Ovatodiolide inhibits SARS-CoV-2 replication and ameliorates pulmonary fibrosis through suppression of the TGF-?/T?Rs signaling pathway

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to pose threats to public health. The clinical manifestations of lung pathology in COVID-19 patients include sustained inflammation and pulmonary fibrosis. The macrocyclic diterpenoid ovatodiolide (OVA) has been reported to have anti-inflammatory, anti-cancer, anti-allergic, and analgesic activities. Here, we investigated the pharmacological mechanism of OVA in suppressing SARS-CoV-2 infection and pulmonary fibrosis in vitro and in vivo. Our results revealed that OVA was an effective SARS-CoV-2 3CLpro inhibitor and showed remarkable inhibitory activity against SARS-CoV-2 infection. On the other hand, OVA ameliorated pulmonary fibrosis in bleomycin (BLM)-induced mice, reducing inflammatory cell infiltration and collagen deposition in the lung. OVA decreased the levels of pulmonary hydroxyproline and myeloperoxidase, as well as lung and serum TNF-alpha, IL-1 beta, IL-6, and TGF-beta in BLM-induced pulmonary fibrotic mice. Meanwhile, OVA reduced the migration and fibroblast-to-myofibroblast conversion of TGF-beta 1-induced fibrotic human lung fibroblasts. Consistently, OVA down-regulated TGF-beta/T beta Rs signaling. In computational analysis, OVA resembles the chemical structures of the kinase inhibitors T beta RI and T beta RII and was shown to interact with the key pharmacophores and putative ATP-binding domains of T beta RI and T beta RII, showing the potential of OVA as an inhibitor of T beta RI and T beta RII kinase. In conclu-sion, the dual function of OVA highlights its potential for not only fighting SARS-CoV-2 infection but also managing injury-induced pulmonary fibrosis.

Automated summary

The study found that OVA can effectively inhibit SARS-CoV-2 infection and improve pulmonary fibrosis. The results showed that OVA is an effective 3CLpro inhibitor of SARS-CoV-2 and has remarkable inhibitory activity against SARS-CoV-2 infection. In addition, OVA can reduce inflammatory cell infiltration and collagen deposition, as well as the levels of pulmonary hydroxyproline, myeloperoxidase, TNF-alpha, IL-1 beta, IL-6, and TGF-beta in the lung. In other words, OVA not only helps fight against SARS-CoV-2 infection, but also helps manage injury-induced pulmonary fibrosis.