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

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.

• Authors: Zhi-Yuan Zhang, Cui-Yu Ju, Liu-Zheng Wu, Han Yan, Wen-Bin Hong, Hang-Zi Chen, Peng-Bo Yang, Bao-Rui Wang, Tong Gou, Xiao-Yan Chen, Zhi-Hong Jiang, Wei-Jia Wang, Tianwei Lin, Fu-Nan Li, Qiao Wu
• Journal: Cell chemical biology (Cell Chem Biol) Vol. 30 Issue 3 Pg. 261-277.e8 (03 16 2023) ISSN: 2451-9448 [Electronic] United States
• PMID: 36889311 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier Ltd. All rights reserved.

Chemical References

• Nucleocapsid Proteins
• nucleocapsid phosphoprotein, SARS-CoV-2

Topics

• Animals
• Mice
• COVID-19 (complications)
• Fibrosis
• Nucleocapsid Proteins (therapeutic use)
• Pulmonary Fibrosis (complications, drug therapy)
• SARS-CoV-2