Furin Inhibitors Block SARS-CoV-2 Spike Protein Cleavage to Suppress Virus Production and Cytopathic Effects

被引：199

作者：

Cheng, Ya-Wen ^{[1
]}

Chao, Tai-Ling ^{[2
]}

Li, Chiao-Ling ^{[1
]}

Chiu, Mu-Fan ^{[1
]}

Kao, Han-Chieh ^{[2
]}

Wang, Sheng-Han ^{[3
]}

Pang, Yu-Hao ^{[2
]}

Lin, Chih-Hui ^{[2
]}

Tsai, Ya-Min ^{[2
]}

Lee, Wen-Hau ^{[2
]}

Tao, Mi-Hua ^{[4
]}

Ho, Tung-Ching ^{[1
]}

Wu, Ping-Yi ^{[4
]}

Jang, Li-Ting ^{[5
]}

Chen, Pei-Jer ^{[6
,7
,8
]}

Chang, Sui-Yuan ^{[2
,9
]}

Yeh, Shiou-Hwei ^{[1
,2
,8
]}

机构：

[1] Natl Taiwan Univ, Dept Microbiol, Coll Med, Taipei 100, Taiwan

[2] Natl Taiwan Univ, Coll Med, Dept Clin Lab Sci & Med Biotechnol, Taipei 100, Taiwan

[3] Natl Taiwan Univ Hosp, Hepatitis Res Ctr, Taipei 100, Taiwan

[4] Acad Sinica, Inst Biomed Sci, Taipei 115, Taiwan

[5] Natl Taiwan Univ, Coll Med, Branch Off Res & Dev, Biomed Resource Core,Core Labs 1, Taipei 100, Taiwan

[6] Natl Taiwan Univ, Grad Inst Clin Med, Coll Med, Taipei 100, Taiwan

[7] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei 100, Taiwan

[8] Natl Taiwan Univ, Ctr Genom Med, Coll Med, Taipei 100, Taiwan

[9] Natl Taiwan Univ Hosp, Dept Lab Med, Taipei 100, Taiwan

来源：

CELL REPORTS | 2020年 / 33卷 / 02期

关键词：

RESPIRATORY SYNDROME CORONAVIRUS; PROPROTEIN CONVERTASES; PROTEOLYTIC CLEAVAGE; MURINE CORONAVIRUS; POTENT INHIBITORS; ACTIVATION; IDENTIFICATION; EPIDEMIOLOGY; INFECTION; RECEPTOR;

D O I：

10.1016/j.celrep.2020.108254

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Development of specific antiviral agents is an urgent unmet need for SARS-coronavirus 2 (SARS-CoV-2) infection. This study focuses on host proteases that proteolytically activate the SARS-CoV-2 spike protein, critical for its fusion after binding to angiotensin-converting enzyme 2 (ACE2), as antiviral targets. We first validate cleavage at a putative furin substrate motif at SARS-CoV-2 spikes by expressing it in VeroE6 cells and find prominent syncytium formation. Cleavage and the syncytium are abolished by treatment with the furin inhibitors decanoyl-RVKR-chloromethylketone (CMK) and naphthofluorescein, but not by the transmembrane protease serine 2 (TMPRSS2) inhibitor camostat. CMK and naphthofluorescein show antiviral effects on SARS-CoV-2-infected cells by decreasing virus production and cytopathic effects. Further analysis reveals that, similar to camostat, CMK blocks virus entry, but it further suppresses cleavage of spikes and the syncytium. Naphthofluorescein acts primarily by suppressing viral RNA transcription. Therefore, furin inhibitors may be promising antiviral agents for prevention and treatment of SARS-CoV-2 infection.

引用

页数：17

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