Cyclic Peptide Inhibitors of Alpha-Synuclein Fibrillation
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Solution Overview
Problem
Current treatments for neurodegenerative diseases such as Parkinson's, Alzheimer's, and Huntington's are non-curable and fail to effectively inhibit the formation of β-sheet rich amyloid fibrils, which are toxic to neurons, as existing inhibitors have not been successful in preventing protein aggregation.
Innovation Solution
A novel peptide with the formula [XiSACX1]mHHHH[X2X3CGG]m is identified using phage display technology to inhibit the fibrillation of intrinsically disordered proteins like α-synuclein, which is then used to develop a pharmaceutical composition to treat amyloid-based disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing inhibitors are used to treat neurodegenerative diseases, then treatment is provided, but they fail to effectively inhibit the formation of β-sheet rich amyloid fibrils
Solution Approach 1:
The patent employs phage display technology to screen and identify peptide sequences with optimized amino acid compositions and structural parameters that specifically target and inhibit amyloid fibril formation. The identified peptides have distinct sequence characteristics and structural properties that enable effective interference with protein aggregation pathways.
Solution Approach 2:
The invention develops pharmaceutical compositions that combine the identified peptide inhibitors with other therapeutic agents or formulation components. These composite formulations enhance the stability, bioavailability, and therapeutic efficacy of the peptide inhibitors while maintaining their ability to prevent protein aggregation.
2Reliability
If pept 2 is used to inhibit α-synuclein aggregation, then fibrillation is reduced, but the peptide structure requires specific cyclic configuration with disulfide bonds
Solution Approach 1:
The peptide inhibitor is designed as a cyclic structure containing a disulfide bond that segments the peptide chain into specific spatial configurations. This segmentation constrains the peptide into a rigid cyclic form that effectively binds to and inhibits α-synuclein aggregation, with the disulfide bond serving as a structural anchor.
Solution Approach 2:
The patent identifies and characterizes specific structural parameters of the peptide including cyclic configuration, disulfide bond formation, and amino acid sequence composition. These parameter optimizations are critical for achieving high-affinity binding to α-synuclein and effective inhibition of fibril formation.
Data Source
AI summary
The present disclosure provides a novel peptide as potent inhibitor of protein aggregation. A peptide for an inhibition of protein aggregation having the general Formula 1, [XiSACX1]mHHHH[X2X3CGG]m (SEQ ID NO. 9) is provided. The m is 0 or 1; Xi is an acetyl group; X1 is a hydrophilic polar uncharged amide group containing amino acid; X2 is His or Leu; and X3 is His or Ser. The present disclosure specifically relates to peptide-based inhibitors useful in treatment of amyloid related disorders.