Bifunctional Stapled Peptides for Targeted Protein Degradation
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Solution Overview
Problem
Peptides as therapeutic agents face limitations due to rapid degradation by proteases, poor cell permeability, and conformational flexibility, which affects their stability and specificity in biological recognition and function.
Innovation Solution
Development of bifunctional peptides with a targeting domain and an effector domain linked by a stabilizing linker, where one or both domains are stapled or stitched to maintain a stable conformation, allowing for specific recruitment of proteins or biomolecules to modulate cellular processes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If peptides are used as therapeutic agents, then biological activity and specificity are achieved, but rapid degradation by proteases occurs
Solution Approach 1:
The peptide is divided into multiple domains (targeting domain and effector domain) that can be independently designed and optimized. The targeting domain binds to specific proteins while the effector domain performs the therapeutic function, allowing each segment to be tailored for stability and activity.
Solution Approach 2:
Different regions of the peptide are given different properties - the targeting domain is optimized for specific binding interactions while the effector domain is designed for stable conformation and protease resistance. This local differentiation allows each region to fulfill its specific function optimally.
2Reliability
If peptides are used as therapeutic agents, then biological recognition is achieved, but conformational flexibility reduces binding specificity
Solution Approach 1:
The peptide conformation is stabilized by changing structural parameters - introducing staples or stitches that lock the peptide into a specific three-dimensional arrangement. This reduces conformational flexibility and ensures consistent binding geometry for high specificity.
Solution Approach 2:
The peptide combines multiple structural elements (alpha-helices, beta-sheets, turns, and loops) in a composite fold that is stabilized by cross-linking. This composite structure provides both the flexibility needed for biological recognition and the rigidity needed for specific binding.
3Stability of the object's composition
If alpha-helical peptides are used, then structural stability is achieved, but propensity for unraveling forms random coils
Solution Approach 1:
Staples or stitches are introduced into the peptide sequence in advance to prevent unraveling before it occurs. These cross-links are positioned to specifically counteract the tendency of alpha-helical structures to open into random coils, maintaining conformational integrity.
Solution Approach 2:
The peptide fold is designed with curved, compact structures where the staple or stitch cross-links connect distant parts of the sequence, creating a tightly packed three-dimensional arrangement that resists unfolding and maintains structural compactness.
4Stability of the object's composition
If covalent cross-links are introduced to stabilize peptides, then conformational stability is improved, but use of polar and labile cross-linking groups reduces stability
Solution Approach 1:
The patent employs simple, non-polar hydrocarbon cross-linkers (such as alkanes with 2-10 carbon atoms) that are chemically stable and resistant to degradation. These straightforward cross-linking groups replace complex polar cross-linking systems, providing durable stabilization without introducing labile functional groups.
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 bifunctional peptides effectively stabilize their conformation, enhancing their biological activity and specificity, enabling targeted protein-protein interactions and post-translational modifications, such as ubiquitination, to address diseases like cancer by promoting protein degradation or other cellular functions.
Implementation Method 1
Peptide stapling is a term coined for a synthetic methodology used to covalently join two olefin-containing side chains present in a polypeptide chain using an olefin metathesis reaction
Data Source
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AI summary
The invention relates to bifunctional stapled or stiched peptides comprising a targeting domain, a linker moiety, and an effector domain, that can be used to tether, or to bring into close proximity, at least two cellular entities (e.g., proteins). Certain aspects relate to bifunctional stapled or stiched peptides that bind to an effector biomolecule through the effector domain and bind to a target biomolecule through the targeting domain. Polypeptides and/or polypeptide complexes that are tethered by the bifunctional stapled or stiched peptides of the invention, where the effector polypeptide bound to the effector domain of the bifunctional stapled or stiched peptide modifies or alters the target polypeptide bound to the targeting domain of the bifunctional peptide. Usesses of the inventive bifunctional stapled or stiched peptides including methods for treatment of disease (e.g., cancer, inflammatory diseases) are also provided.