Targeted protein degradation is an emerging direction in the field of drug research and development. 40% of human genes encode extracellular proteins or membrane proteins. The degradation of cell membrane proteins is usually done through lysosomal pathways. Therefore, lysosomal degradation pathways are also Become the main design idea for targeted degradation of membrane proteins. Lysosomal targeting chimera (LYTAC technology) is an innovative technology that can degrade cell membranes or extracellular proteins, which is conducive to the degradation of more "non-drugable" targets.
The use of relatively non-specific lysosomal degradation pathways to selectively degrade target proteins greatly expands the range of targets. LYTAC uses glycan tags to label extracellular proteins to target lysosomes for degradation. First, let's understand what is a lysosome. The lysosome is a dynamic structure. The shape and size of the lysosome are different in different types of cells. It is generally spherical vesicles with a diameter of 0.25~0.8μm and contains a variety of acid hydrolases, which can decompose various exogenous or endogenous macromolecular substances. So the lysosome is likened to the "enzyme warehouse" and "digestive system" in the cell.
The main function of functional lysosomes is digestion, and the source of digestive substrates can be in the following three ways:
(1) Autophagy, which is the original substance in the cell;
(2) Harmful substances swallowed by phagosomes;
(3) Nutrients entered into the cell.
In addition to phagocytosis and digestion, lysosomes also have autolysis, that is, certain cells that are about to senescence can digest themselves by releasing various hydrolytic enzymes from lysosome rupture. In addition, the enzymes in the lysosome can also be released outside the cell to digest the extracellular matrix.
Some experts pointed out that the lysosome pathway can theoretically degrade various biological macromolecules and even organelles. On the other hand, the lysosome can also degrade proteins that are originally degraded by the proteasome. Therefore, the lysosomal targeted degradation technology may theoretically degrade various disease-related substances such as various pathogenic proteins, protein aggregates, DNA/RNA, organelles, pathogens, lipids, and peroxisomes. LYTAC technology mainly uses the endosome-lysosome pathway, so it is suitable for extracellular proteins and cell membrane proteins.
The target of PROTAC is usually intracellular proteins. Medicilon’s PROTAC drug discovery technology platform summarizes the currently popular and popular target protein ligands; it has established a wide range of popular target proteins with high affinity small molecules and small molecule fragment compound libraries (TPSM). ), a wide range of E3 ligase high-affinity small molecules and small molecule fragments (E3SM); a linker system has been established, including the collection of a large number of bifunctional linkers (BF-Linker) with wide diversity. These accumulated compound libraries can help quickly and efficiently synthesize a large number of highly active PTROTAC bispecific small molecules, which greatly improves the drug development process using PROTAC technology.
LYTAC technology uses the mechanism of cell degradation of proteins to degrade proteins outside the cell or on the cell membrane. The principle is: LYTAC molecule is a bifunctional molecule composed of an oligosaccharide peptide group (which can interact with cell surface receptors). CI-M6PR is combined, CI-M6PR is also called IGF2R) and an antibody that binds to a specific transmembrane protein or extracellular protein (this antibody can also be composed of a small protein binding molecule). When the LYTAC molecule binds to CI-M6PR and the target protein at the same time, the resulting complex is swallowed by the cell membrane to form a transport vesicle, and then this complex is carried to the lysosome, and then the target protein is lysosome Body degradation.
The advantage of LYTAC technology is that it uses the universally expressed endogenous degradation pathway to degrade extracellular proteins and membrane proteins. The main disadvantage is that the molecular weight is large and the antibodies or peptides in the molecule may induce immune responses. At present, the technology is relatively new, and a lot of further verification and mechanism analysis work is needed.