Bifunctional Small Molecules for Selective Circulating Protein Degradation
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Solution Overview
Problem
Current antibody-based therapies for targeting circulating proteins in diseases like Rheumatoid Arthritis and atherosclerosis are limited by high molecular weight, immunogenicity, high cost, and low oral bioavailability, necessitating a more effective and cost-efficient alternative.
Innovation Solution
Development of bifunctional small molecules with a protein targeting moiety and a cellular receptor binding moiety linked by a polyethylene glycol linker, which selectively bind to circulating proteins and facilitate their degradation within hepatocytes, reducing protein levels and alleviating disease symptoms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If antibody-based therapies are used to target circulating proteins, then specificity and affinity for target proteins are improved, but molecular weight increases and oral bioavailability decreases
Solution Approach 1:
The antibody molecule is divided into two separate functional components: a targeting moiety that binds to the circulating protein with high specificity, and a Fc fragment that mediates immune effector functions. This segmentation allows the small molecule targeting moiety to achieve high specificity while avoiding the high molecular weight of intact antibodies.
Solution Approach 2:
The Fc fragment is extracted from the complete antibody structure and separated from the targeting function. This extracted Fc fragment can then be combined with small molecule targeting moieties to create hybrid therapeutics that achieve antibody-like effector functions without the high molecular weight and poor oral bioavailability of full antibodies.
2Measurement precision
If antibody-based therapies are used to target circulating proteins, then specificity and affinity for target proteins are improved, but cost increases
Solution Approach 1:
Small molecule targeting moieties can be synthesized more cheaply than full antibodies using conventional organic synthesis methods. These small molecules serve as cost-effective alternatives to expensive antibody-based therapies while maintaining the ability to achieve high specificity through rational drug design and structure-activity relationship studies.
Solution Approach 2:
The Fc fragment serves as a universal platform that can be combined with various small molecule targeting moieties to create multiple therapeutic agents against different disease targets. This multi-functionality allows a single Fc fragment to be reused across different drug candidates, reducing overall development and manufacturing costs.
3Reliability
If antibody-based therapies are used to target circulating proteins, then therapeutic efficacy is improved, but shelf life decreases
Solution Approach 1:
The molecular weight parameter is changed from high (antibodies) to low (small molecules), which fundamentally alters the physical and chemical stability properties. Small molecules generally exhibit better shelf stability, lower susceptibility to aggregation, and improved resistance to degradation compared to large protein-based therapeutics like antibodies.
4Reliability
If antibody-based therapies are used to target circulating proteins, then therapeutic efficacy is improved, but oral bioavailability decreases
Solution Approach 1:
The antibody is segmented into a small molecule targeting moiety and an Fc fragment, where the small molecule component can be administered orally. Small molecules generally possess better oral bioavailability due to their ability to pass through the gastrointestinal tract and hepatic metabolism, unlike large protein-based antibodies that are degraded in the GI tract.
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 small molecules effectively lower protein levels by degradation, providing a more lasting therapeutic effect compared to inhibition, overcoming the limitations of traditional antibody-based strategies and offering versatility in targeting different disease-related proteins.
Implementation Method 1
The bifunctional molecule construct contains a protein targeting motif derived from known small molecule ligands of the proteins of interest... which can be used to remove circulating proteins
Implementation Method 2
The two motifs are covalently linked via a linker such as a polyethylene glycol (PEG) linker with adjustable length
Data Source
AI summary
The present disclosure is directed to bifunctional small molecules which contain a circulating protein binding moiety (CPBM) linked through a linker group to a cellular receptor binding moiety (CRBM) which is a membrane receptor of degrading cell such as a hepatocyte or other degrading cell. In certain embodiments, the (CRBM) is a moiety which binds to asialoglycoprotein receptor (an asialoglycoprotein receptor binding moiety, or ASGPRBM) of a hepatocyte. In additional embodiments, the (CRBM) is a moiety which binds to a receptor of other cells which can degrade proteins, such as a LRP1, LDLR, FcγRI, FcRN, Transferrin or Macrophage Scavenger receptor.