Ubiquitin-like protein conjugation and the ubiquitin-proteasome system as drug targets

Nat Rev Drug Discov. 2011 Jan;10(1):29-46. doi: 10.1038/nrd3321. Epub 2010 Dec 10.


The ubiquitin-proteasome system (UPS) and ubiquitin-like protein (UBL) conjugation pathways are integral to cellular protein homeostasis. The growing recognition of the fundamental importance of these pathways to normal cell function and in disease has prompted an in-depth search for small-molecule inhibitors that selectively block the function of these pathways. However, our limited understanding of the molecular mechanisms and biological consequences of UBL conjugation is a significant hurdle to identifying drug-like inhibitors of enzyme targets within these pathways. Here, we highlight recent advances in understanding the role of some of these enzymes and how these new insights may be the key to developing novel therapeutics for diseases including immuno-inflammatory disorders, cancer, infectious diseases, cardiovascular disease and neurodegenerative disorders.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Drug Delivery Systems*
  • Drug Design
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Proteasome Endopeptidase Complex / metabolism*
  • Ubiquitin / metabolism*
  • Ubiquitins / metabolism*


  • Enzyme Inhibitors
  • Ubiquitin
  • Ubiquitins
  • Proteasome Endopeptidase Complex