Application of protein knockdown strategy targeting β-sheet structure to multiple disease-associated polyglutamine proteins
| Autor: | Minoru Ishikawa, Kenji Ohgane, Sayaka Nomura, Yuichi Hashimoto, Hiroko Yamashita, Shusuke Tomoshige |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Ataxia
Huntingtin Clinical Biochemistry Mutant Pharmaceutical Science 01 natural sciences Biochemistry Structure-Activity Relationship Atrophy Drug Discovery medicine Humans Ataxin-3 Molecular Biology Gene Cells Cultured Ataxin-7 Gene knockdown Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry Neurodegenerative Diseases Polyglutamine tract Fibroblasts medicine.disease 0104 chemical sciences Cell biology Repressor Proteins 010404 medicinal & biomolecular chemistry Neuroprotective Agents Molecular Medicine medicine.symptom Intracellular |
| Zdroj: | Bioorganicmedicinal chemistry. 28(1) |
| ISSN: | 1464-3391 |
| Popis: | Polyglutamine diseases are a class of neurodegenerative diseases associated with the accumulation of aggregated mutant proteins. We previously developed a class of degradation-inducing agents targeting the β-sheet-rich structure typical of such aggregates, and we showed that these agents dose-, time-, and proteasome-dependently decrease the intracellular level of mutant huntingtin with an extended polyglutamine tract, which correlates well with the severity of Huntington's disease. Here, we demonstrate that the same agents also deplete other polyglutamine disease-related proteins: mutant ataxin-3 and ataxin-7 in cells from spino-cerebellar ataxia patients, and mutant atrophin-1 in cells from dentatorubral-pallidoluysian atrophy patients. Targeting cross-β-sheet structure could be an effective design strategy to develop therapeutic agents for multiple neurodegenerative diseases. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect