Journal
ACTA PHARMACOLOGICA SINICA
Volume 43, Issue 4, Pages 771-780Publisher
NATURE PUBL GROUP
DOI: 10.1038/s41401-021-00714-4
Keywords
Danshensu; SARS-CoV-2; spike protein; acute lung inflammation; inflammatory cytokines
Funding
- Major Scientific and Technological Projects of Guangdong Province [2019B020202002]
- Chinese Academy of Traditional Chinese Medicine [ZZ13-035-02, 2019XZZX-LG04]
- Guangzhou Science and Technology Program [202008040001, 201803040006, 2020B111110001]
- National Natural Science Foundation of China [82070083]
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The study demonstrates that Danshensu exhibits potent antiviral activity against SARS-CoV-2 and can inhibit the entry of the virus into target cells. Both oral and intravenous administration of Danshensu alleviates pathological alterations induced by SARS-CoV-2 in mice, suggesting its potential as a treatment for COVID-19 to inhibit lung inflammation.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can induce acute inflammatory response like acute lung inflammation (ALI) or acute respiratory distress syndrome, leading to severe progression and mortality. Therapeutics for treatment of SARS-CoV-2-triggered respiratory inflammation are urgent to be discovered. Our previous study shows that Salvianolic acid C potently inhibits SARS-CoV-2 infection. In this study, we investigated the antiviral effects of a Salvia miltiorrhiza compound, Danshensu, in vitro and in vivo, including the mechanism of S protein-mediated virus attachment and entry into target cells. In authentic and pseudo-typed virus assays in vitro, Danshensu displayed a potent antiviral activity against SARS-CoV-2 with EC50 of 0.97 mu M, and potently inhibited the entry of SARS-CoV-2 S protein-pseudo-typed virus (SARS-CoV-2 S) into ACE2-overexpressed HEK-293T cells (IC50 = 0.31 mu M) and Vero-E6 cell (IC50 = 4.97 mu M). Mice received SARS-CoV-2 S via trachea to induce ALI, while the VSV-G treated mice served as controls. The mice were administered Danshensu (25, 50, 100 mg/kg, i.v., once) or Danshensu (25, 50, 100 mg center dot kg(-1)center dot d(-1), oral administration, for 7 days) before SARS-CoV-2 S infection. We showed that SARS-CoV-2 S infection induced severe inflammatory cell infiltration, severely damaged lung tissue structure, highly expressed levels of inflammatory cytokines, and activated TLR4 and hyperphosphorylation of the NF-kappa B p65; the high expression of angiotensinogen (AGT) and low expression of ACE2 at the mRNA level in the lung tissue were also observed. Both oral and intravenous pretreatment with Danshensu dose-dependently alleviated the pathological alterations in mice infected with SARS-CoV-2 S. This study not only establishes a mouse model of pseudo-typed SARS-CoV-2 (SARS-CoV-2 S) induced ALI, but also demonstrates that Danshensu is a potential treatment for COVID-19 patients to inhibit the lung inflammatory response.
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