Bifunctional Fusion Proteins for Undrugged Target Degradation
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Solution Overview
Problem
Conventional therapeutics face challenges in effectively targeting intracellular proteins lacking enzymatic domains for proteasomal degradation, particularly for previously undrugged targets, and there is a need for improved compounds and methods to induce proteasomal degradation of therapeutic targets.
Innovation Solution
Development of bifunctional polypeptides comprising a targeting moiety and a ubiquitin-proteasome recruiting domain (URD) to promote the ubiquitination and degradation of target proteins through the proteasome pathway, utilizing specific E3 ubiquitin ligases such as RING family, cullin family, and HECT family ligases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional therapeutics (small molecule or antibody inhibitors) are used to block therapeutic target function, then the target function is modulated, but the target protein remains present in the cellular milieu causing confounding effects
Solution Approach 1:
The invention extracts the target protein from the cellular milieu through proteasomal degradation, completely removing it rather than merely blocking its function. This is achieved by recruiting the ubiquitin-proteasome system to degrade the target protein, thereby eliminating both the functional activity and the physical presence of the target, thus avoiding confounding effects while maintaining therapeutic benefit
Solution Approach 2:
The invention utilizes the cell's existing proteasomal degradation machinery to discard unwanted target proteins. By designing bifunctional molecules that link target protein recognition to proteasome recruitment, the system directs cellular waste disposal mechanisms to eliminate disease-causing proteins, achieving therapeutic effect through natural cellular recycling pathways
2Reliability
If small molecule degraders (PROTACs) are designed to recruit E3 ubiquitin ligases, then proteasomal degradation of target is induced, but significant screening and optimization is required to identify compatible chemical modalities
Solution Approach 1:
The invention uses bifunctional molecules as intermediaries that bridge target protein recognition and proteasome recruitment. These molecules contain distinct domains: one that binds the target protein and another that recruits the ubiquitin-proteasome system, thereby mediating the degradation process without requiring extensive optimization of single-molecule chemical modality compatibility
Solution Approach 2:
The degradation inducer is segmented into functional domains: a target-binding domain and a proteasome-recruitment domain. This segmentation allows independent optimization of each function and simplifies the overall design process, as each domain can be selected or engineered separately based on its specific binding requirements rather than requiring full-molecule optimization
3Adaptability or versatility
If small molecule degraders are used for previously undrugged intracellular targets, then proteasomal degradation can be achieved, but identification of compatible small molecule degraders is particularly challenging for targets lacking enzymatic domains
Solution Approach 1:
The bifunctional molecule acts as an intermediary that does not require direct enzymatic interaction with the target protein. Instead, it uses a target-binding domain (such as an antibody or binding protein) to recognize the target and a separate proteasome-recruitment domain to engage the degradation machinery, thereby enabling degradation of targets regardless of their enzymatic properties and expanding coverage to previously undrugged targets
Solution Approach 2:
The invention replaces traditional small molecule enzymatic inhibition mechanisms with a protein-protein interaction-based approach. By using protein domains or antibody fragments for target recognition instead of small molecule enzymatic binders, the system overcomes the limitation of requiring enzymatic domains for drug binding, enabling targeting of non-enzymatic proteins through structural epitope recognition
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 polypeptides efficiently induce proteasomal degradation of target proteins, offering a targeted and effective approach for treating diseases like cancer and neurodegenerative disorders by reducing the amount of dysfunctional proteins.
Implementation Method 1
proximity of the bifunctional polypeptide to the target protein through binding of the targeting moiety induces ubiquitination of the target protein via the URD, thereby promoting proteosome-mediated degradation of the target protein
Data Source
AI summary
Disclosed herein are polypeptides that have a portion derived from a RING family E3 ubiquitin ligase, a cullin family E3 ubiquitin ligase, a homologous to E6AP carboxyl terminus (HECT) family E3 ubiquitin ligase, and a viral homolog of an E3 ubiquitin ligase, optionally having ubiquitin-proteasome recruiting activity. Also disclosed are bifunctional polypeptides that promote proteasome-mediated degradation of a target protein. In some embodiments, the bifunctional polypeptide comprises a) a targeting moiety that is capable of binding to the target protein; and b) a ubiquitin-proteasome system recruiting domain (URD). In some embodiments, proximity of the bifunctional polypeptide to the target protein through binding of the targeting moiety induces ubiquitination of the target protein via the URD, thereby promoting proteosome-mediated degradation of the target protein. These bifunctional polypeptides may be used for the treatment of a disease in a subject, where the targeting moiety binds a target whose abnormal function and/or expression is associated with the disease.