Constrained Peptide Salts Stabilize Alpha-Helical Structure
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Solution Overview
Problem
Polypeptides are difficult to formulate and are susceptible to degradation, leading to undesired side effects and reduced efficacy due to their susceptibility to proteolytic degradation and inability to maintain secondary or tertiary structure when used as therapeutic agents.
Innovation Solution
Constrained salts of peptides are developed, utilizing self-associating anionic or cationic salts of amphipathic peptides to stabilize the alpha-helical secondary structure, thereby enhancing biological activity and stability, allowing for long-term storage and delivery without the need for refrigeration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional peptide formulations are used, then peptides can be administered therapeutically, but they are susceptible to proteolytic degradation and cannot maintain secondary or tertiary structure
Solution Approach 1:
The patent modifies the peptide structure by introducing cyclic constraints through disulfide bonds or non-natural amino acids with rigidifying groups. This changes the conformational parameters of the peptide backbone, restricting it to specific secondary structures (alpha-helices or beta-sheets) and preventing degradation while maintaining therapeutic activity
Solution Approach 2:
The patent creates composite structures by combining constrained peptides with stabilizing excipients such as sugars, amino acids, or polymers in specific formulations. These composite systems provide both structural support and protection against proteolytic degradation, enabling stable storage and delivery
2Adaptability or versatility
If short peptides are used as therapeutic agents, then they can target specific biological functions, but they form unstructured random coils and have decreased efficacy
Solution Approach 1:
The patent applies conformational constraints through cyclic structures that fix the peptide backbone in specific geometries. This transforms the random coil parameters into defined secondary structures, enabling short peptides to maintain their targeting capability while achieving the structural persistence needed for therapeutic efficacy
Solution Approach 2:
The patent pre-organizes the peptide into its bioactive conformation during synthesis by incorporating constrained residues or disulfide bridges. This preliminary structural arrangement ensures that the peptide adopts the correct shape upon binding to its target, eliminating the need for post-binding folding and improving efficacy
3Reliability
If additives are used to preserve or stabilize peptide formulations, then peptide stability is improved, but undesired side effects occur
Solution Approach 1:
The patent removes the need for conventional stabilizing additives by incorporating stability directly into the peptide structure through conformational constraints. The constrained peptide maintains its structure and resists degradation intrinsically, eliminating or minimizing the need for external stabilizers that could cause side effects
Solution Approach 2:
The patent designs peptides that are self-stabilizing through their constrained structures. The disulfide bonds, cyclic frameworks, or rigidifying residues enable the peptide to maintain its conformation and resist proteolysis without requiring external protective agents, reducing the formulation complexity and potential harmful interactions
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
The constrained peptide compositions maintain therapeutic efficacy and stability at room temperature with reduced use of stabilizers, providing prolonged activity and reduced side effects by integrating into lipid layers, thus enhancing chemical and biological stability.
Implementation Method 1
utilize a self-associating anionic or cationic salt of an amphipathic peptide to provide a lipophilic micelle, lipid bilayer or other lipid surface
Implementation Method 2
self-associating anionic or cationic salt of an amphipathic peptide to provide a lipophilic micelle, lipid bilayer or other lipid surface
Implementation Method 3
provide a lipophilic micelle, lipid bilayer or other lipid surface to the lipophilic face of the amphipathic peptide capable of stabilizing the alpha-helical secondary structure
Data Source
AI summary
This application generally relates to constrained salts of peptides, constrained forms of peptides, and compositions, kits, methods of using, or uses of the same.