| Autor: |
Linyao Fan, Yingqiu Qi, Xi Yang, Yarui Xu, Yana Zhang, Longdi Wang, Anying Zhu, Lirong Zhang, Jian Song, Shengnan Du, Guangjun Nie, Huan Min |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
|
| Zdroj: |
Asian Journal of Pharmaceutical Sciences, Vol 19, Iss 4, Pp 100941- (2024) |
| Druh dokumentu: |
article |
| ISSN: |
1818-0876 |
| DOI: |
10.1016/j.ajps.2024.100941 |
| Popis: |
Leucine-rich α-2 glycoprotein 1 (LRG1), a secreted glycoprotein, has been identified as significantly upregulated in renal fibrosis, potentially exacerbating the condition by enhancing TGF-β-Smad3-dependent signaling pathways. Herein, utilizing our developed LRG1-targeting peptide for LRG1 recruitment and lenalidomide for E3 ubiquitin ligase engagement, we developed an advanced proteolysis targeting chimera, ETTAC-2, specifically designed for LRG1 degradation. Our cellular degradation assays validated that ETTAC-2 effectively degraded LRG1 through a proteasome-dependent mechanism, achieving half-maximal degradation at a concentration of 8.38 µM. Furthermore, anti-fibrotic experiments conducted both in vitro and in vivo revealed that ETTAC-2 efficiently induced LRG1 degradation in fibrotic kidneys. This action effectively inhibited the TGF-β-Smad3 signaling pathway and diminished the secretion of fibrosis-associated proteins, consequently attenuating the progression of renal fibrosis. Our study highlights the pivotal role of LRG1 in renal fibrosis and positions ETTAC-2 as a promising therapeutic candidate for targeted LRG1 intervention. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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