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Updated: Jun 17, 2025
Author Spotlight: A Computational Approach to Decipher Amino Acid Preferences in Multispecific Protein-Protein Interactions
Published on: January 26, 2024
Programmable Protein Stabilization with Language Model-Derived Peptide Guides
Lauren Hong1, Tianzheng Ye2, Tian Zi Wang1
1Department of Biomedical Engineering, Duke University.
Abstract:
Dysregulated protein degradation via the ubiquitin-proteasomal pathway can induce numerous disease phenotypes, including cancer, neurodegeneration, and diabetes. Stabilizing improperly ubiquitinated proteins via target-specific deubiquitination is thus a critical therapeutic goal. Building off the major advances in targeted protein degradation (TPD) using bifunctional small-molecule degraders, targeted protein stabilization (TPS) modalities have been described recently. However, these rely on a limited set of chemical linkers and warheads, which are difficult to generate de novo for new targets and do not exist for classically "undruggable" targets. To address the limited reach of small molecule-based degraders, we previously engineered ubiquibodies (uAbs) by fusing computationally-designed "guide" peptides to E3 ubiquitin ligase domains for modular, CRISPR-analogous TPD. Here, we expand the TPS target space by engineering "deubiquibodies" (duAbs) via fusion of computationally-designed guides to the catalytic domain of the potent OTUB1 deubiquitinase. In human cells, duAbs effectively stabilize exogenous and endogenous proteins in a DUB-dependent manner. To demonstrate duAb modularity, we swap in new target-binding peptides designed via our generative language models to stabilize diverse target proteins, including key tumor suppressor proteins such as p53 and WEE1, as well as heavily-disordered fusion oncoproteins, such as PAX3::FOXO1. In total, our duAb system represents a simple, programmable, CRISPR-analogous strategy for TPS.
Insights
Researchers developed deubiquibodies (duAbs) for targeted protein stabilization (TPS). This new method uses engineered proteins to stabilize disease-related proteins, offering a programmable approach for difficult-to-treat conditions.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Dysregulated protein degradation is implicated in diseases like cancer and neurodegeneration.
- Targeted protein stabilization (TPS) is a therapeutic strategy, but current methods have limitations.
- Existing TPS modalities use limited chemical linkers and warheads, hindering application to new or
- undruggable
- targets.
Purpose of the Study:
- To engineer a novel, modular system for targeted protein stabilization (TPS).
- To expand the range of druggable targets for protein stabilization therapies.
- To develop a programmable, CRISPR-analogous strategy for therapeutic intervention.
Main Methods:
- Engineered deubiquibodies (duAbs) by fusing computationally designed peptides to the OTUB1 deubiquitinase catalytic domain.
- Validated duAb efficacy in stabilizing exogenous and endogenous proteins in human cells.
- Demonstrated modularity by designing new target-binding peptides using generative language models.
Main Results:
- Deubiquibodies (duAbs) effectively stabilized target proteins in a deubiquitinase-dependent manner.
- The duAb system demonstrated modularity, enabling stabilization of diverse targets including p53, WEE1, and PAX3::FOXO1.
- Successfully stabilized key tumor suppressors and disordered oncoproteins, expanding TPS applicability.
Conclusions:
- The engineered deubiquibody (duAb) system provides a versatile and programmable platform for targeted protein stabilization (TPS).
- This approach overcomes limitations of small-molecule-based TPS, offering a new strategy for diseases driven by protein dysregulation.
- Deubiquibodies represent a significant advancement in developing novel therapeutics for challenging diseases.
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