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

• Published in: Cell chemical biology Vol. 30; no. 3; pp. 261 - 277.e8
• Main Authors: Zhang, Zhi-yuan, Ju, Cui-yu, Wu, Liu-zheng, Yan, Han, Hong, Wen-bin, Chen, Hang-zi, Yang, Peng-bo, Wang, Bao-Rui, Gou, Tong, Chen, Xiao-yan, Jiang, Zhi-hong, Wang, Wei-jia, Lin, Tianwei, Li, Fu-nan, Wu, Qiao
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 16.03.2023
• Subjects: Animals; compound RMY-205; COVID-19 - complications; Fibrosis; Mice; N protein; Nucleocapsid Proteins - therapeutic use; pulmonary fibrosis; Pulmonary Fibrosis - complications; Pulmonary Fibrosis - drug therapy; SARS-CoV-2; TGF-β/Smad pathway; SARS-CoV-2; compound RMY-205; N protein; pulmonary fibrosis; TGF-β/Smad pathway
• ISSN: 2451-9456; 2451-9448; 2451-9456
• DOI: 10.1016/j.chembiol.2023.02.004

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. [Display omitted] •SARS-CoV-2-encoded N protein induces pulmonary fibrosis by activating lung fibroblasts•N protein disrupts the interaction of TβRI-FKBP12 to activate TβRI-Smad signaling•Compound RMY-205 binds to Smad3 to impair N protein-induced Smad3 activation•RMY-205 has good therapeutic potential for pulmonary fibrosis induced by N protein Pulmonary fibrosis is a typical sequela of COVID-19. Zhang et al. demonstrate that the nucleocapsid (N) protein of SARS-CoV-2 induces pulmonary fibrosis by activating TβRI-Smad signaling in lung fibroblasts. Furthermore, they identify a compound, RMY-205, that inhibits N protein-activated Smad3 and has good therapeutic potential for N protein-induced pulmonary fibrosis.