USP7 Ligand Bifunctional Compounds for Protein Stabilization
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Solution Overview
Problem
Current treatments for diseases involving protein degradation, such as cystic fibrosis, struggle to effectively stabilize and restore the function of ubiquitinated proteins, leading to inadequate ion transport and other cellular issues due to proteasomal degradation signals.
Innovation Solution
Development of bifunctional molecules comprising a USP7 Targeting Ligand, a Ubiquitinated Protein Targeting Ligand, and optionally a Linker, which deubiquitinate target proteins to prevent proteasomal degradation and restore their function, thereby stabilizing and enhancing protein activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for diseases involving protein degradation, then the treatment approach is simple, but the ability to stabilize and restore function of ubiquitinated proteins is insufficient
Solution Approach 1:
The patent combines a deubiquitinating enzyme (DUB) with a targeting ligand that specifically binds to the ubiquitinated protein of interest, creating a heterobifunctional molecule. This merging allows the molecule to both locate the target protein through the ligand and perform the stabilizing deubiquitination function through the DUB, thereby resolving the contradiction between treatment effectiveness and molecular complexity.
Solution Approach 2:
The targeting ligand acts as an intermediary that bridges the DUB and the ubiquitinated protein. The ligand specifically recognizes and binds to the target protein, bringing the DUB into proximity to remove ubiquitin chains, thus mediating the stabilization process without requiring the DUB to directly locate the target.
2Reliability
If the body ubiquitinates mutant proteins to signal degradation, then protein quality control is maintained, but the function of needed proteins is lost
Solution Approach 1:
The patent exploits the ubiquitin chains that normally signal degradation and convert them into a targeting mechanism. The ubiquitinated protein, which would normally be degraded, now serves as a beacon that recruits the heterobifunctional molecule through the targeting ligand, enabling selective deubiquitination and functional restoration rather than degradation.
Solution Approach 2:
Instead of allowing the ubiquitin signal to lead to degradation as in the normal pathway, the invention inverts the outcome by using the ubiquitin signal to recruit a DUB that removes the ubiquitin chains, thereby preventing degradation and restoring protein function.
3Reliability
If deubiquitinase proteins remove ubiquitin from proteins, then protein degradation is prevented, but selectivity for specific target proteins is reduced
Solution Approach 1:
The heterobifunctional molecule is segmented into two distinct functional modules: a DUB domain responsible for deubiquitination activity and a targeting ligand domain responsible for specific recognition of the ubiquitinated protein. This segmentation allows each module to perform its specialized function independently, with the ligand ensuring target specificity and the DUB providing the enzymatic activity.
Solution Approach 2:
The targeting ligand is designed to recognize a common feature of ubiquitinated proteins or specific mutation patterns, allowing a single ligand structure to target multiple related proteins or mutant variants, thereby providing broad specificity without requiring entirely different molecules for each target.
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 molecules effectively stabilize and restore the function of target ubiquitinated proteins, potentially increasing their activity by up to 100% and treating disorders caused by protein deficiencies or mutations, including difficult-to-treat cancers by preventing degradation and activating immune responses.
Implementation Method 1
The protein stabilizing compounds described herein stabilize a Target Protein by deubiquitinating the Target Protein
Implementation Method 2
USP7 is a 128 kDa cysteine protease that can cleave at least 5 of the major polyubiquitin bonds
Data Source
AI summary
This invention provides protein stabilizing compounds, compositions, and methods of use thereof, that include a USP7 Targeting Ligand, a Protein Targeting Ligand, and optionally a Linker for the restoration of a Target Ubiquitinated Protein to treat a disorder mediated by deficiencies of the Target Protein.