Protein Sequence Design to Prevent Aggregation in RNA-Binding Proteins
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Solution Overview
Problem
Current methods lack an effective way to prevent protein aggregation in RNA-binding proteins associated with neurodegenerative conditions like ALS and FTD, as these proteins are essential and cannot be completely knocked out, and existing approaches struggle to design small molecules that bind and block aggregation-prone regions effectively.
Innovation Solution
Modifying the protein sequences of RNA-binding proteins by adding or replacing amino acids with prolines in aggregation-prone regions to make them aggregation-resistant, and expressing these modified versions in humans using gene therapy or other means to prevent the onset or worsening of neurodegenerative conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If essential RNA-binding proteins are completely knocked out to prevent aggregation, then protein aggregation is prevented, but cellular toxicity occurs and the proteins cannot be eliminated
Solution Approach 1:
The patent applies local quality by making only specific modifications to aggregation-prone regions of the protein sequence while leaving the rest of the protein unchanged. This allows the protein to retain its essential functions in non-aggregation regions while preventing aggregation only in the modified regions, thus avoiding cellular toxicity.
Solution Approach 2:
The patent changes the amino acid sequence parameters in aggregation-prone regions by introducing proline residues or other modifications that alter the physical-chemical properties of these regions, preventing β-sheet formation and aggregation while maintaining the protein's overall structure and function.
2Reliability
If small molecules are designed to bind aggregation-prone regions to block aggregation, then aggregation blocking is attempted, but the unstructured nature of these regions makes effective binding design unlikely
Solution Approach 1:
Instead of attempting to bind to the aggregation-prone regions with small molecules, the patent inverts the approach by directly modifying the protein sequence itself to prevent aggregation. This eliminates the need for small molecule design and binding to unstructured regions.
Solution Approach 2:
The patent extracts the aggregation-prone regions from the protein sequence and applies specific modifications (such as proline insertion) to these extracted regions, separating the aggregation prevention function from the rest of the protein while maintaining overall protein function.
3Reliability
If proline residues are added or replaced in aggregation-prone regions to prevent β-sheet formation, then aggregation is prevented, but the protein sequence is altered
Solution Approach 1:
The patent applies local quality by making modifications only in aggregation-prone regions while leaving the rest of the protein sequence intact, thus preventing aggregation while minimizing changes to the overall protein composition and maintaining sequence integrity in functional regions.
Solution Approach 2:
The patent changes specific parameters of the amino acid sequence (introducing proline residues) in aggregation-prone regions to alter the physical properties and prevent β-sheet formation, while carefully selecting modification sites to maintain overall protein stability and function.
Data Source
AI summary
Provided herein are compositions and methods useful in treating diseases such as ALS and FTD. Disclosed compositions and methods can prevent protein aggregation, particularly with regard to RNA-binding proteins.