Mannose 6-Phosphate Linker Design for Receptor Binding
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Solution Overview
Problem
Current compounds targeting the cation-independent mannose 6-phosphate receptor (CI-M6PR) have poor affinity due to steric hindrance, limiting their effectiveness in enzyme replacement therapies for lysosomal storage disorders.
Innovation Solution
Conjugates of glycoproteins or nanoparticles linked with a specific linker that separates the mannose 6-phosphate analogue from the product of interest by 4 to 15 consecutive atoms, reducing steric hindrance and increasing affinity for CI-M6PR, allowing for efficient targeting of lysosomes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If mannose 6-phosphate containing compounds are used to target CI-M6PR, then affinity for the receptor is improved, but steric hindrance from vicinal aldehyde groups reduces binding affinity
Solution Approach 1:
The patent removes the problematic vicinal aldehyde groups from the mannose 6-phosphate structure, retaining only the essential phosphate group and mannose moiety. This extraction of harmful structural elements eliminates steric hindrance while preserving receptor binding affinity.
Solution Approach 2:
The patent modifies the chemical structure by changing the configuration and positioning of functional groups in the mannose 6-phosphate molecule. Specifically, it optimizes the spatial arrangement of the phosphate group and mannose units to achieve optimal binding geometry without steric conflicts.
2Ease of manufacture
If lysosomal enzymes are purified from recombinant expression systems, then enzyme production is simplified, but M6P phosphorylation is insufficient reducing therapeutic efficacy
Solution Approach 1:
The patent applies M6P phosphorylation to lysosomal enzymes during the purification process from recombinant expression systems. This preliminary phosphorylation action ensures that enzymes acquire the necessary M6P markers before therapeutic administration, enabling proper receptor-mediated uptake by target cells.
3Measurement precision
If M6P-containing compounds are used for enzyme replacement therapy, then specific addressing to lysosomes is achieved, but supply limitations and production difficulties arise
Solution Approach 1:
The patent creates a universal M6P-phosphorylated enzyme preparation method that can be applied to multiple lysosomal enzymes produced in recombinant expression systems. This multi-functional approach enables standardized phosphorylation processing across different enzyme types, facilitating large-scale production while maintaining lysosome targeting specificity.
Data Source
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Figure 4A~5B
Figure 6A~7C
AI summary
The invention relates to conjugates of products of interest and of compounds targeting the cation-independent mannose 6-phosphate receptor with a high affinity. The invention also relates to their applications, for instance in enzyme replacement therapies.