A research group led by Professor Akimitsu Okamoto of the Graduate School of Engineering, The University of Tokyo, and Professor Yasushi Saeki of the Institute of Medical Science, The University of Tokyo, has developed an indirect ubiquitination method.
In this study, they observed chemical protein degradation by indirectly ubiquitinating target proteins using a molecule that combines a ubiquitin chain and a protein-binding unit. By using the molecule developed by the research group to specifically target proteins that were difficult to degrade using the cell's inherent protein degradation system, these proteins can be directed into the degradation system, thereby reducing their quantity. Compared to previous studies, this research offers the advantage of being ubiquitin ligase-independent and is expected to contribute to novel drug design strategies utilizing protein degradation.
The proteolysis method, capable of inducing degradation of only targeted proteins, is a drug discovery technology that can remove disease-causing proteins from cells, such as those involved in cancer and neurodegenerative diseases. It is gaining attention as a groundbreaking drug discovery concept poised to revolutionize medicine, as it can target proteins that were previously inaccessible to conventional methods. Previous proteolysis molecular research has primarily utilized PROTACs (PROteolysis-TArgeting Chimeras) that leverage endogenous ubiquitinating enzymes, E3 ligases. However, this approach has limitations: only a few of the over 600 known E3 ligases can be used, and E3 ligases can easily mutate, leading to drug resistance.
The research team observed chemical proteolysis by indirectly ubiquitinating the target protein using a molecule that combines the ubiquitin chain and the protein-binding unit into one entity. This approach mimics the effect of direct ubiquitination. The chimeric molecule, composed of a protein-binding unit (peptide or nucleic acid molecule) and a ubiquitin chain, indirectly ubiquitinated target proteins (such as Bcl-2 and NF-κB p50) via non-covalent interactions, leading to their proteasome degradation. Furthermore, the ubiquitin chain used here possesses the characteristic of avoiding degradation by endogenous deubiquitinating enzymes by partially modifying the C-terminal sequence of ubiquitin, contributing to improved protein degradation efficiency. Indirect ubiquitination provides a design platform for non-covalently fixing ubiquitin-based protein degradation modifiers, adding them to the molecular toolbox for target protein degradation.
Through approximately three years of research, we synthesized indirect ubiquitinylation molecules and confirmed E3 ligase-independent protein degradation. This enables drug design even for “undruggable” proteins that were previously untargetable by conventional drug discovery methods. It is expected to contribute to the advancement of novel drug discovery research targeting inflammatory diseases and autoimmune disorders such as cancer, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis.
Papers
Journal: Communications Chemistry
Title: Indirect Ubiquitination Independent of Endogenous Ubiquitination Machinery for Targeted Protein Degradation
Authors: Takafumi Furuhata, Kazuki Yoshida, Ryoka Fujita, Jotaro Miyamoto, Chiharu Moriyama, Tokiha Masuda-Ozawa, Hikaru Tsuchiya, Yasushi Saeki, and Akimitsu Okamoto
DOI: 10.1038/s42004-026-01895-x
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