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Programmable protein stabilization with language model-derived peptide guides.

Lauren Hong1, Tianzheng Ye2, Tian Z Wang1

  • 1Department of Biomedical Engineering, Duke University, Durham, NC, USA.

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Summary
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Researchers engineered novel deubiquibodies (duAbs) to stabilize proteins, expanding targeted protein stabilization (TPS) for diseases like cancer. This approach targets previously undruggable proteins, including tumor suppressors and fusion oncoproteins.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Dysregulated protein degradation via the ubiquitin-proteasomal pathway is implicated in diseases such as cancer, neurodegeneration, and diabetes.
  • Current targeted protein stabilization (TPS) and targeted protein degradation (TPD) platforms require structured binding pockets, limiting their application to "undruggable" targets.
  • There is a need for novel therapeutic strategies to address protein dysregulation in diseases with limited treatment options.

Purpose of the Study:

  • To expand the scope of targeted protein stabilization (TPS) by developing a novel platform for stabilizing proteins lacking traditional binding pockets.
  • To engineer deubiquibodies (duAbs) by fusing computationally designed peptides to the OTUB1 deubiquitinase catalytic domain.
  • To demonstrate the efficacy of duAbs in stabilizing diverse protein targets, including tumor suppressors and fusion oncoproteins, and their potential for therapeutic applications.

Main Methods:

  • Computational design of peptides targeting specific proteins using protein language models.
  • Fusion of designed peptides to the catalytic domain of OTUB1 to create deubiquibodies (duAbs).
  • Validation of duAb-mediated protein stabilization in human cells, assessing deubiquitinase (DUB) dependence.
  • Engineering duAbs against conformationally diverse targets like p53, WEE1, and PAX3::FOXO1.
  • Encapsulation of p53-targeting duAb mRNA in lipid nanoparticles for intracellular delivery.

Main Results:

  • Engineered duAbs effectively stabilize exogenous and endogenous proteins in a DUB-dependent manner.
  • DuAbs were successfully engineered to target conformationally diverse proteins, including tumor suppressors (p53, WEE1) and disordered fusion oncoproteins (PAX3::FOXO1).
  • mRNA-encapsulated p53-targeting duAbs demonstrated effective intracellular delivery, p53 stabilization, and apoptosis activation in cellular models.

Conclusions:

  • Deubiquibodies (duAbs) represent a novel platform for targeted protein stabilization (TPS), overcoming limitations of traditional drug design.
  • This approach expands the druggable proteome, offering potential therapeutic strategies for diseases driven by protein dysregulation.
  • The successful in vitro demonstration of mRNA-delivered duAbs warrants further investigation for in vivo translation and clinical development.