Design of a highly potent GLP-1R and GCGR dual-agonist for recovering hepatic fibrosis.

Nazi Song; Hongjiao XU; Jiahua Liu; Qian Zhao; Hui Chen; Zhibin Yan; Runling Yang; Zhiteng Luo; Qi Liu; Jianmei Ouyang; Shuohan WU; Suijia Luo; Shuyin YE; Runfeng Lin; Xi Sun; Junqiu Xie; Tian Lan; Zhongdao WU; Rui Wang; Xianxing Jiang

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Design of a highly potent GLP-1R and GCGR dual-agonist for recovering hepatic fibrosis.

Author: Nazi SONG ¹ ; Hongjiao XU ¹ ; Jiahua LIU ² ; Qian ZHAO ¹ ; Hui CHEN ¹ ; Zhibin YAN ³ ; Runling YANG ³ ; Zhiteng LUO ¹ ; Qi LIU ⁴ ; Jianmei OUYANG ⁴ ; Shuohan WU ¹ ; Suijia LUO ⁴ ; Shuyin YE ⁴ ; Runfeng LIN ¹ ; Xi SUN ² ; Junqiu XIE ³ ; Tian LAN ⁵ ; Zhongdao WU ² ; Rui WANG ³ ; Xianxing JIANG ¹
Author Information

1. School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Sun Yat-sen University, Guangzhou 510006, China.
2. Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510006, China.
3. Research Unit of Peptide Science, Chinese Academy of Medical Sciences, Lanzhou 730000, China.
4. Shenzhen Turier Biotech. Co., Ltd., Shenzhen 518118, China.
5. Guangdong Pharmaceutical University, Guangzhou 510006, China.
Publication Type:Journal Article
Keywords: Apoptosis; Candidate peptides; GCGR; GLP-1R; Inflammation; Liver fibrosis
From: Acta Pharmaceutica Sinica B 2022;12(5):2443-2461
CountryChina
Language:English
Abstract: Currently, there is still no effective curative treatment for the development of late-stage liver fibrosis. Here, we have illustrated that TB001, a dual glucagon-like peptide-1 receptor/glucagon receptor (GLP-1R/GCGR) agonist with higher affinity towards GCGR, could retard the progression of liver fibrosis in various rodent models, with remarkable potency, selectivity, extended half-life and low toxicity. Four types of liver fibrosis animal models which were induced by CCl₄, α-naphthyl-isothiocyanate (ANIT), bile duct ligation (BDL) and Schistosoma japonicum were used in our study. We found that TB001 treatment dose-dependently significantly attenuated liver injury and collagen accumulation in these animal models. In addition to decreased levels of extracellular matrix (ECM) accumulation during hepatic injury, activation of hepatic stellate cells was also inhibited via suppression of TGF-β expression as well as downstream Smad signaling pathways particularly in CCl₄-and S. japonicum-induced liver fibrosis. Moreover, TB001 attenuated liver fibrosis through blocking downstream activation of pro-inflammatory nuclear factor kappa B/NF-kappa-B inhibitor alpha (NFκB/IKBα) pathways as well as c-Jun N-terminal kinase (JNK)-dependent induction of hepatocyte apoptosis. Furthermore, GLP-1R and/or GCGR knock-down results represented GCGR played an important role in ameliorating CCl₄-induced hepatic fibrosis. Therefore, TB001 can be used as a promising therapeutic candidate for the treatment of multiple causes of hepatic fibrosis demonstrated by our extensive pre-clinical evaluation of TB001.