ASGPR-Binding Compounds for Extracellular Protein Degradation
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Solution Overview
Problem
Current therapeutic strategies are inadequate for selectively degrading extracellular proteins, such as immunoglobulins and cytokines, which play a significant role in mediating serious diseases, as they cannot be targeted by existing intracellular protein degradation methods due to their location outside cells.
Innovation Solution
Development of novel compounds with specific modifications to the C2-position of ASGPR ligands, incorporating galactose or talose stereochemistry, which bind to the asialoglycoprotein receptor (ASGPR) to facilitate the selective degradation of extracellular proteins by recruiting them for endocytosis and degradation in the liver.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If intracellular protein degradation methods are used, then intracellular proteins can be selectively degraded, but extracellular proteins cannot be targeted
Solution Approach 1:
The patent uses the ASGPR receptor as an intermediary to bridge extracellular proteins and the intracellular degradation machinery. The compound consists of an ASGPR-binding ligand connected to an extracellular protein ligand, which recruits the protein-degrading machinery to degrade target extracellular proteins through the ASGPR pathway, thereby extending intracellular degradation capability to extracellular targets.
Solution Approach 2:
The invention creates a universal degradation platform that can target both intracellular and extracellular proteins. By using the ASGPR pathway as a common route, the system achieves multi-functionality in protein degradation, overcoming the limitation that traditional methods could only degrade intracellular proteins.
2Adaptability or versatility
If existing therapeutic strategies are used, then some proteins can be inhibited, but extracellular proteins like immunoglobulins and cytokines cannot be effectively targeted
Solution Approach 1:
The compound is segmented into distinct functional modules: an ASGPR-binding ligand portion and an extracellular protein ligand portion. This segmentation allows independent optimization of each module's function while maintaining overall effectiveness in targeting extracellular proteins that were previously undruggable.
3Measurement precision
If ASGPR ligands are modified at the C2-position with galactose or talose stereochemistry, then binding specificity to ASGPR is improved, but molecular complexity increases
Solution Approach 1:
The patent applies local quality by introducing specific stereochemical modifications (galactose or talose) only at the C2-position of the ASGPR ligand. This localized modification enhances binding specificity to ASGPR without unnecessarily complicating the entire molecular structure, achieving high specificity with controlled complexity.
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 compounds effectively target and degrade disease-mediating extracellular proteins, including immunoglobulins and cytokines, by utilizing the ASGPR pathway, providing a novel approach to treat disorders mediated by these proteins.
Implementation Method 1
facilitate the selective degradation of extracellular proteins by recruiting them for endocytosis and degradation in the liver
Data Source
AI summary
Compounds and compositions that have an asialoglycoprotein receptor (ASGPR) binding ligand bound to an extracellular protein binding ligand for the selective degradation of the target extracellular protein in vivo to treat disorders mediated by the extracellular protein are described.