Efficacy of GC-376 against SARS-CoV-2 virus infection in the K18 hACE2 transgenic mouse model

Abstract

The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the defining global health emergency of this century. GC-376 is a Mpro inhibitor with antiviral activity against SARS-CoV-2 in vitro. Using the K18-hACE2 mouse model, the in vivo antiviral efficacy of GC-376 against SARS-CoV-2 was evaluated. GC-376 treatment was not toxic in K18-hACE2 mice. Overall outcome of clinical symptoms and survival upon SARS-CoV-2 challenge were not improved in mice treated with GC-376 compared to controls. The treatment with GC-376 slightly improved survival from 0 to 20% in mice challenged with a high virus dose at 105 TCID50/mouse. Most notably, GC-376 treatment led to milder tissue lesions, reduced viral loads, fewer presence of viral antigen, and reduced inflammation in comparison to vehicle-treated controls in mice challenged with a low virus dose at 103 TCID50/mouse. This was particularly the case in the brain where a 5-log reduction in viral titers was observed in GC-376 treated mice compared to vehicle controls. This study supports the notion that GC-376 represents a promising lead candidate for further development to treat SARS-CoV-2 infection and that the K18-hACE2 mouse model is suitable to study antiviral therapies against SARS-CoV-2.

Mild and Severe SARS-CoV-2 Infection Induces Respiratory and Intestinal Microbiome Changes in the K18-hACE2 Transgenic Mouse Model

“…Taking advantage of a study evaluating antiviral activity of GC-376 against SARS-CoV-2 virus in the K18-hACE2 mouse model, we evaluated the microbiome composition at different times after SARS-CoV-2 challenge. We and others have shown that mice challenged with 10 3 50% tissue culture infectious dose (TCID 50 )/mouse of the SARS-CoV-2 virus (low/vehicle) presented with brief reduced activity and clinical signs leading to ∼60% survival ( 43 ). In contrast, mice challenged with 10 5 TCID 50 /mouse of SARS-CoV-2 (high/vehicle) presented initially with relatively normal activity followed by rapid weight loss and substantial deterioration of clinical outcomes ( 43 ).…”

“…We and others have shown that mice challenged with 10 3 50% tissue culture infectious dose (TCID 50 )/mouse of the SARS-CoV-2 virus (low/vehicle) presented with brief reduced activity and clinical signs leading to ∼60% survival ( 43 ). In contrast, mice challenged with 10 5 TCID 50 /mouse of SARS-CoV-2 (high/vehicle) presented initially with relatively normal activity followed by rapid weight loss and substantial deterioration of clinical outcomes ( 43 ). By 6 dpc, mice in the high-virus-dose group showed ∼20% weight loss, and all mice died or had to be euthanized by 8 dpc ( 43 ).…”

“…In contrast, mice challenged with 10 5 TCID 50 /mouse of SARS-CoV-2 (high/vehicle) presented initially with relatively normal activity followed by rapid weight loss and substantial deterioration of clinical outcomes ( 43 ). By 6 dpc, mice in the high-virus-dose group showed ∼20% weight loss, and all mice died or had to be euthanized by 8 dpc ( 43 ). Peak virus titers for the low- and high-dose groups were observed at 2 and then 5 dpc in the nasal turbinates and lungs ( 43 ).…”

“…By 6 dpc, mice in the high-virus-dose group showed ∼20% weight loss, and all mice died or had to be euthanized by 8 dpc ( 43 ). Peak virus titers for the low- and high-dose groups were observed at 2 and then 5 dpc in the nasal turbinates and lungs ( 43 ). Antiviral GC-376 treatment resulted in milder inflammation and reduced lesions and viral loads compared to those in the vehicle group, although it did not improve clinical outcomes ( 43 ).…”

Recent advances in developing small-molecule inhibitors against SARS-CoV-2

“…In addition, Hu et al 89 found that boceprevir, calpain inhibitors II and XII, and GC-376 showed broad-spectrum antiviral activity against SARS-CoV-2, SARS-CoV and MERS-CoV infection, as well as human coronaviruses (CoVs) 229E, OC43, and NL63. In addition, Cáceres et al 90 has reported that GC376 is effective in inhibiting SARS-CoV-2 infection in vivo . Treatment of SARS-CoV-2-infected K18-hACE2 mice with GC376 resulted in decreased viral loads and reduced inflammation.…”