Bipartite Molecules for Targeted Protein Aggregate Disruption
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Solution Overview
Problem
Current therapies for neurodegenerative diseases such as Alzheimer's and Huntington's disease are ineffective due to a lack of understanding of the underlying processes, and existing treatments often have undesired side effects.
Innovation Solution
Development of bipartite molecules comprising a peptide affinity moiety that binds to abnormal protein aggregates and a charged moiety to prevent or reduce their formation, using peptides like polyR and PEI to target and disrupt toxic protein aggregates.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies are used for neurodegenerative diseases, then treatment is provided, but the therapies are ineffective due to lack of understanding of underlying processes and have undesired side effects
Solution Approach 1:
The therapeutic agent is divided into two distinct functional modules: an affinity moiety (peptide or protein domain) that specifically binds to abnormal protein aggregates, and a charged moiety (polybasic peptide or polyethyleneimine) that provides charge-based therapeutic action. This segmentation allows each module to perform its specialized function independently, improving overall therapeutic effectiveness while reducing off-target side effects.
Solution Approach 2:
The invention creates a composite therapeutic molecule by covalently linking an affinity moiety (such as a peptide sequence derived from the target protein or a protein domain like TDP-43 RRM) with a charged moiety (such as polybasic peptide sequences or PEI). This composite structure combines the specific binding capability of the affinity moiety with the therapeutic charge-based mechanism, achieving both targeted effectiveness and reduced harmful side effects.
2Reliability
If bipartite molecules are used to target abnormal protein aggregates, then aggregation is decreased and neurologic dysfunctions are ameliorated, but the molecular structure becomes more complex
Solution Approach 1:
The complex therapeutic function is segmented into two manageable modules: an affinity moiety that provides specific target recognition and a charged moiety that provides the therapeutic mechanism. This segmentation makes the design and optimization of complex bipartite molecules more systematic and controllable.
Solution Approach 2:
The charged moiety serves multiple functions: it provides the therapeutic charge-based mechanism, enhances solubility of the bipartite molecule, and can facilitate cellular uptake. This multi-functionality reduces the need for additional separate components, managing overall molecular complexity while maintaining therapeutic effectiveness.
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 bipartite molecules effectively decrease abnormal protein aggregation, ameliorate neurologic dysfunctions, and extend lifespan in murine models, providing a promising therapeutic approach for neurodegenerative diseases.
Implementation Method 1
The bipartite molecules described herein all contain an affinity moiety (e.g., the polyQ portion, the Aβ40 (25-35) portion, and the V24P (10-40) portion) capable of binding to an abnormal protein aggregate or a component thereof and a charged moiety (e.g., the polyR portion or the PEI portion)
Implementation Method 2
the affinity moiety is linked (e.g., covalently) to the at least one charged moiety... capable of binding to an abnormal protein aggregate or a component thereof
Data Source
AI summary
Bipartite molecules comprising a peptide affinity moiety and at least one charged moiety and uses thereof in reducing formation of abnormal protein aggregate and treating diseases associated with such abnormal protein aggregate, including neurodegenerative disease characterized by formation of protein aggregates.