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Targeted degradation of LRG1 to attenuate renal fibrosis.

Authors :
Linyao Fan
Yingqiu Qi
Xi Yang
Yarui Xu
Yana Zhang
Longdi Wang
Anying Zhu
Lirong Zhang
Jian Song
Shengnan Du
Guangjun Nie
Huan Min
Source :
Asian Journal of Pharmaceutical Sciences. Aug2024, Vol. 19 Issue 4, p1-15. 15p.
Publication Year :
2024

Abstract

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, ET TAC-2, specifically designed for LRG1 degradation. Our cellular degradation assays validated that ET TAC-2 effectively degraded LRG1 through a proteasome-dependent mechanism, achieving halfmaximal degradation at a concentration of 8.38 μM. Furthermore, anti-fibrotic experiments conducted both in vitro and in vivo revealed that ET TAC-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 ET TAC-2 as a promising therapeutic candidate for targeted LRG1 intervention. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
18180876
Volume :
19
Issue :
4
Database :
Academic Search Index
Journal :
Asian Journal of Pharmaceutical Sciences
Publication Type :
Academic Journal
Accession number :
179548148
Full Text :
https://doi.org/10.1016/j.ajps.2024.100941