological activity, thereby maintaining reliability while improving stability
2Reliability
If naturally occurring peptides are used to target GPCRs, then they provide selective and efficacious signaling, but they exhibit short circulating plasma half-life
Solution Approach 1:
By creating composite molecules that integrate fluorocarbon moieties with the peptide structure, the invention produces hybrid compounds with extended plasma half-life. The fluorocarbon components confer metabolic stability and resistance to enzymatic breakdown, allowing the conjugates to circulate longer in the bloodstream while maintaining their ability to bind GPCRs and elicit therapeutic effects
Solution Approach 2:
The patent alters the physicochemical parameters of the peptide by incorporating fluorocarbon groups, which change the molecule's interaction with plasma proteins and enzymes. These parameter changes result in reduced clearance rates and extended circulating half-life, enabling the fluoropeptides to maintain therapeutic concentrations for longer periods while preserving their signaling efficacy
3Duration of action of moving object
If PEG is incorporated into peptides to increase plasma half-life, then glomerular filtration is limited and plasma half-life increases, but safety and tolerability concerns arise
Solution Approach 1:
The invention substitutes PEGylation with fluorocarbon conjugation, changing the chemical parameter of the modification group. Fluorocarbon groups provide similar pharmacokinetic benefits by reducing glomerular filtration and extending plasma half-life, but without the immunogenicity and safety concerns associated with PEG. This parameter substitution resolves the contradiction between achieving extended half-life and maintaining safety/tolerability
Solution Approach 2:
The patent replaces the problematic PEG component with fluorocarbon groups that achieve the same functional goal (extending plasma half-life) without the harmful side effects. This substitution eliminates the need to deal with PEG-related immunogenicity and tolerability issues while maintaining the desired pharmacokinetic profile
4Duration of action of moving object
If peptide is acylated with hydrocarbon tail to bind to circulating protein albumin, then plasma half-life increases, but selectivity for target decreases and toxicity increases
Solution Approach 1:
The patent changes the chemical parameter of the modifying group from hydrocarbon tail to fluorocarbon group. This substitution maintains the ability to extend plasma half-life through reduced filtration and albumin binding, but the fluorocarbon's unique properties (higher polarity, different hydrophobicity) preserve peptide selectivity for the target GPCR and reduce off-target toxicity effects
Data Source
AI summary
The present invention relates to metabolically stable and non- immunogen analogs completely hydrosolubleat physiological pH, and their use for the prevention or treatment of diseases mediated by G-protein coupled receptor (GPCR), in particular (Central Nervous System) CNS and cardiovascular diseases or disorders, or their use in diagnostic methods.