Fig. 1

Targeted degradation via five distinct degradation pathways. (A) Proteasome pathway. Molecule glue is a monovalent small molecule degrader that employs a single interaction with the POI or an E3 ligase, whereas PROTAC, hydrophobic tags (HyT), and SNIPER are chimeric molecules that simultaneously bind to the POI and the E3 ubiquitin ligase. These degraders enable POI ubiquitination and subsequent proteasomal degradation. TRIM-away system consists of an antibody and TRIM21. TRIM21, an E3 ligase recognizing the Fc fragment of an antibody, can facilitate the antibody-POI complex or antibody-bound pathogens to the proteasome for degradation. (B) Endosome-lysosome pathway. AbTAC, LYTAC, bispecific aptamer chimeras, GlueTAC, sweeping antibody, and Seldegs develop an ‘outside-in’ strategy to shutter extracellular/membrane POIs to the endosome and undergo lysosomal degradation. (C) Autophagy-lysosome pathway. AUTAC, ATTEC, and AUTOTAC, also chimeric molecules, link the intracellular substrate and adaptor proteins (e.g. LC3, p62) or autophagosome, which was fused with lysosome and processed to degradation. CMA-based degraders degrade membrane/intracellular proteins by harnessing chaperone-mediated autophagy (CMA), rather than macroautophagy. (D) Ribonuclease pathway. RIBOTAC is a targeted RNA degradation technology, which recruits a nuclease to a specific RNA and triggers its collapse. (E) ClpCP proteases pathway (bacterial degradation machinery). BacPROTAC tethers the target bacterial protein to the ClpC:ClpP protease and then primes the neo-substrates for degradation. The figure was created in BioRender.com