Discovery of zolinium TSG1180 as a novel agonist of transgelin-2 for treating asthma

Hong-Kai Yuan; Bo Li; Leyun Wu; Xue-Ling Wang; Zhi-Ying Lv; Zhikai Liu; Zhijian Xu; Jin Lu; Cai-Tao Chen; Yong-Qing Yang; Weiliang Zhu; Lei-Miao Yin

doi:10.1016/j.biopha.2023.115556

Discovery of zolinium TSG1180 as a novel agonist of transgelin-2 for treating asthma

Biomed Pharmacother. 2023 Nov:167:115556. doi: 10.1016/j.biopha.2023.115556. Epub 2023 Sep 29.

Authors

Hong-Kai Yuan¹, Bo Li², Leyun Wu², Xue-Ling Wang¹, Zhi-Ying Lv¹, Zhikai Liu³, Zhijian Xu², Jin Lu¹, Cai-Tao Chen¹, Yong-Qing Yang⁴, Weiliang Zhu⁵, Lei-Miao Yin⁶

Affiliations

¹ Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200030, China.
² Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China.
³ Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁴ Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200030, China. Electronic address: yyq@shutcm.edu.cn.
⁵ Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: wlzhu@simm.ac.cn.
⁶ Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200030, China. Electronic address: collegeylm@shutcm.edu.cn.

PMID: 37778269
DOI: 10.1016/j.biopha.2023.115556

Abstract

Asthma is a complex and heterogeneous respiratory disease that causes serious social and economic burdens. Current drugs such as β₂-agonists cannot fully control asthma. Our previous study found that Transgelin-2 is a potential target for treating asthmatic pulmonary resistance. Herein, we discovered a zolinium compound, TSG1180, that showed a strong interaction with Transgelin-2. The equilibrium dissociation constants (KD) of TSG1180 to Transgelin-2 were determined to be 5.363 × 10^-6 and 9.81 × 10^-6 M by surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC). Cellular thermal shift assay (CETSA) results showed that the thermal stability of Transgelin-2 increased after coincubation of TSG1180 with lysates of airway smooth muscle cells (ASMCs). Molecular docking showed that Arg39 may be the key residue for the binding. Then, the SPR result showed that the binding affinity of TSG1180 to Transgelin-2 mutant (R39E) was decreased by 1.69-fold. Real time cell analysis (RTCA) showed that TSG1180 treatment could relax ASMCs by 19 % (P < 0.05). Once Transgelin-2 was inhibited, TSG1180 cannot induce a relaxation effect, suggesting that the relaxation effect was specifically mediated by Transgelin-2. In vivo study showed TSG1180 effectively reduced pulmonary resistance by 64 % in methacholine-induced mice model (P < 0.05). Furthermore, the phosphorylation of Ezrin at T567 was increased by 8.06-fold, the phosphorylation of ROCK at Y722 was reduced by 38 % and the phosphorylation of RhoA at S188 was increased by 52 % after TSG1180 treatment. These results suggested that TSG1180 could be a Transgelin-2 agonist for further optimization and development as an anti-asthma drug.

Keywords: Agonist; Asthma; Ezrin; Mechanism; Molecular docking; Transgelin-2.

MeSH terms

Animals
Asthma* / drug therapy
Asthma* / metabolism
Lung
Mice
Microfilament Proteins / metabolism
Molecular Docking Simulation
Myocytes, Smooth Muscle / metabolism

Substances

transgelin
Microfilament Proteins