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LYTAC technology, a lysosomal degradation technology

2021-04-28
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Targeted protein degradation is an emerging direction in the field of drug development. 40% of human genes encode extracellular proteins or membrane proteins. The degradation of cell membrane proteins is usually accomplished through lysosomal pathways. lysosome targeting chimeras lytacs (Lytac technology) are an innovative technology that degrades cell membrane or extracellular proteins, enabling degradation of more “non-prescriptable” targets.

The use of relatively non-specific lysosomal degradation pathways to selectively degrade target proteins greatly expands the range of targets. LYTAC technology 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. Generally, it is 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 digestion substrates can be in the following three ways:

(1) Autophagocytosis, phagocytosis is the original material in the cell;

(2) the harmful substances consumed by the phagosome;

(3) Nutrients entered into the cell.

In addition to the function of phagocytosis and digestion, lysosomes also have the function of autolysis, that is, some soon-to-be senescent cells digest themselves by releasing various hydrolases by lysosome rupture.In addition, enzymes in lysosomes can also be released extracellular for digestion of the extracellular matrix.

Some experts pointed out that the lysosome pathway can theoretically degrade various biological macromolecules and even organelles. On the other hand, lysosomes 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 disease-causing 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 protein. 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); the 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 achieve degradation of 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). Combine with CI-M6PR, CI-M6PR is also called IGF2R) and an antibody that binds to a specific transmembrane protein or extracellular protein (this antibody can also consist 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, 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.

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