Engineered fibrotic liver-targeted truncated transforming growth factor β receptor type II variant for superior anti-liver fibrosis therapy

IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL Archives of Pharmacal Research Pub Date : 2023-03-11 DOI:10.1007/s12272-023-01435-4
Manman Ma, Xiaohua Wang, Xiaohui Liu, Yang Han, Yanhui Chu, Yanzhong Guan, Haifeng Liu
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引用次数: 2

Abstract

Truncated transforming growth factor β receptor type II (tTβRII) is a promising anti-liver fibrotic candidate because it serves as a trap for binding excessive TGF-β1 by means of competing with wild type TβRII (wtTβRII). However, the widespread application of tTβRII for the treatment of liver fibrosis has been limited by its poor fibrotic liver-homing capacity. Herein, we designed a novel tTβRII variant Z-tTβRII by fusing the platelet-derived growth factor β receptor (PDGFβR)-specific affibody ZPDGFβR to the N-terminus of tTβRII. The target protein Z-tTβRII was produced using Escherichia coli expression system. In vitro and in vivo studies showed that Z-tTβRII has a superior specific fibrotic liver-targeting potential via the engagement of PDGFβR-overexpressing activated hepatic stellate cells (aHSCs) in liver fibrosis. Moreover, Z-tTβRII significantly inhibited cell migration and invasion, and downregulated fibrosis- and TGF-β1/Smad pathway-related protein levels in TGF-β1-stimiluated HSC-T6 cells. Furthermore, Z-tTβRII remarkably ameliorated liver histopathology, mitigated the fibrosis responses and blocked TGF-β1/Smad signaling pathway in CCl4-induced liver fibrotic mice. More importantly, Z-tTβRII exhibits a higher fibrotic liver-targeting potential and stronger anti-fibrotic effects than either its parent tTβRII or former variant BiPPB-tTβRII (PDGFβR-binding peptide BiPPB modified tTβRII). In addition, Z-tTβRII shows no significant sign of potential side effects in other vital organs in liver fibrotic mice. Taken together, we conclude that Z-tTβRII with its a high fibrotic liver-homing potential, holds a superior anti-fibrotic activity in liver fibrosis in vitro and in vivo, which may be a potential candidate for targeted therapy for liver fibrosis.

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工程纤维化肝靶向截断转化生长因子β受体II型变异体用于卓越的抗肝纤维化治疗
截断型转化生长因子β受体II (tTβRII)是一种很有前途的抗肝纤维化候选者,因为它通过与野生型TβRII (wtTβRII)竞争,作为结合过量TGF-β1的陷阱。然而,由于其纤维化肝归巢能力差,t - β rii在肝纤维化治疗中的广泛应用受到限制。本文通过将血小板衍生生长因子β受体(PDGFβR)特异性粘附体ZPDGFβR融合到t β rii的n端,设计了一种新的t β rii变体z -t β rii。目的蛋白Z-tTβRII通过大肠杆菌表达系统得到。体外和体内研究表明,Z-tTβRII通过参与pdgf β r-过表达的活化肝星状细胞(aHSCs)在肝纤维化中具有优越的特异性纤维化肝靶向潜力。此外,z - tt -β rii显著抑制细胞迁移和侵袭,下调TGF-β1刺激的HSC-T6细胞的纤维化和TGF-β1/Smad通路相关蛋白水平。此外,z - tt -β rii显著改善ccl4诱导的肝纤维化小鼠的肝脏组织病理学,减轻纤维化反应,阻断TGF-β1/Smad信号通路。更重要的是,z -t - β rii比其亲本t - β rii或前变体BiPPB-t - β rii (pdgf - β r结合肽BiPPB修饰的t - β rii)具有更高的纤维化肝靶向潜力和更强的抗纤维化作用。此外,Z-tTβRII在肝纤维化小鼠的其他重要器官中未显示出明显的潜在副作用迹象。综上所述,我们得出结论,Z-tTβRII具有高纤维化肝归巢潜力,在体外和体内对肝纤维化具有卓越的抗纤维化活性,可能是肝纤维化靶向治疗的潜在候选药物。
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来源期刊
CiteScore
13.40
自引率
9.00%
发文量
48
审稿时长
3.3 months
期刊介绍: Archives of Pharmacal Research is the official journal of the Pharmaceutical Society of Korea and has been published since 1976. Archives of Pharmacal Research is an interdisciplinary journal devoted to the publication of original scientific research papers and reviews in the fields of drug discovery, drug development, and drug actions with a view to providing fundamental and novel information on drugs and drug candidates.
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