Triple-Stranded Coiled Coil Scaffold for Stable Peptide Binding
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Solution Overview
Problem
Current protein-based scaffolds for molecular recognition, such as immunoglobulins, face challenges including labor-intensive production, immunogenicity, and limited ability to bind peptide ligands, necessitating the development of alternative, stable, and specific proteinaceous molecules for therapeutic, diagnostic, and purification applications.
Innovation Solution
A non-natural, thermodynamically stable proteinaceous scaffold composed of three non-covalently associated peptides with specific amino acid sequences forming triple-stranded, parallel alpha-helical coiled coils, which are tolerant to amino acid substitutions and exhibit high binding affinity to target molecules, offering a distinct composition and structure compared to immunoglobulins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immunoglobulins are used as protein-based scaffolds for molecular recognition, then they provide good binding capability, but they suffer from labor-intensive production and immunogenicity issues
Solution Approach 1:
The invention changes the fundamental parameters of the scaffold system by transitioning from immunoglobulin-based scaffolds to triple-stranded coiled coil scaffolds with a different structural architecture. This parameter change enables simplified production through chemical synthesis of short peptides (less than 50 amino acid residues per chain) while maintaining binding capability through the stable triple-helical structure that can be engineered for specific molecular recognition
Solution Approach 2:
The invention employs short peptide chains (less than 50 amino acid residues) that can be chemically synthesized rather than requiring complex biological production systems. These short peptides form stable triple-stranded coiled coils that provide durable binding functionality without the production complexities and immunogenicity issues of full-length immunoglobulins
2Reliability
If immunoglobulins are used as protein-based scaffolds, then they provide molecular recognition function, but they exhibit immunogenicity that limits therapeutic application
Solution Approach 1:
The invention uses short peptide chains (less than 50 amino acid residues) to construct the scaffold, which are inherently less immunogenic than full-length immunoglobulins. These short peptides can be chemically synthesized with precise control over sequence and structure, enabling molecular recognition function while minimizing immune system recognition and response
Solution Approach 2:
The invention localizes the molecular recognition function to specific regions of the triple-stranded coiled coil structure, particularly at the N-terminal and C-terminal ends where peptide ligands can bind. This local quality approach allows the scaffold to provide targeted recognition without requiring the complex immunoglobulin structure, thereby reducing immunogenicity while preserving functional capability
3Stability of the object's composition
If traditional protein-based scaffolds are used, then they provide structural stability, but they have limited ability to bind peptide ligands
Solution Approach 1:
The invention creates distinct functional regions within the triple-stranded coiled coil structure: the central hydrophobic core provides structural stability through tight packing of non-polar residues, while the N-terminal and C-terminal regions are engineered with specific properties to bind peptide ligands. This local quality differentiation enables simultaneous optimization of stability and peptide binding capability
Solution Approach 2:
The invention segments the scaffold function into distinct regions: the triple-helical coiled coil domain provides structural stability, while separate N-terminal and C-terminal domains are designed for peptide ligand binding. This segmentation allows each region to be optimized independently for its specific function, achieving both stability and 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
The triple-stranded coiled coil scaffold provides enhanced stability, specificity, and binding capabilities, enabling effective molecular recognition and interaction with target molecules, potentially overcoming the limitations of existing protein-based scaffolds in therapeutic, diagnostic, and purification contexts.
Implementation Method 1
the said peptide sequences associate into trimers by way of their heptad repeats forming triple-stranded, parallel, alpha-helical coiled coils wherein the said c-residues form the core
Implementation Method 2
triple-stranded, parallel, alpha-helical coiled coils
Data Source
AI summary
The present invention is related to a non-natural, thermodynamically stable, proteinaceous scaffold consisting of three non-covalently associated peptides, wherein each peptide sequence comprises less than fifty amino acid residues and wherein at least 50% of the said residues are substitutable amino acids into at least ten different amino acid residue types. The present invention is further related to a non-natural, triple-stranded, parallel alpha-helical coiled coil scaffold wherein each of the three constituting peptide sequences comprise between 2 and 7 consecutive heptad repeats of the formula cxxcxxx (SEQ ID NO: 10), wherein at least 70% of the core c-residues are isoleucines, wherein all non-core x-residues are alanines, and wherein the constituting peptide sequences remain associated under physical conditions that are significantly different from physiological conditions.