Redefining the Scope of Targeted Protein Degradation: Translational Opportunities in Hijacking the Autophagy–Lysosome Pathway

Abstract

The advent of multi-specific targeted protein degradation (TPD) therapies has made it possible to drug targets that have long been considered to be inaccessible. For this reason, the foremost TPD modalities - molecular glues and proteolysis targeting chimeras (PROTACs) -have been widely adopted and developed in therapeutic programs across the pharmaceutical and biotechnology industries. While there are many clear advantages to these two approaches, there are also blind spots. Specifically, PROTACs and molecular glues are inherently mechanistically analogous in that targets of both are degraded via the 26s proteasome; however, not all disease-relevant targets are suitable for ubiquitin proteasome system (UPS)-mediated degradation. The alternative mammalian protein degradation pathway, the autophagy–lysosome system (or ALS), is capable of degrading targets that elude the UPS such as long-lived proteins, insoluble protein aggregates, and even abnormal organelles. Emerging TPD strategies- such as ATTEC, AUTAC, and LYTAC- take advantage of the substrate diversity of the ALS to greatly expand the clinical utility of TPD. In this Perspective, we will discuss the array of current TPD modalities, with a focus on critical evaluation of these novel ALS-mediated degradation techniques.

Rab21 Protein Is Degraded by Both the Ubiquitin-Proteasome Pathway and the Autophagy-Lysosome Pathway

“…In contrast, the autophagy-lysosome pathway is mainly recruited for digesting a variety of bulky substrates, including long-lived proteins, protein complexes, oligomers, insoluble aggregates, and even abnormal organelles [30]. These two proteolytic pathways are distinct in mechanism but are inextricably connected.…”

The Dawn of a New Era: Targeting the “Undruggables” with Antibody-Based Therapeutics

“…Catalyzed by the cascades of activation by E1, transfer by E2, and ligation by E3 of the ubiquitin molecule covalently to the lysine residues of a substrate protein, the resulting mono- or poly ubiquitinated protein could be recognized and degraded by the 26S proteasome or deubiquitinated by a DUB. , The lysosomal degradation system on the other hand, normally degrades long-lived proteins, insoluble proteins, macromolecular compounds, bacteria as well as organelles. Lysosomes are acidic organelles that can receive substances from the plasma membrane or cytoplasm through endocytosis, phagocytosis, or autophagy, then degrade and recycle them, as well as eliminate damaged organelles directly. , Current targeted protein degradation (TPD) technologies are mainly developed based on these two degradation pathways (i.e., UPS and lysosomal system), and are capable of degrading human proteins and pathogens such as viral proteins . As antibodies can be applied to a wide range of target proteins by using off-the-shelf reagents, significant progress has been made to utilize them for targeted protein degradation, and representative examples are summarized below.…”

“…Lysosomes are acidic organelles that can receive substances from the plasma membrane or cytoplasm through endocytosis, phagocytosis, or autophagy, then degrade and recycle them, as well as eliminate damaged organelles directly. 407,408 Current targeted protein degradation (TPD) technologies are mainly developed based on these two degradation pathways (i.e., UPS and lysosomal system), and are capable of degrading human proteins and pathogens such as viral proteins. 37 As antibodies can be applied to a wide range of target proteins by using off-the-shelf reagents, significant progress has been made to utilize them for targeted protein degradation, and representative examples are summarized below.…”

Progress and Challenges in Targeted Protein Degradation for Neurodegenerative Disease Therapy

“…Autophagosome-tethering compound is an autophagy-mediated TPD method. ATTEC molecules can bind the autophagic protein LC3 on the surface of the autophagy membrane to the target protein, thereby degrading the target protein through the autophagy pathway . The molecular structure of an ATTEC is more like a molecular glue than a PROTAC.…”