論文 - 詳細
| RRC ID | 82656 |
|---|---|
| 著者 | Dileep KV, Sakai N, Ihara K, Nakata A, Ito A, Sivaraman DM, Yip CW, Shin JW, Yoshida M, Shirouzu M, Zhang KYJ. |
| タイトル | Identification of benzimidazole-6-carboxamide based inhibitors of secretory glutaminyl cyclase for the treatment of Alzheimer's disease. |
| ジャーナル | Int J Biol Macromol |
| Abstract |
The formation of the pyroglutamate variant of amyloid beta (pGlu-Aβ), which is extremely hydrophobic, rapidly aggregating, and highly neurotoxic, is mediated by the action of secretory glutaminyl cyclase (sQC). The pGlu-Aβ often acts as a seed for the aggregation of the full length Aβ and contributes to the overall load of Aβ plaques in Alzheimer's disease (AD). Therefore, inhibiting sQC is a potential approach to limit the formation of pGlu-Aβ and to modify the progression of AD. This study presents two novel molecules containing benzimidazole-6-carboxamide, namely LSB-09 and LSB-24, as promising sQC inhibitors. These inhibitors demonstrated moderate toxicity in human neuroblastoma cell lines and possessed IC50 values in the micromolar range (40 and 4 μM for LSB-09 and LSB-24, respectively). Additionally, the X-ray crystal structure of the sQC-LSB-09 complex revealed a unique binding mode, and a systematic computational investigation elucidated the binding mode for LSB-24. The binding mode of these two benzimidazole-6-carboxamide inhibitors offers a potential platform for designing attractive lead candidates against sQC. |
| 巻・号 | 293 |
| ページ | 139320 |
| 公開日 | 2025-3-1 |
| DOI | 10.1016/j.ijbiomac.2024.139320 |
| PII | S0141-8130(24)10131-6 |
| PMID | 39740711 |
| MeSH | Alzheimer Disease* / drug therapy Alzheimer Disease* / metabolism Aminoacyltransferases* / antagonists & inhibitors Aminoacyltransferases* / chemistry Aminoacyltransferases* / metabolism Benzimidazoles* / chemistry Benzimidazoles* / pharmacology Cell Line, Tumor Enzyme Inhibitors* / chemistry Enzyme Inhibitors* / pharmacology Humans Molecular Docking Simulation Protein Binding |
| IF | 5.162 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | News |
| 各媒体での言及数の合計 | 2 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | NH-12(RCB2108) |