SURTAC Molecules Protect Proteins from Ubiquitin-Proteasome Degradation
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Solution Overview
Problem
Current technologies lack effective methods to specifically protect proteins from ubiquitin-proteasome system (UPS)-related degradation, which is a critical issue in various human diseases such as cancer and Cystic Fibrosis, where unwanted protein degradation contributes to disease pathology.
Innovation Solution
Development of survival-targeting chimeric (SURTAC) molecules comprising a first binding domain that binds to ubiquitinylated proteins, a second binding domain that binds to ubiquitin proteases, and a linker domain that links the two, allowing for the recruitment of deubiquitinating enzymes to remove ubiquitin molecules from target proteins, thereby reducing their degradation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the UPS system actively degrades proteins, then protein turnover and quality control are maintained, but desired proteins are degraded when their levels need to be maintained or increased
Solution Approach 1:
The patent employs deubiquitinating enzymes (DUBs) as intermediary molecules that specifically remove ubiquitin tags from target proteins, preventing their degradation by the proteasome. This intermediary mechanism allows selective protection of desired proteins while maintaining the overall UPS function for quality control and turnover of unwanted proteins.
Solution Approach 2:
The invention applies local quality control by using DUBs with specific substrate recognition capabilities. Each DUB targets particular ubiquitinylated proteins based on their unique recognition motifs, allowing selective deubiquitination and protection of specific proteins while leaving other ubiquitinylated proteins unaffected, thus maintaining local precision in protein level regulation.
2Quantity of substance
If ubiquitin proteases remove ubiquitin molecules from target proteins, then protein degradation is reduced, but specificity in protecting only desired proteins is lost
Solution Approach 1:
The patent utilizes the inherent substrate specificity of different deubiquitinating enzymes, which recognize specific motifs or structural features on their target proteins. This ensures that only desired ubiquitinylated proteins are deubiquitinated and protected, while other proteins remain subject to normal degradation pathways, maintaining high target specificity.
Solution Approach 2:
The invention employs a feedback mechanism where DUBs continuously monitor and regulate the ubiquitination status of target proteins. When a protein is ubiquitinylated, the specific DUB recognizes it and removes the ubiquitin tag, preventing degradation. This feedback loop ensures precise control over protein levels while maintaining specificity for the intended targets.
3Ease of operation
If small molecules are used to inhibit UPS, then ease of administration is improved, but lack of protein-specific protection results in off-target effects
Solution Approach 1:
The patent uses deubiquitinating enzymes as intermediary agents that provide protein-specific protection. Unlike small molecules that non-specifically inhibit the entire UPS, DUBs act as selective intermediaries that recognize and protect only specific ubiquitinylated proteins, thereby avoiding off-target effects while maintaining ease of administration as pharmacological agents.
Solution Approach 2:
The invention changes the key parameter of specificity by transitioning from small molecule inhibitors that affect the entire UPS to DUB-based approaches that selectively modify individual protein targets. This parameter change from non-specific to specific inhibition eliminates off-target degradation while maintaining the therapeutic benefit of UPS modulation.
Data Source
AI summary
Survival-targeting chimeric (SURTAC) molecules are provided herein, as well as methods for their use in removing ubiquitin molecules from ubiquitinylated proteins. In one embodiment, the SURTAC molecule comprises a first binding domain, a second binding domain, and a linker domain, wherein the first binding domain is configured to bind to an ubiquitinylated protein; the second binding domain is configured to bind to an ubiquitin protease that cleaves one or more ubiquitin from the ubiquitinylated protein bound to the first binding domain, and the linker domain is configured to link the first binding domain to the second binding domain.