Programmable protein stabilization with language model-derived peptide guides

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 and Pranam Chatterjee ()
Additional contact information
Lauren Hong: Duke University
Tianzheng Ye: Cornell University
Tian Z. Wang: Duke University
Divya Srijay: Duke University
Howard Liu: Duke University
Lin Zhao: Duke University
Rio Watson: Duke University
Sophia Vincoff: Duke University
Tianlai Chen: Duke University
Kseniia Kholina: Duke University
Shrey Goel: Duke University
Matthew P. DeLisa: Cornell University
Pranam Chatterjee: Duke University

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: 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.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-58872-6 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58872-6

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-58872-6

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().