Protease-Resistant Peptide Shuttles for Blood-Brain Barrier Transport
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Solution Overview
Problem
Delivering therapeutic agents and diagnostic substances to specific regions of the brain is challenging due to the blood-brain barrier (BBB), which restricts the entry of most compounds, including large molecules and many small molecule drugs, limiting the treatment of brain disorders such as Parkinson's and Alzheimer's diseases.
Innovation Solution
Development of specific peptides with the fragment KAPETAL, which utilize an active transport mechanism to cross the BBB, allowing for the transport of larger cargoes like proteins and antibodies, and are stable across various pH values and temperatures, making them suitable for therapeutic and diagnostic applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If BBB-shuttle peptides are used to transport therapeutic agents across the blood-brain barrier, then the delivery of large molecules and diagnostic substances to the brain is improved, but the half-life time of the peptides in human serum decreases
Solution Approach 1:
The patent creates shuttle-cargo constructs by combining BBB-shuttle peptides with therapeutic or diagnostic cargo molecules. This composite structure allows the peptide to fulfill its transport function while the cargo provides stability and therapeutic activity, effectively resolving the short half-life issue by protecting the peptide through conjugation.
Solution Approach 2:
The patent uses linkers as intermediary components to connect the BBB-shuttle peptide to the cargo. These linkers serve as mediators that maintain the functionality of both the peptide (for BBB crossing) and the cargo (for therapeutic effect), while also providing structural stability that extends the overall half-life of the construct in serum.
2Reliability
If the blood-brain barrier is made more permeable to allow therapeutic agents to pass, then the treatment effectiveness of brain disorders is improved, but the protection of the central nervous system from harmful chemicals is reduced
Solution Approach 1:
The BBB-shuttle peptide acts as an intermediary that facilitates the selective transport of therapeutic agents across the intact blood-brain barrier. This approach maintains the barrier's protective function against harmful substances while enabling controlled delivery of beneficial compounds through specific transport mechanisms.
Solution Approach 2:
The patent employs peptides with specific local properties (amino acid sequences like KAPETAL) that are designed to interact with BBB transport systems. This localized functional modification allows selective permeability enhancement for therapeutic agents without compromising the overall integrity and protective function of the blood-brain barrier.
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
These peptides effectively facilitate the transport of substances across the BBB, maintaining cargo activity and stability, enabling the delivery of therapeutic and diagnostic agents to the brain, overcoming the limitations of existing delivery methods.
Implementation Method 1
These peptides, which are derivatives of apamin, are not toxic and are able to cross the BBB. In particular, the high permeability values obtained together with the evidence of an active transport mechanism make these peptides very promising BBB-shuttles.
Data Source
AI summary
It is described a peptidic compound having in its structure a biradical of a peptide having 9-20 amino acids residues in length having at least a intrapeptide disulfide bond, a intrapeptide amide bond, an intrapeptide thioether bond, a Se-Se bond, an intrapeptide C-C bond, or an intrapeptide C=C bond; and comprising the amino acid sequence Xaa 1KAPETALXaa 2 (A)n1(A)n2(A)n3 (SEQ ID NO:1) Xaa 1 and Xaa 2 are an amino acid independently selected form C, D, E, K, O, Dap, Dab, Sec, Pen, AIGly, and alpha-Me-alpha-alkGly; n1, n2 and n3 are integers independently selected from 0 an 1, with the proviso that when at least one of n1, n2 and n3 is 0, then at least an intrapeptide bond is between Xaa 1 and Xaa 2.These peptidic compounds are useful as shuttles through the blood brain barrier (BBB). The constructs BBB-shuttle-cargo, being the cargo of a biologically active substance or for use in a diagnostic method, are useful in therapy and diagnosis.