Stapled Peptide-Degron Chimeras for Intracellular Protein Degradation
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Solution Overview
Problem
Current methods for targeting and degrading disease-causing proteins are limited by their inability to access intracellular proteins previously inaccessible to small molecules, and they lack the potency to effectively induce protein degradation.
Innovation Solution
Development of stabilized peptide-degron chimeras that combine a protein-targeting stapled peptide with a small molecule or peptide degron moiety, allowing for the recruitment of degrader proteins to degrade specific disease-related proteins, thereby expanding the reach and potency of protein degradation technologies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If small molecules are used to target proteins, then the ability to access intracellular proteins is limited, but the simplicity of the approach is maintained
Solution Approach 1:
The patent combines a stapled peptide targeting moiety with a degron moiety into a single chimera molecule. The stapled peptide portion provides access to intracellular proteins by mimicking natural peptide substrates, while the degron portion recruits E3 ubiquitin ligases for degradation. This merging allows the molecule to overcome the limitations of small molecules in accessing intracellular targets while maintaining a unified structure rather than requiring separate delivery systems.
Solution Approach 2:
The chimera represents a composite molecular structure combining two distinct functional elements: the stapled peptide (typically 10-30 amino acids with stabilized alpha-helical structure) and the degron sequence (short peptide motif recognized by E3 ligases). This composite approach allows each component to contribute its specialized function, with the stapled peptide providing target recognition and cellular penetration capabilities that small molecules lack, while the degron provides the degradation signaling function.
2Reliability
If traditional degradation methods are used, then the potency to induce protein degradation is insufficient, but the simplicity of the method is maintained
Solution Approach 1:
The chimera merges the target-specific stapled peptide with the degradation-inducing degron into a single molecular entity. This combination ensures that upon binding to the target protein, the chimera directly recruits E3 ubiquitin ligases through the degron, forming a complete degradation-inducing complex without requiring separate delivery of degradation components. This merging significantly enhances degradation potency compared to traditional methods that rely on endogenous degrons alone.
Solution Approach 2:
The stapled peptide acts as an intermediary that bridges the target protein and the degron-E3 ligase complex. By stabilizing the peptide structure through stapling (typically using non-natural amino acids to form covalent crosslinks), the chimera maintains the conformation necessary for high-affinity target binding while presenting the degron in an orientation that facilitates E3 ligase recruitment. This intermediary role of the stapled peptide enhances the reliability of the degradation process.
3Adaptability or versatility
If stapled peptides are used to target proteins, then the ability to target large protein interaction surfaces is improved, but the ability to induce degradation is reduced
Solution Approach 1:
The chimera merges the target-binding stapled peptide with a degradation-inducing degron sequence. The stapled peptide portion (typically 15-30 amino acids) is designed to mimic natural peptide substrates and bind to large protein interaction surfaces with high affinity, while the attached degron (5-15 amino acids) provides the degradation signal. This merging ensures that when the stapled peptide binds to its target, the degron is positioned to recruit E3 ubiquitin ligases, thereby inducing degradation. This resolves the contradiction by adding degradation functionality to the target-binding capability of stapled peptides.
Data Source
AI summary
The present application describes stapled peptide degron chimeras, which act as protein degradation inducing moieties, either by combining a stapled peptide that binds a disease-related protein with a small molecule degron, such as a cereblon- or VHL-binding small molecule as the degron, or a polypeptide sequence degron, such as a Cop1-binding Trib peptide as the degron; or by combining a stapled peptide degron with a peptide, such as a stapled peptide, or a small molecule that binds a disease-related protein. The present application also relates to methods for the targeted degradation of endogenous proteins through the use of stapled peptide degron chimeras which can be utilized in the treatment of proliferative disorders or other conditions whereby elimination of a disease-causing or disease-related protein would have a therapeutic benefit. The present application also provides methods for making compounds of the application and intermediates thereof.