D-Enantiomeric Peptides for α-Synuclein Aggregate Disassembly
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Solution Overview
Problem
Current therapies for synucleinopathies such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy are unable to cure or halt the progression of these neurodegenerative diseases, as there are no substances that can effectively disassemble toxic α-synuclein aggregates into native functional monomers.
Innovation Solution
Development of D-enantiomeric peptides, identified through mirror-image phage display, that specifically bind to α-synuclein monomers, stabilizing them and shifting the balance towards natively folded conformations, thereby breaking down existing toxic oligomers and fibrils into monomeric constituents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional therapies are used for synucleinopathies, then symptoms can be treated, but the disease progression cannot be halted and toxic aggregates cannot be disassembled
Solution Approach 1:
The patent uses D-enantiomeric peptides that mimic the structure of alpha-synuclein to bind to and neutralize toxic aggregates. By converting the harmful aggregation-prone L-enantiomeric form into a beneficial D-enantiomeric therapeutic agent, the invention transforms the understanding of protein misfolding into a cure mechanism where the peptide acts as a decoy that sequesters toxic species and promotes their conversion to harmless monomers
Solution Approach 2:
The invention changes the stereochemical parameter of the peptide structure by using D-enantiomeric amino acids instead of the natural L-enantiomeric form. This parameter change allows the therapeutic peptide to have different binding properties and stability characteristics, enabling it to effectively bind to toxic aggregates while resisting degradation, thereby halting disease progression
2Stability of the object's composition
If alpha-synuclein aggregates are present in synucleinopathies, then disease pathology occurs, but no substance can disassemble these aggregates into functional monomers
Solution Approach 1:
The D-enantiomeric peptide acts as an intermediary substance that mediates the conversion of toxic aggregates to functional monomers. The peptide binds to oligomers and fibrils, serving as a molecular chaperone that facilitates their disassembly into monomers, which are then released to restore normal cellular function
Solution Approach 2:
Instead of trying to prevent aggregate formation or directly degrade toxic species, the invention inverts the approach by using D-enantiomeric peptides that bind to aggregates and promote their conversion to the native monomeric form. This inversion of the normal L-enantiomeric protein structure into D-enantiomeric therapeutics creates a reverse chiral environment that destabilizes toxic aggregates while stabilizing monomers
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 peptides effectively convert toxic α-synuclein aggregates into functional monomers, potentially providing a therapeutic approach to treat synucleinopathies by reducing the accumulation of toxic forms of α-synuclein.
Implementation Method 1
The chemical entity or variants thereof to be used in the therapy is intended to bind to the native, endogenous α-synuclein protein with as great an affinity and specificity as possible... The peptides specifically bind to α-synuclein monomers, stabilizing them
Implementation Method 2
As a result, the balance between misfolded and natively folded α-synuclein conformations is shifted in favor of the latter
Implementation Method 3
Thus, in an ideal case, α-synuclein oligomers and fibrils that are already present can be broken down into their monomeric constituents and thereby eliminated
Data Source
AI summary
The invention relates to a peptide, comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6 or SEQ ID NO: 7 and also to such a peptide for use in the treatment of synucleinopathies.