Ubr E3 Ligase Peptidomimetic Platform for Protein Degradation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current E3 ligase ligands, such as Proteolysis Targeting Chimeras (PROTACS), are limited in their ability to target a diversity of substrate proteins for ubiquitination and proteasome-mediated degradation due to compartmentalization issues, buried lysine residues, and limited available E3 ligase ligands, leading to unpredictable effects and off-target issues.
Innovation Solution
Development of single protein E3 ligases, specifically members of the Ubr family, which can target a variety of substrate proteins through bi-functional peptidomimetic compounds that engage the Ubr-box domain, enhancing affinity, specificity, and stability compared to natural amino acid residues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If PROTAC ligands are used to target substrate proteins, then protein degradation can be achieved, but the ability to target diverse substrate proteins is limited due to compartmentalization issues and buried lysine residues
Solution Approach 1:
The patent uses peptidomimetic compounds as intermediary molecules that bridge the target substrate protein and the Ubr E3 ligase. These compounds contain a ligand portion that binds to the substrate protein and a peptidomimetic portion that mimics natural amino acid sequences to engage the Ubr E3 ligase, enabling reliable ubiquitination and degradation of diverse substrates without being limited by compartmentalization or buried lysine residues
Solution Approach 2:
The patent changes the chemical and structural parameters of the E3 ligase engagement moiety by using peptidomimetic compounds with specific amino acid sequences (e.g., containing proline, arginine, lysine, histidine, or a combination thereof) that can adapt to different substrate proteins. This allows the system to overcome structural constraints like buried lysine residues and achieve reliable degradation across diverse substrate types
2Reliability
If multiple E3 ligase components are used in a complex, then substrate ubiquitination can occur, but the complexity of the system increases and off-target effects occur
Solution Approach 1:
The patent extracts and isolates the Ubr family E3 ligase as a single-component system, separating it from the complex multi-protein E3 ligase assemblies used in conventional PROTAC approaches. This extraction simplifies the system while maintaining specificity, as the Ubr E3 ligase alone (without requiring additional cullin-RING or other E3 components) can mediate ubiquitination of the target substrate through the peptidomimetic compound
Solution Approach 2:
The Ubr family E3 ligase serves as a universal platform that can target multiple different substrate proteins through the peptidomimetic compound, which can be designed with different ligand portions to engage various substrates. This multi-functionality allows a single E3 ligase system to handle diverse degradation targets without requiring separate E3 ligase complexes for each substrate, thereby reducing system complexity while maintaining specificity
3Measurement precision
If natural amino acid residues are used to engage E3 ligase, then the system is simple, but affinity and specificity are insufficient
Solution Approach 1:
The patent changes the parameters of the E3 ligase engagement moiety by replacing natural amino acid residues with peptidomimetic compounds that have optimized chemical structures. These compounds contain specific amino acid sequences (proline, arginine, lysine, histidine, or combinations) arranged in configurations that enhance binding affinity and specificity to the Ubr E3 ligase, while the overall compound structure remains manageable in complexity
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 use of Ubr family E3 ligases with peptidomimetic compounds achieves predictable and efficient ubiquitination and degradation of target substrate proteins, offering therapeutic potential for diseases like cancer and neurodegenerative disorders.
Implementation Method 1
bi-functional peptidomimetic compounds that engage a target substrate protein and one or more members of the Ubr family of E3 ligases
Implementation Method 2
The E3 ligases are useful for targeting proteins for ubiquitination and subsequent proteolysis through proteasome-mediated degradation
Implementation Method 3
subsequent proteolysis through proteasome-mediated degradation
Data Source
AI summary
The disclosure is directed to peptidomimetic compounds, or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising such peptidomimetic compounds, and methods for degrading target substrate proteins using such compounds.