Peptide Segmentation for Huntington's Disease Aggregation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for Huntington's chorea are ineffective, and existing approaches to combat the aggregation of polyQ domains in the Huntingtin protein, which cause neuronal degeneration, are not practical for therapeutic use due to the large size of proteins involved.
Innovation Solution
Development of novel peptide compounds, specifically peptides of 200 amino acids or less, with sequences showing high identity to the N-terminal parts of the Huntingtin protein, which can inhibit polyQ-hHtt protein aggregation, such as Pep42, and their use in fusion proteins with protein transduction domains for enhanced cellular penetration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type hHtt protein or its Drosophila counterpart is used to combat polyQ-hHtt aggregation, then protective effect against aggregation is achieved, but the protein size (548 or 620 amino acids) is too large for practical gene therapy application
Solution Approach 1:
The wild-type hHtt protein sequence (548 amino acids) is divided into multiple smaller peptide fragments. Specifically, the invention identifies and isolates a protective peptide sequence (amino acids 480-502: SAGHDIITEQPRS) from the N-terminal region of hHtt. This segmentation allows the therapeutic function to be achieved with a much smaller molecular entity suitable for gene therapy delivery.
Solution Approach 2:
The invention extracts the specific protective functional domain from the full-length wild-type hHtt protein. By analyzing the sequence and testing various fragments, the patent identifies and isolates the critical 23-amino acid peptide (SAGHDIITEQPRS) that contains the aggregation-inhibiting activity, separating it from the rest of the protein structure.
2Length of moving object
If smaller peptide sequences are used to reduce protein size, then gene therapy applicability is improved, but the protective effect against aggregation may be reduced
Solution Approach 1:
The invention applies local quality by focusing on the specific region of the hHtt protein that contains the protective function. Rather than using the entire protein or random smaller fragments, the patent identifies the precise local sequence (amino acids 480-502) within the N-terminal region that exhibits aggregation-inhibiting activity, optimizing both size and function.
Solution Approach 2:
The invention changes the parameter of peptide length from hundreds of amino acids to just 23 amino acids, while maintaining the critical protective function. This parameter optimization allows the peptide to be small enough for gene therapy delivery while retaining sufficient functional activity to inhibit polyQ-hHtt aggregation.
3Reliability
If the N-terminal part of hHtt protein is used to prevent aggregation, then protective effect is achieved, but other uncontrolled functions of the full protein may be performed
Solution Approach 1:
The invention extracts only the specific N-terminal sequence (amino acids 480-502) that is responsible for the protective aggregation-inhibiting function. By isolating this specific functional element, the patent eliminates the risk of other uncontrolled functions associated with the full-length protein while preserving the desired therapeutic effect.
Data Source
Figure 1A~1B
Figure 2A~2D
Figure 3
AI summary
The invention relates to novel therapeutic compounds for use against Huntington's disease. More specifically, the invention relates to an isolated peptide which is less than 100 amino acids in size and which comprises: a first sequence having at least 80% identity with sequence AASSG (SEQ ID No 1), or a second sequence having at least 80% identity with sequence XAGXDXXTEXPXS (SEQ ID No 2), in which X denotes any amino acid. The present invention also relates to the use of an isolated peptide, which is less than 200 amino acids in size and which comprises the above-mentioned sequence(s), as a drug.