Pharmacological Modulation of the N-End Rule Pathway and Its Therapeutic Implications

The N-end rule pathway is a proteolytic system in which single N-terminal amino acids of short-lived substrates determine their metabolic half-lives. Substrates of this pathway have been implicated in the pathogenesis of many diseases, including malignancies, neurodegeneration, and cardiovascular disorders. This review provides a comprehensive overview of current knowledge about the mechanism and functions of the N-end rule pathway. Pharmacological strategies for the modulation of target substrate degradation are also reviewed, with emphasis on their in vivo implications. Given the rapid advances in structural and biochemical understanding of the recognition components (N-recognins) of the N-end rule pathway, small-molecule inhibitors and activating ligands of N-recognins emerge as therapeutic agents with novel mechanisms of action.