4.6 Review

Ubiquitin Engineering for Interrogating the Ubiquitin-Proteasome System and Novel Therapeutic Strategies

Journal

CELLS
Volume 12, Issue 16, Pages -

Publisher

MDPI
DOI: 10.3390/cells12162117

Keywords

ubiquitin; ubiquitin variants (UbVs); ubiquitin-proteasome system (UPS); deubiquitinating enzymes (DUBs); degradation

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Protein turnover, regulated by the ubiquitin-proteasome system (UPS), is important for cellular homeostasis. Dysregulation of the UPS is associated with diseases and UPS enzymes are attractive therapeutic targets. However, redundancies of UPS enzymes make it challenging to identify precise drug targets. Engineered ubiquitin has emerged as a promising alternative to guide the development of small molecules targeting novel surfaces.
Protein turnover, a highly regulated process governed by the ubiquitin-proteasome system (UPS), is essential for maintaining cellular homeostasis. Dysregulation of the UPS has been implicated in various diseases, including viral infections and cancer, making the proteins in the UPS attractive targets for therapeutic intervention. However, the functional and structural redundancies of UPS enzymes present challenges in identifying precise drug targets and achieving target selectivity. Consequently, only 26S proteasome inhibitors have successfully advanced to clinical use thus far. To overcome these obstacles, engineered peptides and proteins, particularly engineered ubiquitin, have emerged as promising alternatives. In this review, we examine the impact of engineered ubiquitin on UPS and non-UPS proteins, as well as on viral enzymes. Furthermore, we explore their potential to guide the development of small molecules targeting novel surfaces, thereby expanding the range of druggable targets.

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