Background: The proteasome is the major proteolytic site on the eukaryotic cell, degrading most of its short-lived or misfolded polypeptides. The ubiquitin-proteasome pathway has been found to play a fundamental role in the development of several pathologies, from cancer to neurodegenerative diseases, or even retroviral infections. Nature remains a powerful source for the discovery of bioactive compounds. Recently, a number of molecules of natural origin, as well as natural product derivatives, have been described as proteasome inhibitors. Most of these molecules directly block one or more catalytic sites of the 20S proteasome, but some of them act upstream of proteolytic degradation, for instance, inhibiting the ubiquitin tagging process.
Objectives: The present review focuses on recent patents on proteasome inhibitors of natural origin, their derivatives and synthetic routes to obtain such molecules, as well as their application as a tool in chemotherapy.
Conclusion: With several of these modulators of the ubiquitin-proteasome system under clinical trials, we hope that the next few years lead to the development of new pharmaceutical drugs and characterization of new proteasome inhibitors of natural origin or inspiration.
Keywords: Marine-derived natural products; proteasome inhibitors; proteostasis; proteotoxicity; terrestrial-derived natural products; ubiquitin-proteasome system.
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