Macrocyclic Peptides for SOD1 Misfolding and Aggregation Control
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Solution Overview
Problem
Current treatments for protein misfolding diseases, such as amyotrophic lateral sclerosis (ALS), are inadequate in addressing the toxic gain-of-function properties of misfolded Cu/Zn superoxide dismutase (SOD1) leading to motor neuron degeneration, as they do not effectively inhibit the aggregation and neurotoxicity of SOD1 variants.
Innovation Solution
Development of macrocyclic peptides, particularly cyclic pentapeptides with the cyclo-TXSXW motif, specifically targeting SOD1 variants to modulate their aggregation and inhibit neurotoxicity, using a bacterial high-throughput genetic screen and split intein circular ligation of peptides and proteins (SICLOPPS) technology.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments are used for protein misfolding diseases, then general symptom management is achieved, but the toxic gain-of-function properties of misfolded SOD1 and its aggregation are not effectively inhibited
Solution Approach 1:
The patent employs small molecule compounds as intermediaries that specifically bind to misfolded SOD1 variants, preventing their aggregation and neutralizing their neurotoxic effects. These compounds act as mediators between the misfolded proteins and the cellular environment, blocking the harmful interactions without requiring removal of the toxic proteins.
Solution Approach 2:
The invention identifies and utilizes compounds that specifically recognize and bind to the misfolded conformation of SOD1, converting the harmful aggregated state into a benign complex that can be managed therapeutically. The compounds transform the toxic gain-of-function into a detectable and treatable state through specific molecular recognition.
2Measurement precision
If high-throughput genetic screening is performed to identify effective compounds, then compounds with specific activity against SOD1 variants are discovered, but the complexity and resource requirements of the screening process increase
Solution Approach 1:
The patent utilizes a bacterial high-throughput genetic screening system where the bacteria themselves express the misfolded SOD1 variants and serve as the screening platform. The system is self-sufficient, using the bacterial cellular machinery to produce, fold, and present the target proteins for compound screening, eliminating the need for complex external expression systems.
Solution Approach 2:
The screening approach segments the complex problem of identifying anti-aggregation compounds into manageable bacterial colonies, each expressing specific SOD1 variants. This segmentation allows parallel screening of multiple variants simultaneously, reducing overall complexity while maintaining high specificity through variant-specific selection.
3Reliability
If macrocyclic peptides are designed to target SOD1 variants, then aggregation inhibition is achieved, but the manufacturing and synthesis complexity increases
Solution Approach 1:
The patent employs systematic variation of peptide sequence parameters within the cyclo-TXSXW motif to optimize both activity and manufacturability. By changing specific amino acid residues at defined positions, the invention balances aggregation inhibition efficacy with synthetic accessibility, allowing selection of variants that are both effective and amenable to standard peptide synthesis protocols.
Data Source
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AI summary
Aspects of the present invention disclose compounds that modulate the aggregation of amyloidogenic proteins or peptides. In some aspects, disclosed compounds modulate the aggregation of disease-associated proteins and natural β-amyloid peptides. In a preferred embodiment, the compounds can inhibit natural amyloid aggregation. Pharmaceutical compositions comprising the compounds of the embodiments, and diagnostic and treatment methods for diseases (e.g., amyloidogenic diseases) using the compounds, are also disclosed. In addition, there is provided an integrated bacterial platform for the discovery of rescuers of disease-associated protein misfolding.