| 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
|
| リソース情報 |
| ヒト・動物細胞 |
NH-12(RCB2108) |
