The COVID-19 pandemic continues to progress unabated in many parts of the world. An effective antiviral drug against SARS-CoV-2, suitable for oral administration following high-risk exposure, would provide significant benefits in controlling the COVID-19 pandemic. Here, we demonstrate that the oral nucleoside analog MK-4482 can inhibit SARS-CoV-2 replication in a Syrian hamster model. In a high-risk exposure model, inhibition of SARS-CoV-2 replication was observed when MK-4482 treatment was initiated either 12 hours before or 12 hours after infection. These data support the potential utility of MK-4482 in controlling human SARS-CoV-2 infection following high-risk exposure and in treating patients with COVID-19.

Epidemiological studies on COVID-19 patients indicate a male bias in pulmonary disease outcomes. To experimentally validate these epidemiological findings, we conducted animal studies by infecting male and female Syrian hamsters with SARS-CoV-2. Notably, male hamsters exhibited significant symptoms such as weight loss, lethargy, piloerection, hunching, and abdominal breathing, along with severe pneumonia, pulmonary edema, consolidation, and fibrosis, with high viral titers detected in nasal washes. In contrast, female hamsters had much lower viral titers, exhibited milder symptoms, and showed relatively less severe lung pathology. The marked differences in susceptibility to SARS-CoV-2 and severity of pulmonary pathogenesis between male and female hamsters provide experimental evidence that the severity of SARS-CoV-2 infection and COVID-19 is associated with sex.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 (COVID-19), has emerged as a public health emergency of international concern. Angiotensin-converting enzyme 2 (ACE2) serves as the cellular entry receptor for Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV). Here, we infected transgenic mice expressing human ACE2 (referred to as hACE2 mice) with SARS-CoV-2 and studied the pathogenicity of the virus. We observed weight loss and viral replication in the lungs of hACE2 mice infected with SARS-CoV-2. The typical histopathology was interstitial pneumonia, with a significant infiltration of macrophages and lymphocytes into the alveolar interstitium and the accumulation of macrophages in the alveolar cavities. Viral antigens were detected in bronchial epithelial cells, macrophages, and alveolar epithelial cells. These phenomena were not observed in wild-type mice infected with SARS-CoV-2. Notably, we confirmed the pathogenicity of SARS-CoV-2 in hACE2 mice. This SARS-CoV-2-infected mouse model is of significant value for evaluating antiviral agents and vaccines, as well as for understanding the pathogenesis of COVID-19.