Hydrophilic-Hydrophobic Polypeptides for Protein Aggregate Dissolution
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Solution Overview
Problem
Current therapeutics are ineffective in reversing the progressive degeneration of neurons caused by protein aggregation in neurodegenerative diseases such as ALS, Alzheimer's, and Parkinson's, as they primarily focus on inhibiting aggregation rather than dissolving existing aggregates.
Innovation Solution
Development of a polypeptide with a specific hydrophilic and hydrophobic segment structure that can dissolve protein aggregates, including FUS, TDP43, and alpha-synuclein, by administering it via vectors like AAV to target neurons, thereby reducing aggregate formation and promoting neuronal health.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-generated harmful factors
If current therapeutics inhibit protein aggregation, then aggregate formation is reduced, but existing aggregates cannot be dissolved and neuronal degeneration continues
Solution Approach 1:
Instead of only inhibiting aggregate formation (conventional approach), the patent applies inverse action by using chemical agents that actively dissolve existing aggregates. The patent describes compounds that promote aggregation in normal conditions but reverse this effect to dissolve pathogenic aggregates when administered, directly addressing the limitation of conventional inhibition-only therapies.
Solution Approach 2:
The patent modifies the chemical environment parameters (pH, ionic strength, temperature) to facilitate aggregate dissolution. It describes conditions under which aggregates become soluble through parameter changes, and uses compounds that induce these changes in the cellular environment to reverse aggregation and dissolve existing aggregates.
2Quantity of substance
If protein concentration exceeds thermodynamic solubility, then supersaturation occurs, but metastable liquid-like state is maintained by buffering interactions
Solution Approach 1:
The patent exploits the metastable state's vulnerability to disturbance by introducing agents that trigger phase transition from liquid-like to solid aggregate. It converts the potentially beneficial metastable storage state into a harmful aggregate state when pathogenic, and reverses this by using dissolution agents that restore solubility, effectively using the same supersaturation phenomenon for both aggregate formation and dissolution.
3Object-generated harmful factors
If disturbance of metastable form causes loss of protein solubility, then aggregation occurs, but no known method exists to reverse progressive neuronal degeneration
Solution Approach 1:
The patent introduces chemical compounds as intermediary agents that mediate between the aggregated protein state and the soluble state. These compounds act as mediators that facilitate the transition from aggregate to dissolved protein, and can be delivered to neurons through various administration routes to reverse aggregation and potentially prevent further degeneration.
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 polypeptide effectively dissolves protein aggregates in vitro and in vivo, improving neuronal function and alleviating motor dysfunction in animal models of neurodegenerative diseases, demonstrating therapeutic potential for conditions like ALS and Parkinson's.
Implementation Method 1
the polypeptide comprises a hydrophilic segment and a hydrophobic segment, said hydrophilic segment having a length of 10-20 amino acid residues among which at least 50% are Asp, Glu, Lys, or Arg, said hydrophobic segment having a length of 10-20 amino acid residues among which at least 50% are Tyr, Phe, Trp, Leu, Ile, Val, Met, Pro, Ala, or Cys
Data Source
AI summary
The present disclosure provides a polypeptide capable of dissolving protein aggregates. Also provided is a method of treating a neurodegeneration disease using the polypeptide.