Peptide Linkers for Targeted Enzyme Delivery
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Solution Overview
Problem
Current treatments for lysosomal storage disorders, such as Sanfilippo disease, lack effective methods for delivering therapeutic enzymes to affected tissues, particularly those lacking specific cell-surface receptors, limiting the efficacy of enzyme replacement therapy.
Innovation Solution
Development of novel polypeptide compositions using peptide linkers, such as those with sequential repeats of the amino acid sequence GGGGGAAAAAGGGGG, to facilitate the targeted delivery of therapeutic agents to specific cells and tissues by connecting therapeutic peptides with receptor-binding domains, enhancing expression and activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If enzyme replacement therapy is administered to treat lysosomal storage disorders, then the therapeutic enzyme can be delivered to patients, but the delivery to affected tissues particularly those lacking specific cell-surface receptors is limited
Solution Approach 1:
The patent combines a therapeutic enzyme with a cell-penetrating peptide (CPP) to create a fusion protein. This merging allows the enzyme to be delivered to cells that lack specific surface receptors, as the CPP provides an alternative entry mechanism through direct cellular uptake, thereby resolving the contradiction between delivery reliability and tissue targeting versatility.
Solution Approach 2:
The cell-penetrating peptide acts as an intermediary between the therapeutic enzyme and the target cells. The CPP facilitates cellular entry by interacting with the cell membrane and transporting the fused enzyme into the cell, enabling delivery to tissues that would otherwise be inaccessible to traditional enzyme replacement therapy.
2Reliability
If peptide linkers are used to connect therapeutic peptides with receptor-binding domains, then targeted delivery to specific cells and tissues is enhanced, but the complexity of polypeptide composition increases
Solution Approach 1:
The polypeptide is segmented into distinct functional domains: a therapeutic enzyme domain, a cell-penetrating peptide domain, and a linker domain. This segmentation allows each component to perform its specific function while maintaining overall structural organization, facilitating targeted delivery without excessive complexity.
Solution Approach 2:
Different regions of the polypeptide are assigned specific local qualities: the enzyme domain provides catalytic activity, the CPP domain provides membrane penetration capability, and the linker domain provides structural flexibility and proper spacing. This local differentiation optimizes each region's function while managing overall complexity.
Data Source
AI summary
Disclosed herein are novel peptide linkers and polypeptide compositions comprising the linkers (e.g., chimeric polypeptides) and methods of using the polypeptide compositions. The compositions and methods are particularly useful for targeting/delivering a polypeptide or protein of interest (e.g., a therapeutic polypeptide) to a cell, tissue or organ of interest in order to treat various diseases or disorders (e.g., lysosomal storage disorders).