Bifunctional Sortilin Binders for Extracellular Protein Degradation
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Solution Overview
Problem
Current drug development methods are limited in their ability to target and degrade extracellular proteins, as existing technologies like PROTACs and LYTACs rely on natural cellular mechanisms and are not effective for non-cytosolic proteins, and sortilin-mediated degradation of proteins like Progranulin is a therapeutic target but lacks effective oral modalities.
Innovation Solution
Development of bifunctional compounds that bind to Sortilin through a linker to an extracellular target molecule, facilitating targeted lysosomal degradation of these proteins, including the use of small molecule sortilin binders and peptides to form ternary complexes with Sortilin and the target protein, recruiting them into lysosomal pathways for degradation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If PROTACs are used to degrade intracellular proteins, then cytoplasmic protein degradation is achieved, but extracellular protein degradation cannot be accomplished
Solution Approach 1:
The bifunctional molecule is segmented into two distinct functional moieties: a first moiety that binds to the extracellular target protein and a second moiety that binds to sortilin. This segmentation allows the molecule to selectively target extracellular proteins for lysosomal degradation, resolving the limitation of PROTACs that can only degrade intracellular proteins.
Solution Approach 2:
Sortilin serves as an intermediary protein that mediates the degradation process. The bifunctional molecule exploits sortilin's natural role in lysosomal trafficking by binding to it, thereby recruiting the extracellular target protein into the lysosomal degradation pathway. This intermediary mechanism enables extracellular protein degradation without requiring direct lysosomal penetration.
2Reliability
If LYTACs with M6P-R binding motifs are used, then lysosomal degradation of extracellular proteins is achieved, but oral availability is compromised due to complex sugar moieties
Solution Approach 1:
The invention changes the binding mechanism parameter from carbohydrate-based (M6P-R binding) to protein-based (sortilin binding). By using a protein-protein interaction interface instead of sugar moieties, the molecule achieves oral bioavailability while maintaining lysosomal degradation capability, as protein binders are more suitable for oral administration than complex carbohydrate structures.
3Reliability
If sortilin binders are developed to inhibit Progranulin degradation, then FTD therapy is achieved, but current modalities lack oral bioavailability
Solution Approach 1:
The bifunctional molecule design allows the sortilin binding moiety to utilize sortilin's natural cellular function in lysosomal trafficking. By hijacking this self-service mechanism, the molecule achieves effective delivery and degradation of extracellular targets without requiring complex delivery systems, thereby enabling oral bioavailability for therapeutic applications.
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 bifunctional compounds effectively induce targeted lysosomal degradation of extracellular proteins, such as TNFa, across various body compartments where Sortilin is expressed, providing a therapeutic approach for conditions mediated by these proteins.
Implementation Method 1
bifunctional compounds having the structure according to formula (I): wherein, SL is a moiety that binds to Sortilin; LI is a linker or a bond; and TL is a moiety that binds an extracellular target molecule
Implementation Method 2
The bifunctional compounds effectively induce targeted lysosomal degradation of extracellular proteins, such as TNFa
Data Source
AI summary
The present invention relates to bifunctional molecules which contain a protein-of-interest binding moiety linked through a linker group to a cellular receptor binding moiety preferably a moiety which binds to the receptor sortilin encoded by the gene SORT 1.