Danshensu alleviates pseudo-typed SARS-CoV-2 induced mouse acute lung inflammation

Abstract

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 EC 50 of 0.97 μM, and potently inhibited the entry of SARS-CoV-2 S protein-pseudo-typed virus (SARS-CoV-2 S) into ACE2-overexpressed HEK-293T cells (IC 50 = 0.31 μM) and Vero-E6 cell (IC 50 = 4.97 μM). 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·kg -1 ·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-κB 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.

Ginkgolic acids inhibit SARS-CoV-2 and its variants by blocking the spike protein/ACE2 interplay

“…Traditional Chinese medicine (TCM) has shown great potential in preventing and treating COVID-19 as more and more active antiviral TCM ingredients are emerging [8] , [9] , [10] , [11] . Lyu et al summarized and discussed the clinical effects and potential mechanisms of TCM at different disease stages for the treatment of COVID-19, emphasizing the scientific value of TCM in combating COVID-19 [12] .…”

SARS‐CoV‐2 spike spurs intestinal inflammation via VEGF production in enterocytes

“…Here, we provide an alternative route by showing that the ERK/VEGF axis in enterocytes plays a pivotal role in SARS‐CoV‐2‐induced intestinal inflammation. However, we have no adequate evidence to support the mediating role of ACE2 in the SARS‐CoV‐2 spike‐induced effects since the affinity of murine ACE2 and SARS‐CoV‐2 spike is still debatable (Li et al , 2004; Kuba et al , 2005; Zhao et al , 2020; Gu et al , 2021; Nuovo et al , 2021; Raghavan et al , 2021; Shin et al , 2021; Wang et al , 2021). We consider that whether the effect of spike RBD is through or fully through ACE2 is beyond the scope of this work.…”

Small molecules in the treatment of COVID-19

“…According to a study by Wang et al, Sal-A dose-dependently alleviates the pathological alterations in mice with acute lung inflammation due to infection with SARS-CoV-2 S protein-pseudotyped virus in a dose-dependent manner. 378 Sal-C has been reported to potently bind to the 6-HB core of S protein, thereby inhibiting SARS-CoV-2 infection. 379 According to the in vitro results, Sal-C potently inhibits the membrane fusion of S protein–overexpressing HEK293T and Vero E6 cells with an IC50 of 1.71 μM.…”