Programmable protein stabilization with language model-derived peptide guides
Abstract Dysregulated protein degradation via the ubiquitin-proteasomal pathway can induce numerous disease phenotypes, including cancer, neurodegeneration, and diabetes. While small molecule-based targeted protein degradation (TPD) and targeted protein stabilization (TPS) platforms can address this...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58872-6 |
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| _version_ | 1849699132981116928 |
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| author | Lauren Hong Tianzheng Ye Tian Z. Wang Divya Srijay Howard Liu Lin Zhao Rio Watson Sophia Vincoff Tianlai Chen Kseniia Kholina Shrey Goel Matthew P. DeLisa Pranam Chatterjee |
| author_facet | Lauren Hong Tianzheng Ye Tian Z. Wang Divya Srijay Howard Liu Lin Zhao Rio Watson Sophia Vincoff Tianlai Chen Kseniia Kholina Shrey Goel Matthew P. DeLisa Pranam Chatterjee |
| author_sort | Lauren Hong |
| collection | DOAJ |
| description | Abstract Dysregulated protein degradation via the ubiquitin-proteasomal pathway can induce numerous disease phenotypes, including cancer, neurodegeneration, and diabetes. While small molecule-based targeted protein degradation (TPD) and targeted protein stabilization (TPS) platforms can address this dysregulation, they rely on structured and stable binding pockets, which do not exist to classically “undruggable” targets. Here, we expand the TPS target space by engineering “deubiquibodies” (duAbs) via fusion of computationally-designed peptide binders to the catalytic domain of the potent OTUB1 deubiquitinase. In human cells, duAbs effectively stabilize exogenous and endogenous proteins in a DUB-dependent manner. Using protein language models to generate target-binding peptides, we engineer duAbs to conformationally diverse target proteins, including key tumor suppressor proteins p53 and WEE1, and heavily-disordered fusion oncoproteins, such as PAX3::FOXO1. We further encapsulate p53-targeting duAbs as mRNA in lipid nanoparticles and demonstrate effective intracellular delivery, p53 stabilization, and apoptosis activation, motivating further in vivo translation. |
| format | Article |
| id | doaj-art-5f511d12c5fa4aaf81c0ed756ca76c4f |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-5f511d12c5fa4aaf81c0ed756ca76c4f2025-08-20T03:18:42ZengNature PortfolioNature Communications2041-17232025-04-0116111010.1038/s41467-025-58872-6Programmable protein stabilization with language model-derived peptide guidesLauren Hong0Tianzheng Ye1Tian Z. Wang2Divya Srijay3Howard Liu4Lin Zhao5Rio Watson6Sophia Vincoff7Tianlai Chen8Kseniia Kholina9Shrey Goel10Matthew P. DeLisa11Pranam Chatterjee12Department of Biomedical Engineering, Duke UniversityRobert F. Smith School of Chemical and Biomolecular Engineering, Cornell UniversityDepartment of Biomedical Engineering, Duke UniversityDepartment of Biomedical Engineering, Duke UniversityDepartment of Biomedical Engineering, Duke UniversityDepartment of Biomedical Engineering, Duke UniversityDepartment of Biomedical Engineering, Duke UniversityDepartment of Biomedical Engineering, Duke UniversityDepartment of Biomedical Engineering, Duke UniversityDepartment of Biomedical Engineering, Duke UniversityDepartment of Biomedical Engineering, Duke UniversityRobert F. Smith School of Chemical and Biomolecular Engineering, Cornell UniversityDepartment of Biomedical Engineering, Duke UniversityAbstract Dysregulated protein degradation via the ubiquitin-proteasomal pathway can induce numerous disease phenotypes, including cancer, neurodegeneration, and diabetes. While small molecule-based targeted protein degradation (TPD) and targeted protein stabilization (TPS) platforms can address this dysregulation, they rely on structured and stable binding pockets, which do not exist to classically “undruggable” targets. Here, we expand the TPS target space by engineering “deubiquibodies” (duAbs) via fusion of computationally-designed peptide binders to the catalytic domain of the potent OTUB1 deubiquitinase. In human cells, duAbs effectively stabilize exogenous and endogenous proteins in a DUB-dependent manner. Using protein language models to generate target-binding peptides, we engineer duAbs to conformationally diverse target proteins, including key tumor suppressor proteins p53 and WEE1, and heavily-disordered fusion oncoproteins, such as PAX3::FOXO1. We further encapsulate p53-targeting duAbs as mRNA in lipid nanoparticles and demonstrate effective intracellular delivery, p53 stabilization, and apoptosis activation, motivating further in vivo translation.https://doi.org/10.1038/s41467-025-58872-6 |
| spellingShingle | Lauren Hong Tianzheng Ye Tian Z. Wang Divya Srijay Howard Liu Lin Zhao Rio Watson Sophia Vincoff Tianlai Chen Kseniia Kholina Shrey Goel Matthew P. DeLisa Pranam Chatterjee Programmable protein stabilization with language model-derived peptide guides Nature Communications |
| title | Programmable protein stabilization with language model-derived peptide guides |
| title_full | Programmable protein stabilization with language model-derived peptide guides |
| title_fullStr | Programmable protein stabilization with language model-derived peptide guides |
| title_full_unstemmed | Programmable protein stabilization with language model-derived peptide guides |
| title_short | Programmable protein stabilization with language model-derived peptide guides |
| title_sort | programmable protein stabilization with language model derived peptide guides |
| url | https://doi.org/10.1038/s41467-025-58872-6 |
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