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

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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 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

• 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.