Indirect ubiquitination developed by the University of Tokyo enables novel drug design

With the goal of degrading target proteins using the body's biological systems, a research group led by Professor Akimitsu Okamoto of the Graduate School of Engineering at the University of Tokyo and Professor Yasushi Saeki of the Division of Protein Metabolism, the Institute of Medical Science at the same university has developed an indirect ubiquitination method. From this, for the first time in the world, a technique that induces chemical protein degradation by indirectly ubiquitinating target proteins using molecules that combine ubiquitin chains with protein-binding units was developed. These molecules can be used to target proteins that are difficult to degrade through the body's protein degradation systems, deliver these proteins to the protein degradation system, and reduce their numbers. This approach is expected to be useful for novel drug design utilizing protein degradation in the future. The research was published in Communications Chemistry.

Protein degradation methods that can induce degradation of only target proteins are drug discovery technologies that can remove disease-causing proteins from cells in conditions such as cancer and neurodegenerative diseases. Because they can target proteins that cannot be targeted by conventional methods, they are attracting attention as a revolutionary drug discovery concept that will transform medicine.

In the past, protein degradation molecule research used many PROTACs (proteolysis-targeting chimeras) utilizing endogenous ubiquitination enzyme E3 ligases. However, there were problems in that only a few types of E3 ligases could be used, and that E3 ligases easily mutate to acquire drug resistance.

The research team observed, for the first time in the world, a chemical approach that uses molecules combining ubiquitin chains with protein-binding units to "indirectly ubiquitinate target proteins and lead them to degradation," rather than directly ubiquitinating target proteins.

Chimeric molecules composed of protein-binding units (peptides or nucleic acid molecules) and ubiquitin (chains) were used by the research team to indirectly ubiquitinate target proteins (such as Bcl-2 and NF-κB) through non-covalent interactions and induce their proteasomal degradation. The ubiquitin chains used have 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 is designed to non-covalently attach ubiquitin-based proteolytic modifiers to be added to the molecular toolbox for targeted protein degradation.

Through this research, which spanned approximately three years, indirect ubiquitination molecules were synthesized and E3 ligase-independent protein degradation was confirmed. This enables drug design for even undruggable proteins that could not be targeted by conventional drug discovery methods. It is also expected to contribute to the development of new drug discovery research targeting inflammatory diseases and autoimmune diseases such as cancer, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis.

Journal Information
Publication: Communications Chemistry
Title: Indirect ubiquitination independent of endogenous ubiquitination machinery for targeted protein degradation
DOI: 10.1038/s42004-026-01895-x