Programmable Protein Stabilization with Language Model-Derived Peptide Guides.

Autor:	Hong L; Department of Biomedical Engineering, Duke University., Ye T; Robert F. Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY, USA., Wang TZ; Department of Biomedical Engineering, Duke University., Srijay D; Department of Biomedical Engineering, Duke University., Zhao L; Department of Biomedical Engineering, Duke University., Watson R; Department of Biomedical Engineering, Duke University., Vincoff S; Department of Biomedical Engineering, Duke University., Chen T; Department of Biomedical Engineering, Duke University., Kholina K; Department of Biomedical Engineering, Duke University., Goel S; Department of Biomedical Engineering, Duke University., DeLisa MP; Robert F. Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY, USA.; Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA.; Cornell Institute of Biotechnology, Cornell University, Ithaca, NY, USA., Chatterjee P; Department of Biomedical Engineering, Duke University.; Department of Computer Science, Duke University.; Department of Biostatistics and Bioinformatics, Duke University.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2024 Jul 26. Date of Electronic Publication: 2024 Jul 26.
DOI:	10.21203/rs.3.rs-4670386/v1
Abstrakt:	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. Competing Interests: Competing Interests Statement P.C., L.H., and M.P.D. are listed as inventors on US Patent Application 63/541,921: “Peptide-Guided Protein Stabilizers and Uses Thereof”. P.C. and M.D. are co-founded of UbiquiTx, Inc., which commercializes genetically-encoded proteome editing technologies, and are co-inventors of duAb patents. P.C.’s interests are reviewed and managed by Duke University in accordance with their conflict-of-interest policies. M.P.D.’s interests are reviewed and managed by Cornell University in accordance with their conflict-of-interest policies.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu