tetano
Editor, Senior Moderator
Cell Chem Biol
. 2023 Feb 28;S2451-9456(23)00053-3.
doi: 10.1016/j.chembiol.2023.02.004. Online ahead of print.
Therapeutic potency of compound RMY-205 for pulmonary fibrosis induced by SARS-CoV-2 nucleocapsid protein
Zhi-Yuan Zhang[SUP] 1 [/SUP], Cui-Yu Ju[SUP] 1 [/SUP], Liu-Zheng Wu[SUP] 1 [/SUP], Han Yan[SUP] 2 [/SUP], Wen-Bin Hong[SUP] 1 [/SUP], Hang-Zi Chen[SUP] 1 [/SUP], Peng-Bo Yang[SUP] 1 [/SUP], Bao-Rui Wang[SUP] 2 [/SUP], Tong Gou[SUP] 2 [/SUP], Xiao-Yan Chen[SUP] 1 [/SUP], Zhi-Hong Jiang[SUP] 1 [/SUP], Wei-Jia Wang[SUP] 1 [/SUP], Tianwei Lin[SUP] 3 [/SUP], Fu-Nan Li[SUP] 4 [/SUP], Qiao Wu[SUP] 5 [/SUP]
Affiliations
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.
. 2023 Feb 28;S2451-9456(23)00053-3.
doi: 10.1016/j.chembiol.2023.02.004. Online ahead of print.
Therapeutic potency of compound RMY-205 for pulmonary fibrosis induced by SARS-CoV-2 nucleocapsid protein
Zhi-Yuan Zhang[SUP] 1 [/SUP], Cui-Yu Ju[SUP] 1 [/SUP], Liu-Zheng Wu[SUP] 1 [/SUP], Han Yan[SUP] 2 [/SUP], Wen-Bin Hong[SUP] 1 [/SUP], Hang-Zi Chen[SUP] 1 [/SUP], Peng-Bo Yang[SUP] 1 [/SUP], Bao-Rui Wang[SUP] 2 [/SUP], Tong Gou[SUP] 2 [/SUP], Xiao-Yan Chen[SUP] 1 [/SUP], Zhi-Hong Jiang[SUP] 1 [/SUP], Wei-Jia Wang[SUP] 1 [/SUP], Tianwei Lin[SUP] 3 [/SUP], Fu-Nan Li[SUP] 4 [/SUP], Qiao Wu[SUP] 5 [/SUP]
Affiliations
- 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.