The role of reversible and irreversible covalent chemistry in targeted protein degradation

Proteolysis-targeting chimeras (PROTACs) that degrade disease-causing proteins by hijacking the endogenous ubiquitin-proteasome system have emerged as an exciting and transformative technology in both chemical biology drug discovery. Currently, majority of PROTACs use reversible non-covalent ligands for target protein interest (POI) E3 ligase. In this review, we explore burgeoning role irreversible covalent chemistry targeted degradation. We highlight key advantages inhibitors, whether POI or ligase ligand, such their ability to enhance selectivity PROTACs, enable access more “undruggable” proteome expand repertoire recruited ligases. The medicinal properties natural products isolated from plants, microbes, other organisms been harnessed humans thousands years continue influence modern discovery today. 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