Fan Linyao, Qi Yingqiu, Yang Xi, Xu Yarui, Zhang Yana, Wang Longdi, Zhu Anying, Zhang Lirong, Song Jian, Du Shengnan, Nie Guangjun, Min Huan
Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou 450003, China.
Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
Asian J Pharm Sci. 2024 Aug;19(4):100941. doi: 10.1016/j.ajps.2024.100941. Epub 2024 Jul 10.
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, TAC-2, specifically designed for LRG1 degradation. Our cellular degradation assays validated that TAC-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 and revealed that 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 TAC-2 as a promising therapeutic candidate for targeted LRG1 intervention.
富含亮氨酸的α-2糖蛋白1（LRG1）是一种分泌型糖蛋白，已被确定在肾纤维化中显著上调，可能通过增强转化生长因子-β（TGF-β）-Smad3依赖的信号通路而加重病情。在此，我们利用开发的靶向LRG1的肽来募集LRG1，并利用来那度胺参与E3泛素连接酶作用，开发了一种先进的蛋白酶靶向嵌合体TAC-2，专门设计用于降解LRG1。我们的细胞降解试验证实，TAC-2通过蛋白酶体依赖机制有效降解LRG1，在浓度为8.38 μM时达到最大降解量的一半。此外，在体内和体外进行的抗纤维化实验表明，TAC-2能有效诱导纤维化肾脏中的LRG1降解。这一作用有效抑制了TGF-β-Smad3信号通路，减少了纤维化相关蛋白的分泌，从而减缓了肾纤维化的进展。我们的研究突出了LRG1在肾纤维化中的关键作用，并将TAC-2定位为LRG1靶向干预的有前景的治疗候选物。
