Phenothiazines Inhibit SARS-CoV-2 Entry through Targeting Spike Protein

作者：Liang, Taizhen; Xiao, Shiqi; Wu, Ziyao; Lv, Xi; Liu, Sen; Hu, Meilin; Li, Guojie; Li, Peiwen; Ma, Xiancai^*

来源：Viruses-Basel, 2023, 15(8): 1666.

DOI：10.3390/v15081666

• SARS-CoV-2
• phenothiazine
• entry inhibitor
• spike
• cathepsin L

Novel coronavirus disease 2019 (COVID-19), a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought an unprecedented public health crisis and continues to threaten humanity due to the persistent emergence of new variants. Therefore, developing more effective and broad-spectrum therapeutic and prophylactic drugs against infection by SARS-CoV-2 and its variants, as well as future emerging CoVs, is urgently needed. In this study, we screened several US FDA-approved drugs and identified phenothiazine derivatives with the ability to potently inhibit the infection of pseudotyped SARS-CoV-2 and distinct variants of concern (VOCs), including B.1.617.2 (Delta) and currently circulating Omicron sublineages XBB and BQ.1.1, as well as pseudotyped SARS-CoV and MERS-CoV. Mechanistic studies suggested that phenothiazines predominantly inhibited SARS-CoV-2 pseudovirus (PsV) infection at the early stage and potentially bound to the spike (S) protein of SARS-CoV-2, which may prevent the proteolytic cleavage of the S protein, thereby exhibiting inhibitory activity against SARS-CoV-2 infection. In summary, our findings suggest that phenothiazines can serve as a potential broad-spectrum therapeutic drug for the treatment of SARS-CoV-2 infection as well as the infection of future emerging human coronaviruses (HCoVs).

• 单位
  中山大学; 广州医学院; 南方医科大学