PRÉVENTION ET TRAITEMENT DE MALADIES NEURODÉGÉNÉRATIVES PAR ACTIVITÉ AUTOPHAGIQUE INDUITE PAR LIGAND OU PAR BIP ARGINYLÉE SE LIANT AU DOMAINE ZZ DE P62
Seoul National University R&DB Foundation;Korea Research Institute of Bioscience and Biotechnology
发明人:
申请号：
EP16837234.0
公开号：
EP3338787A1
申请日:
2016.07.15
申请国别(地区):
EP
年份:
2018
代理人:
摘要：
The pharmacokinetics and key technologies of the present invention are summarized in Figure 1. Particularly, malignant misfolded proteins such as mutant huntingtin and alpha-synuclein are coagulated and grow into oligomeric coagulum (①, ②), fibrillar coagulum (③) and eventually inclusion body (④). Young neurons produce a large amount of Nt-Arg through N-terminal arginylation (⑤) of vesicle chaperones such as BiP secreted into the cytoplasm, and then arginylated BiP (R-BiP) is secreted binds to the misfolded proteins (⑥). As a ligand, the Nt-Arg of R-BiP binds to the p62 ZZ domain (⑦), and the normally inactivated closed form of p62 is changed to an open form, leading to structural activation (⑧). As a result, PB1 and LC3-binding domains are exposed. The PB1 domain induces oligomerization (⑨), leading to the concentration as a p62 body (⑩) that is a coagulum capable of being degraded by autophagy. Then, p62 binds to LC3, which is protruding from the autopagosomal membranes, leading to the completion of autophagy targeting (⑪) and lysosomal proteolysis. Since autophagy proteolysis including steps ⑤-⑪ is strong in young neurons, cytotoxic protein coagulums (①-⑤) do not accumulate. However in aged neurons, autophagy proteolysis including steps ⑤-⑪ is weakened, and protein coagulums (①-⑤) accumulate and become cytotoxic. In this invention, p62 is intentionally activated (⑫, ⑬) by using low mass ligands of the p62 ZZ domain to effectively remove huntingtin and alpha-synuclein protein coagulums. Particularly, in step ⑫, p62 ligated with a ligand accelerates the oligomerization of p62-R-BiP-misfolded protein (⑨) and the formation of autophagy coagulum (⑩). In step ⑬, the ligand-p62 conjugate acts as an autophagy activator (⑭) to induce the synthesis of LC3 and the conversion of LC3-I into LC3-II in order to accelerate the formation of autophagosomes (⑮).
