Targeted protein degradation directly engaging lysosomes or proteasomes

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Targeted protein degradation (TPD) is a powerful therapeutic strategy to modulate protein function.
• Conventional TPD methods, such as proteolysis-targeting chimeras (PROTACs), rely on E3 ubiquitin ligase recruitment.
• There is a growing need for TPD strategies that overcome the limitations of PROTACs and target a broader range of proteins.

Purpose of the Study:

• To provide an overview of emerging TPD modalities that engage lysosomes and proteasomes directly.
• To discuss the advantages, limitations, and chemical characteristics of these novel TPD approaches.
• To explore the potential of these alternative TPD strategies for targeting intracellular, cell membrane, and extracellular proteins.

Main Methods:

• Review and analysis of current literature on TPD strategies.
• Categorization of direct lysosome- and proteasome-engaging modalities.
• Discussion of chemical composition, biochemical activity, and pharmaceutical properties of described degraders.

Main Results:

• Identification of innovative TPD strategies that do not require E3 ligase recruitment.
• Detailed examination of direct lysosome- and proteasome-engaging degradation mechanisms.
• Highlighting the potential for targeting proteins beyond the intracellular space, including cell surface and extracellular proteins.

Conclusions:

• Alternative TPD modalities offer complementary approaches to PROTACs for intracellular protein degradation.
• These novel strategies expand the druggable proteome and provide new avenues for treating diseases caused by pathologic proteins.
• Direct lysosome- and proteasome-engaging methods represent a significant advancement in TPD, broadening therapeutic possibilities.