2. Academic Validation
  3. Therapeutic potency of compound RMY-205 for pulmonary fibrosis induced by SARS-CoV-2 nucleocapsid protein

Therapeutic potency of compound RMY-205 for pulmonary fibrosis induced by SARS-CoV-2 nucleocapsid protein

  • Cell Chem Biol. 2023 Feb 28;S2451-9456(23)00053-3. doi: 10.1016/j.chembiol.2023.02.004.
Zhi-Yuan Zhang 1,  Cui-Yu Ju 1,  Liu-Zheng Wu 1,  Han Yan 2,  Wen-Bin Hong 1,  Hang-Zi Chen 1,  Peng-Bo Yang 1,  Bao-Rui Wang 2,  Tong Gou 2,  Xiao-Yan Chen 1,  Zhi-Hong Jiang 1,  Wei-Jia Wang 1,  Tianwei Lin 3,  Fu-Nan Li 4,  Qiao Wu 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China.
  • 2 Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
  • 3 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China. Electronic address: twlin@xmu.edu.cn.
  • 4 Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China. Electronic address: fnlee5@xmu.edu.cn.
  • 5 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China. Electronic address: qiaow@xmu.edu.cn.
PMID: 36889311 DOI: 10.1016/j.chembiol.2023.02.004
Abstract

Pulmonary fibrosis is a typical sequela of coronavirus disease 2019 (COVID-19), which is linked with a poor prognosis for COVID-19 patients. However, the underlying mechanism of pulmonary fibrosis induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear. Here, we demonstrated that the nucleocapsid (N) protein of SARS-CoV-2 induced pulmonary fibrosis by activating pulmonary fibroblasts. N protein interacted with the transforming growth factor β receptor I (TβRI), to disrupt the interaction of TβRI-FK506 Binding Protein12 (FKBP12), which led to activation of TβRI to phosphorylate SMAD3 and boost expression of pro-fibrotic genes and secretion of cytokines to promote pulmonary fibrosis. Furthermore, we identified a compound, RMY-205, that bound to SMAD3 to disrupt TβRI-induced SMAD3 activation. The therapeutic potential of RMY-205 was strengthened in mouse models of N protein-induced pulmonary fibrosis. This study highlights a signaling pathway of pulmonary fibrosis induced by N protein and demonstrates a novel therapeutic strategy for treating pulmonary fibrosis by a compound targeting SMAD3.

Keywords

N protein; SARS-CoV-2; TGF-β/Smad pathway; compound RMY-205; pulmonary fibrosis.

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