Cyclic Amyloid Inhibitory Peptides for BBB-Penetrant α-Synuclein Binding
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Solution Overview
Problem
Current inhibitors for amyloid self-assembly, particularly for α-synuclein (αSyn) and islet amyloid polypeptide (IAPP), face challenges such as high conformational flexibility, low blood-brain-barrier permeability, high production costs, potential immunogenicity, and lack of specificity and affinity, making them unsuitable for clinical use in treating synucleinopathies like Parkinson's disease.
Innovation Solution
Development of cyclic peptides with specific amino acid sequences that bind to α-synuclein and IAPP with nanomolar affinity, inhibiting amyloid self-assembly and cross-seeding interactions, and are capable of crossing the blood-brain barrier.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If linear peptides are used to inhibit amyloid self-assembly, then they can bind to amyloidogenic polypeptides, but they have low blood-brain-barrier permeability and cannot cross the BBB
Solution Approach 1:
The patent applies parameter changes by converting linear peptides into cyclic structures through disulfide bonds between cysteine residues. This structural transformation changes the conformational flexibility parameter, creating a more rigid and stable cyclic peptide architecture that maintains amyloid binding capability while improving blood-brain-barrier permeability for CNS delivery
Solution Approach 2:
The invention employs spheroidality by introducing cyclic structures with curved three-dimensional conformations. The cyclic peptides adopt defined spatial arrangements that differ from linear extensions, creating a more compact and potentially BBB-penetrable structure while maintaining the ability to bind amyloidogenic polypeptides
2Reliability
If antibodies are used to inhibit amyloid self-assembly, then they have high affinity and specificity, but they have high production costs and potential immunogenicity
Solution Approach 1:
The patent applies extraction by isolating and utilizing only the essential antigen-binding fragments (peptides) from antibody structures. By extracting the functional binding domain and removing the problematic Fc region and other antibody components, the invention achieves high affinity binding with reduced production costs and immunogenicity
Solution Approach 2:
The invention employs cheap short-living objects by using synthetic peptides instead of full-length antibodies. These peptides are cheaper to produce, can be synthesized readily, and while potentially having shorter half-lives, provide cost-effective therapeutic or diagnostic solutions for amyloid-related diseases
3Ease of manufacture
If small molecules are used to inhibit amyloid self-assembly, then they have low production costs and good permeability, but they lack high affinity and specificity and cannot block interactions involving large interfaces
Solution Approach 1:
The patent applies composite materials by creating hybrid structures that combine the advantages of peptides and small molecules. The cyclic peptides incorporate rigid aromatic residues (phenylalanine, tryptophan) and charged residues that provide both the affinity and specificity of large molecules and the permeability characteristics of smaller compounds, effectively blocking large interface interactions
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 suppress both self-seeded and cross-seeded amyloid self-assembly of α-synuclein, offering therapeutic and diagnostic potential for synucleinopathies by binding to key amyloid polypeptides with high affinity, thus providing a treatment and diagnostic tool for diseases like Parkinson's disease.
Implementation Method 1
Amyloid self-assembly is linked to devastating cell-degenerative diseases including Alzheimer's disease (AD), type 2 diabetes (T2D), Parkinson's disease (PD) and dementia with Lewy bodies
Data Source
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AI summary
The present invention relates to peptides, in particular of amyloid inhibitory peptides, and to pharmaceutical compositions comprising such peptides, for use in methods of treating or preventing or delaying the onset of synucleinopathies, in particular of Parkinson's disease (PD) or dementia with Lewy bodies, and their comorbidities, in particular PD/type 2 diabetes (T2D) and PD/Alzheimer's disease (AD). Furthermore, the present invention relates to such peptides, in particular such amyloid inhibitory peptides, for use in methods of diagnosing such synucleinopathies and related comorbidities. Furthermore, the present invention also relates to a kit for the in-vitro or in-vivo detection and, optionally, quantification of amyloidogenic polypeptides, amyloid fibrils or amyloid aggregates, and/or for the diagnosis of synucleinopathies and related comorbidities, in particular PD/type 2 diabetes (T2D) and PD/Alzheimer's disease (AD), in a patient.