Fu-nan Li | Cell Chemical Biology: Therapeutic potency of compound RMY-205 for pulmonary fibrosis induced by SARS-CoV-2 nucleocapsid protein

Highlights

• 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

Summary

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.

Link: https://www.cell.com/cell-chemical-biology/fulltext/S2451-9456(23)00053-3#%20