Research Center for Epidemic Prevention and One Health, National Yang Ming Chiao Tung University(RCEP-NYCU)

The research team formed by Professor Chang Shu-Yuan from the Department of Medical Laboratory Science and Biotechnology at National Taiwan University and Associate Professor Hsu Chia-Lin (second from the right) from the Institute of Microbiology and Immunology at Yang-Ming University has discovered a transport protein responsible for delivering essential nutrients to cells, inadvertently becomes a pathway and vulnerable point for the invasion of enterovirus type 71 and other similar viruses.

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-ɑ, IL-1β, IL-6, and TGF-β in BLM-induced pulmonary fibrotic mice. Meanwhile, OVA reduced the migration and fibroblast-to-myofibroblast conversion of TGF-β1-induced fibrotic human lung fibroblasts. Consistently, OVA downregulated TGF-β/TβRs signaling. In computational analysis, OVA resembles the chemical structures of the kinase inhibitors TβRI and TβRII and was shown to interact with the key pharmacophores and putative ATP-binding domains of TβRI and TβRII, showing the potential of OVA as an inhibitor of TβRI and TβRII kinase. In conclusion, the dual function of OVA highlights its potential for not only fighting SARS-CoV-2 infection but also managing injury-induced pulmonary fibrosis.

The team has previously confirmed that GMI can prevent SARS-CoV-2 infection by inducing the degradation of ACE2 in host cells, inhibiting cell fusion, and disrupting the binding between ACE2 and spike protein. In this study, the team further established the anti-inflammatory effects and mechanisms of GMI in SARS-CoV-2 infection. They measured the inflammation caused by SARS-CoV-2 subunits in mouse macrophages and lung tissues and confirmed through animal experiments that GMI can suppress SARS-CoV-2-related inflammation and elucidated its inhibitory mechanisms.