M6PR Binding Compounds for Lysosomal Protein Degradation
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Solution Overview
Problem
Current therapeutic approaches are limited in targeting a wide range of proteins, as many are considered 'undruggable' due to their inability to be effectively targeted by existing methods, necessitating new strategies for protein modulation or immune effector recruitment.
Innovation Solution
Development of compounds with a mannose-6-phosphate receptor (M6PR) binding moiety that can internalize into cells, allowing for the sequestration or degradation of target proteins through conjugation with biomolecules like antibodies, leveraging the cellular pathways for lysosomal targeting.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If conventional therapeutic approaches are used, then current drugs can target limited proteins, but many medically important proteins remain 'undruggable' and cannot be effectively targeted
Solution Approach 1:
The patent uses mannose-6-phosphate (M6P) ligands as intermediary molecules that exploit the natural M6PR-mediated lysosomal targeting pathway. These ligands act as mediators between the therapeutic agent and the cell's endogenous protein degradation system, enabling targeting of previously undruggable proteins by hijacking the cell's own quality control machinery for lysosomal degradation
Solution Approach 2:
The invention leverages the cell's self-service lysosomal degradation pathway to eliminate target proteins. By conjugating therapeutic agents with M6P ligands, the system exploits the cell's endogenous M6PR receptors and lysosomal machinery to automatically handle the degradation of targeted proteins, requiring no additional external degradation mechanisms
2Reliability
If M6PR binding compounds are used, then specific internalization and degradation of target proteins is achieved, but the complexity of conjugate design and manufacturing increases
Solution Approach 1:
The conjugate is divided into distinct functional segments: an M6P-binding ligand portion and a therapeutic agent portion connected by a linker. This segmentation allows independent optimization of each component's function while maintaining overall system effectiveness, simplifying both design and manufacturing by treating the conjugate as modular building blocks
Solution Approach 2:
The M6P ligand portion serves multiple functions: it provides specific binding to M6PR receptors, mediates cellular internalization, and directs lysosomal targeting. This multi-functionality reduces the need for additional complex components, as a single ligand structure accomplishes multiple critical tasks in the drug delivery process
3Productivity
If M6PR-mediated internalization is utilized, then therapeutic compounds can be delivered intracellularly, but selectivity for specific target proteins must be ensured to avoid off-target effects
Solution Approach 1:
The linker portion of the conjugate is specifically designed with local qualities that enable selective protein targeting while the M6P ligand handles general cellular internalization. This division of functional quality allows the system to achieve both efficient intracellular delivery via M6PR and specific target protein recognition through the tailored linker structure, minimizing off-target effects
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 M6PR binding compounds enable specific and efficient internalization and degradation of target proteins, expanding therapeutic options for previously 'undruggable' proteins by utilizing cellular pathways for lysosomal processing.
Implementation Method 1
a ligand moiety that specifically binds to a cell surface mannose-6-phosphate receptor (M6PR). The cell surface M6PR binding compounds can trigger the receptor to internalize into the cell a bound compound
Implementation Method 2
the conjugates described herein may sequester and/or degrade a target molecule of interest in a cell's lysosome
Data Source
AI summary
The present disclosure provides a class of compounds including a ligand moiety that specifically binds to a cell surface mannose-6-phosphate receptor (M6PR). The M6PR binding compounds can trigger the receptor to internalize into the cell a bound compound. The ligand moieties of this disclosure can be linked to a variety of moieties of interest without impacting the specific binding to, and function of, the M6PR. Also provided are compound that are conjugates of the ligand moieties linked to a biomolecule, such as an antibody, which conjugates can harness cellular pathways to remove specific target proteins from the cell surface or the extracellular milieu. For example, the conjugates described herein may sequester and/or degrade a target molecule of interest in a cell's lysosome. Also provided are methods of using the conjugates to target a protein for sequestration and/or lysosomal degradation.