http://rdf.ncbi.nlm.nih.gov/pubchem/patent/US-10391067-B2
Outgoing Links
| Predicate | Object |
|---|---|
| assignee | http://rdf.ncbi.nlm.nih.gov/pubchem/patentassignee/MD5_12b6ff8018d11555296aa1b6b50202a0 http://rdf.ncbi.nlm.nih.gov/pubchem/patentassignee/MD5_050fc7b82c5d17d9aeb63a7cdcc546b3 http://rdf.ncbi.nlm.nih.gov/pubchem/patentassignee/MD5_0624908c7150e45bdd907be4f162057e |
| classificationCPCAdditional | http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/Y02A50-30 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/Y02A50-401 |
| classificationCPCInventive | http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K38-16 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K38-1709 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P25-28 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K31-122 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K31-13 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K31-138 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K38-05 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K38-10 |
| classificationIPCInventive | http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/A61P25-28 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/A61K38-10 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/A61K38-05 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/A61K38-16 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/A61K31-13 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/A61K31-122 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/A61K31-138 |
| filingDate | 2016-07-15-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| grantDate | 2019-08-27-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| inventor | http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_65187474a19cea257e650e111fdf5cc1 http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_210529d5f2821398a5f989305a0d1cf8 http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_41fdcb61c671c8ffec81a8e67782194c http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_23a7c5d01c2c9dce634eb4d0e90be37e http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_a7b2973b34b2ec41a863c47664c0bc62 |
| publicationDate | 2019-08-27-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| publicationNumber | US-10391067-B2 |
| titleOfInvention | Prevention and treatment of neurodegenerative diseases through autophagy activity mediated by a synthetic ligand or arginylated BIP binding to the P62 ZZ domain |
| abstract | The pharmacokinetics and key technologies of the present invention are summarized in FIG. 1 . Particularly, malignant misfolded proteins such as mutant huntingtin and alpha-synuclein are coagulated and grow into oligomeric coagulum ({circle around (1)}, {circle around (2)}, fibrillar coagulum ({circle around (3)}) and eventually inclusion body ({circle around (4)}). Young neurons produce a large amount of Nt-Arg through N-terminal arginylation ({circle around (5)}) of vesicle chaperones such as BiP secreted into the cytoplasm, and then arginylated BiP (R-BiP) is secreted binds to the misfolded proteins ({circle around (6)}). As a ligand, the Nt-Arg of R-BiP binds to the p62 ZZ domain ({circle around (7)}), and the normally inactivated closed form of p62 is changed to an open form, leading to structural activation ({circle around (8)}). As a result, PB1 and LC3-binding domains are exposed. The PB1 domain induces oligomerization ({circle around (9)}), leading to the concentration as a p62 body ({circle around (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 ({circle around (11)}) and lysosomal proteolysis. Since autophagy proteolysis including steps ({circle around (5)})-({circle around (11)}) is strong in young neurons, cytotoxic protein coagulums ({circle around (1)}-{circle around (5)}) do not accumulate. However in aged neurons, autophagy proteolysis including steps {circle around (5)}-{circle around (11)} is weakened, and protein coagulums ({circle around (1)}-{circle around (5)}) accumulate and become cytotoxic. In this invention, p62 is intentionally activated ({circle around (12)}, {circle around (13)}) by using low mass ligands of the p62 ZZ domain to effectively remove huntingtin and alpha-synuclein protein coagulums. Particularly, in step {circle around (12)}, p62 ligated with a ligand accelerates the oligomerization of p62-R-BiP-misfolded protein ({circle around (9)}) and the formation of autophagy coagulum ({circle around (10)}). In step ({circle around (13)}), the ligand-p62 conjugate acts as an autophagy activator ({circle around (14)}) to induce the synthesis of LC3 and the conversion of LC3-I into LC3-II in order to accelerate the formation of autophagosomes ({circle around (15)}). |
| priorityDate | 2015-08-18-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| type | http://data.epo.org/linked-data/def/patent/Publication |
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