Degradation of huntingtin mediated by a hybrid molecule composed of IAP antagonist linked to phenyldiazenyl benzothiazole derivative
| Autor: | Minoru Ishikawa, Yuichi Hashimoto, Shusuke Tomoshige, Kenji Ohgane, Sayaka Nomura |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
congenital hereditary and neonatal diseases and abnormalities Huntingtin Clinical Biochemistry Mutant Pharmaceutical Science Protein aggregation Ligands Inhibitor of apoptosis Biochemistry Inhibitor of Apoptosis Proteins 03 medical and health sciences Ubiquitin mental disorders Drug Discovery Humans Benzothiazoles Molecular Biology Huntingtin Protein biology Chemistry Organic Chemistry Fibroblasts Ligand (biochemistry) Small molecule Ubiquitin ligase Cell biology 030104 developmental biology biology.protein Molecular Medicine Oligopeptides Protein Binding |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 28:707-710 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2018.01.012 |
| Popis: | Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by aggregation of mutant huntingtin (mHtt), and removal of mHtt is expected as a potential therapeutic option. We previously reported protein knockdown of Htt by using hybrid small molecules (Htt degraders) consisting of BE04, a ligand of ubiquitin ligase (E3), linked to probes for protein aggregates. Here, in order to examine the effect of changing the ligand, we synthesized a similar Htt degrader utilizing MV1, an antagonist of the inhibitor of apoptosis protein (IAP) family (a subgroup of ubiquitin E3 ligases), which is expected to have a higher affinity and specificity for IAP, as compared with BE04. The MV1-based hybrid successfully induced interaction between Htt aggregates and IAP, and reduced mHtt levels in living cells. Its mode of action was confirmed to be the same as that of the BE04-based hybrid. However, although the affinity of MV1 for IAP is greater than that of BE04, the efficacy of Htt degradation by the MV1-based molecule was lower, suggesting that linker length between the ligand and probe might be an important determinant of efficacy. |
| Databáze: | OpenAIRE |
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