Sertraline Is an Effective SARS-CoV-2 Entry Inhibitor Targeting the Spike Protein.

Abstract

The global spread of the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the continuously emerging new variants underscore an urgent need for effective therapeutics for the treatment of coronavirus disease 2019 (COVID-19). Here, we screened several FDA-approved amphiphilic drugs and determined that sertraline (SRT) exhibits potent antiviral activity against infection of SARS-CoV-2 pseudovirus (PsV) and authentic virus in vitro. It effectively inhibits SARS-CoV-2 spike (S)-mediated cell-cell fusion. SRT targets the early stage of viral entry. It can bind to the S1 subunit of the S protein, especially the receptor binding domain (RBD), thus blocking S-hACE2 interaction and interfering with the proteolysis process of S protein. SRT is also effective against infection with SARS-CoV-2 PsV variants, including the newly emerging Omicron. The combination of SRT and other antivirals exhibits a strong synergistic effect against infection of SARS-CoV-2 PsV. The antiviral activity of SRT is independent of serotonin transporter expression. Moreover, SRT effectively inhibits infection of SARS-CoV-2 PsV and alleviates the inflammation process and lung pathological alterations in transduced mice in vivo. Therefore, SRT shows promise as a treatment option for COVID-19. IMPORTANCE The study shows SRT is an effective entry inhibitor against infection of SARS-CoV-2, which is currently prevalent globally. SRT targets the S protein of SARS-CoV-2 and is effective against a panel of SARS-CoV-2 variants. It also could be used in combination to prevent SARS-CoV-2 infection. More importantly, with long history of clinical use and proven safety, SRT might be particularly suitable to treat infection of SARS-CoV-2 in the central nervous system and optimized for treatment in older people, pregnant women, and COVID-19 patients with heart complications, which are associated with severity and mortality of COVID-19.

• Authors: Yuliu Chen, Yan Wu, Shaoying Chen, Qingping Zhan, Dingzhou Wu, Chan Yang, Xiaoxue He, Mengjie Qiu, Nannan Zhang, Zhaofeng Li, Yunhua Guo, Minjun Wen, Lu Lu, Cuiqing Ma, Jiayin Guo, Wei Xu, Xiaojuan Li, Lin Li, Shibo Jiang, Xiaoyan Pan, Shuwen Liu, Suiyi Tan
• Journal: Journal of virology (J Virol) Vol. 96 Issue 24 Pg. e0124522 (12 21 2022) ISSN: 1098-5514 [Electronic] United States
• PMID: 36468859 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Sertraline
• Spike Glycoprotein, Coronavirus
• spike protein, SARS-CoV-2

Topics

• Animals
• Humans
• Mice
• Antiviral Agents (pharmacology)
• COVID-19
• SARS-CoV-2 (drug effects, physiology)
• Sertraline (pharmacology)
• Spike Glycoprotein, Coronavirus (antagonists & inhibitors)
• Virus Internalization (drug effects)