Research Progress of Targeted Protein Degradation Technology

Posted by Ellen Burns on January 14th, 2022

The mode of action of currently developed drugs is mostly to achieve the purpose of disease treatment by inhibiting or enhancing the activity of target proteins. However, these drugs have to bind to the active site of target proteins to work. Among the known drug target proteins, only about 20% of the target proteins contain bindable active site, and 80% of the target proteins are non-druggable targets. How to develop drugs by acting on the vast majority of non-druggable targets has become the research and development focus of many companies, and the most current research is to control the gene level of these targets using nucleic acid drugs or gene therapy to achieve the purpose of controlling the target protein level.

In recent years, the development of protein-targeted degradation technology based on intracellular protein degradation pathways has become a new hot direction for drug research and development. The study of protein degradation technology makes many known non-druggable targets druggable targets and hopefully overcomes the problem of drug resistance. The study of protein-targeted degradation technology is mainly used to remove specific tumor proteins, and great breakthroughs have also been made in the study of autoimmune diseases and other treatments.

Intracellular protein degradation pathways are mainly lysosomal pathways and ubiquitin-proteasome system (UPS). Among them, the ubiquitin-proteasome system is the main pathway of protein degradation in vivo, and 80% of proteins in vivo are degraded through this pathway. Therefore, the research related to protein degradation technology is also mainly carried out around this pathway, and the progress of related projects is also faster.

Proteolysis-Targeting Chimera, a protein degradation technology based on the ubiquitin-proteasome system, is currently the most well-known and studied. PROTAC is generally composed of three parts: a target protein-binding ligand, an E3 ligase-binding ligand, and a Linker that links the two. PROTAC binds to target proteins and E3 ligases through its two ligands, respectively, linking the two together, thereby initiating the ubiquitination process to degrade proteins, and the released PROTAC will continue to repeat the degradation process of the next protein.

The discovery of PROTAC technology has attracted many scientific research institutions to carry out related research. A number of researchers who have studied early and achieved certain results have begun to start a business, and the layout has also been intensified in various ways.

Molecular gel is another well-studied technology of ubiquitin-proteasome system in addition to PROTAC technology. Such technology is a small molecule that closes the distance between E3 ubiquitin ligase and target protein by specifically mediating the interaction between protein and protein, realizing the ubiquitination and degradation of protein. The study of molecular glue is earlier than PROTAC technology. Unlike PROTAC, molecular glue is a single molecule with a smaller molecular weight than PROTAC. Linker is not required to connect the two molecules to play a role, but the design of molecular glue is also difficult.

Since the degradation target proteins of the ubiquitin-proteasome system are mainly intracellular proteins, the degradation of membrane proteins, endocytosed extracellular proteins, organelles, and protein multimers is usually accomplished through the lysosomal pathway. Therefore, the study of relevant technologies based on the lysosomal pathway is complementary to the ubiquitin-proteasome system. Lysosomal pathways, including endosomal/lysosomal pathways and autophagic pathways, have been developed with related technologies.

Endosomal/lysosomal pathway: it is the transport of target proteins to lysosomes for degradation by endocytosis. The reported technologies mainly include lysosome targeting chimaeras (LYTAC). LYTAC system is a system that uses cell surface lysosome targeting receptors (LTRs) -mediated protein transport to lysosomes. LYTAC consists of two parts, one is specific antibody or small molecule bound to target protein, and the other is long chain that can bind to LTRs (such as long chain containing oligomannose 6-phosphate), which can ensure that target protein can be mediated by LTR into lysosome degradation.

Autophagy pathway: It transports target proteins to lysosomes for degradation through autophages, mainly including autophagy-targeting chimera (AUTAC) and autophagosome-tethering compound (ATTEC).

The research and application of protein degradation technology provides a new research direction for drug research and development, especially compared with traditional small molecules and antibody drugs, which helps to solve many problems facing current drug research. With the deepening of the research on the mechanism of protein degradation pathway, there will be a great breakthrough in assisted protein degradation technology. Once the products that have been clinically studied are successfully marketed, it is very likely to detonate the development of protein degradation technology.