摘要 |
The drug action mechanisms and core techniques of the present invention are summarized in figure 1. Specifically, malignant denatured proteins, such as mutant Huntingtin protein or α-synuclein, stick together to grow into oligomer aggregates (①, ②), fibrillar aggregates (③), and ultimately inclusion bodies (④). Young neuronal cells produce a large quantity of Nt-Arg through N-terminal arginylation (⑤) of endoplasmic reticulum chaperones, such as BiP, and thereafter, arginylated BiP (R-BiP) comes into the cytoplasm and binds with denatured proteins (⑥). Nt-Arg of R-BiP, as a ligand, binds with the ZZ domain of p62 (⑦) to induce the structural activation of p62 (⑧) while the ordinarily closed inactive form of p62 is changed with an open form thereof, and thus PB1 and LC3-binding domains are exposed. On the basis of oligomerization (⑨) by the PB1 domain, p62 binds with the denatured protein aggregates to be concentrated to autophagically degradable aggregates, that is, p62 bodies (⑩). Thereafter, p62 completes autophagy targeting (⑪) and lysosomal proteolysis through binding with LC3 protruding on the autophagosomal membranes. In young neuronal cells, the autophagic proteolysis occurring through steps ⑤-⑪ is strong, and thus the cytotoxic protein aggregates (①-⑤) do not accumulate, but in aged neuronal cells, the autophagic proteolysis occurring through steps ⑤-⑪ is weakened, and thus the protein aggregates (①-⑤) accumulate, resulting in a vicious cycle. The present invention attempts to effectively remove Huntingtin and α-synuclein protein aggregates and the like by artificially activating p62 using low-mass ligands of the p62 ZZ domain (⑫, ⑬). Specifically, p62 binding the ligands through step ⑫ promotes p62-R-BiP-denatured protein oligomerization (⑨) and autophagy aggregate formation (⑩). In addition, the ligand-62 conjugates step ⑬ act as autophagy activators (⑭), to promote LC3 synthesis, the conversion of LC3-I into LC3-II, and the like, thereby promoting the formation of autophagosomes (⑮). |
申请人 |
SEOUL NATIONAL UNIVERSITY R&DB FOUNDATION;KOREA RESEARCH INSTITUTE OF BIOSCIENCE AND BIOTECHNOLOGY |
发明人 |
KWON, Yong Tae;KIM, Bo Yeon;CHA, Hyunjoo;YOO, Young Dong;YU, Ji-eun |