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

Taizhen Liang; Shiqi Xiao; Ziyao Wu; Xi Lv; Sen Liu; Meilin Hu; Guojie Li; Peiwen Li; Xiancai Ma

doi:10.3390/v15081666

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

Viruses. 2023 Jul 31;15(8):1666. doi: 10.3390/v15081666.

Authors

Taizhen Liang^{1

2}, Shiqi Xiao¹, Ziyao Wu³, Xi Lv⁴, Sen Liu^{1

5}, Meilin Hu^{1

2}, Guojie Li¹, Peiwen Li¹, Xiancai Ma^{1

2

6}

Affiliations

¹ Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou 510005, China.
² State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou 511400, China.
³ School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
⁴ School of Medicine, South China University of Technology, Guangzhou 510006, China.
⁵ School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China.
⁶ Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.

Abstract

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).

Keywords: SARS-CoV-2; cathepsin L; entry inhibitor; phenothiazine; spike.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

COVID-19*
Humans
Phenothiazines / pharmacology
SARS-CoV-2*
Spike Glycoprotein, Coronavirus

Substances

Phenothiazines
spike protein, SARS-CoV-2
Spike Glycoprotein, Coronavirus

Supplementary concepts

SARS-CoV-2 variants

Grants and funding

This research was funded by the R&D Programs of Guangzhou National Laboratory (Grant numbers: SRPG22-002, SRPG22-006) and the National Natural Science Foundation of China (NSFC) (Grant number: 82102385) to X.M.