Targeted protein degradation using the lysosomal pathway. Issue 12 (25th October 2022)

• Record Type: Journal Article
• Authors: Ghosh, Samrajni; Ramadas, Bhavana; Manna, Debasish
• Is Part Of: RSC medicinal chemistry. Volume 13:Issue 12(2022)
• Page Start: 1476
• Page End: 1494
• Publication Date: 2022-10-25
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1039/d2md00273f
• Languages: English
• ISSNs: 2632-8682

Abstract

Abstract : This review provides an overview of the recent development of targeted protein degradation strategies beyond PROTACs, which utilize the lysosomal pathway to clear up extracellular, membrane and/or cytosolic proteins. Abstract : Degradation strategies have shown enormous promise after the inception of molecules like PROTACs (PRoteolysis TArgeting Chimeras) that induce the degradation of the substrate of choice rather than depending on blocking their catalytic activity like conventional inhibitory drugs. Over the past two decades, the application of PROTACs has made quite an impact, even reaching clinical translations. However, a major class of macromolecular targets, be that large proteins, aggregates, organelles or non-protein substrates, remain untouched when utilizing the ubiquitin–proteasomal pathway of degradation. In this review, we have attempted to cover modalities of targeted degradation that instead focus on recruiting the lysosomal pathway of degradation, which is gaining importance and being explored extensively as alternate and efficient approaches for treating disease-related milieus.