Development of inhibitors in the ubiquitination cascade.
The ubiquitin proteasome system (UPS) is essential in regulating myriad aspects of protein functions. It is therefore a fundamentally important regulatory mechanism that impacts most if not all aspects of cellular processes. Indeed, malfunction of UPS components is implicated in human diseases such as neurodegenerative and immunological disorders and many cancers. The success of proteasome inhibitors in cancer therapy suggests that modulating enzymes in the ubiquitination cascade would be clinically important for therapeutic benefits. In this review, we summarize advances in developing inhibitors of a variety of UPS components. In particular, we highlight recent work done on the protein engineering of ubiquitin as modulators of the UPS, a novel approach that may shed light on innovative drug discovery in the future.
Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, University of Toronto, 160 College Street, Toronto, Ontario M5S3E1, Canada; Department of Molecular Genetics, University of Toronto, 160 College Street, Toronto, Ontario M5S3E1, Canada.
Wei
W
Zhang
Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, University of Toronto, 160 College Street, Toronto, Ontario M5S3E1, Canada; Department of Molecular Genetics, University of Toronto, 160 College Street, Toronto, Ontario M5S3E1, Canada. Electronic address: sachdev.sidhu@utoronto.ca.
Sachdev S
SS
Sidhu
D000818:Animals; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000494:pharmacology; D054875:Ubiquitination / Q000187:drug effects*; D014452:Ubiquitins / Q000037:antagonists & inhibitors / Q000378:metabolism
D061988:Proteasome Inhibitors; D054852:Small Molecule Libraries; D014452:Ubiquitins; D046988:Proteasome Endopeptidase Complex
Deubiquitinating enzyme (DUB); Phage display; Protein engineering; Small molecule; Ubiquitin variant (Ubv); Ubiquitination