puc-header

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

43 Pages Posted: 1 Jun 2020 Publication Status: Published

See all articles by Ya-Wen Cheng

Ya-Wen Cheng

National Taiwan University - Department of Microbiology

Tai-Ling Chao

National Taiwan University - Department of Laboratory Medicine

Chiao-Ling Li

National Taiwan University - Department of Microbiology

Mu-Fan Chiu

National Taiwan University - Department of Microbiology

Han-Chieh Kao

National Taiwan University - Department of Clinical Laboratory Sciences and Medical Biotechnology

Sheng-Han Wang

National Taiwan University Hospital - Hepatitis Research Center

Yu-Hao Pang

National Taiwan University - Department of Laboratory Medicine

Chih-Hui Lin

National Taiwan University - Department of Laboratory Medicine

Ya-Min Tsai

National Taiwan University - Department of Laboratory Medicine

Wen-Hau Lee

National Taiwan University - Department of Laboratory Medicine

Mi-Hua Tao

Academia Sinica - Institute of Biomedical Sciences

Tung-Ching Ho

National Taiwan University - Department of Microbiology

Ping-Yi Wu

Academia Sinica - Institute of Biomedical Sciences

Li-Ting Jang

National Taiwan University - Biomedical Resource Core at the First Core Labs

Pei-Jer Chen

National Taiwan University - Graduate Institute of Clinical Medicine

Sui-Yuan Chang

National Taiwan University - Department of Laboratory Medicine

Shiou-Hwei Yeh

National Taiwan University - Department of Microbiology

More...

Abstract

Development of specific antivirals is an urgent unmet need for SARS-coronavirus 2 (SARS-CoV-2) infections. This study focuses on host proteases that proteolytically activate the SARS-CoV-2 spike protein, critical for its fusion activity after binding to ACE2 receptor, as antiviral targets. We first validated cleavage at a putative furin substrate motif at SARS-CoV-2 spike by expressing it in VeroE6 cells and found prominent syncytium formation. Both cleavage and syncytium were abolished by treatment with the furin inhibitors decanoyl-RVKR-chloromethylketone (CMK) and naphthofluorescein but not by the TMPRSS2 inhibitor camostat. CMK and naphthofluorescein showed antiviral effects in SARS-CoV-2-infected cells by decreasing viral production and cytopathic effects. Further analysis revealed that, similar to camostat, CMK blocks virus entry, but it further suppresses the cleavage of spike and syncytium. Naphthofluorescein instead acts primarily by suppressing viral RNA transcription after viral entry. Therefore, furin inhibitors may become promising antivirals for prevention and treatment of SARS-CoV-2 infections.

Funding: This study was supported by grants from the Ministry of Science and Technology, Taiwan (106-2622-B-002-002-CC2, 107-3017-F-002-002) and the “Center of Precision Medicine” from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan.

Conflict of Interest: The authors declare no competing interests.

Keywords: SARS-CoV-2, Spike, Furin, Syncytium, Cytopathic effect.

Suggested Citation

Cheng, Ya-Wen and Chao, Tai-Ling and Li, Chiao-Ling and Chiu, Mu-Fan and Kao, Han-Chieh and Wang, Sheng-Han and Pang, Yu-Hao and Lin, Chih-Hui and Tsai, Ya-Min and Lee, Wen-Hau and Tao, Mi-Hua and Ho, Tung-Ching and Wu, Ping-Yi and Jang, Li-Ting and Chen, Pei-Jer and Chang, Sui-Yuan and Yeh, Shiou-Hwei, Furin Inhibitors Block SARS-CoV-2 Spike Protein Cleavage to Suppress Virus Production and Cytopathic Effects. Available at SSRN: https://ssrn.com/abstract=3613035 or http://dx.doi.org/10.2139/ssrn.3613035
This version of the paper has not been formally peer reviewed.

Ya-Wen Cheng

National Taiwan University - Department of Microbiology ( email )

Taiwan

Tai-Ling Chao

National Taiwan University - Department of Laboratory Medicine ( email )

1 Sec. 4, Roosevelt Road
Taipei 106, 106
Taiwan

Chiao-Ling Li

National Taiwan University - Department of Microbiology ( email )

Taiwan

Mu-Fan Chiu

National Taiwan University - Department of Microbiology ( email )

Taiwan

Han-Chieh Kao

National Taiwan University - Department of Clinical Laboratory Sciences and Medical Biotechnology ( email )

1 Sec. 4, Roosevelt Road
Taipei 106, 106
Taiwan

Sheng-Han Wang

National Taiwan University Hospital - Hepatitis Research Center ( email )

1 Sec. 4, Roosevelt Road
Taipei 106, 106
Taiwan

Yu-Hao Pang

National Taiwan University - Department of Laboratory Medicine ( email )

1 Sec. 4, Roosevelt Road
Taipei 106, 106
Taiwan

Chih-Hui Lin

National Taiwan University - Department of Laboratory Medicine ( email )

1 Sec. 4, Roosevelt Road
Taipei 106, 106
Taiwan

Ya-Min Tsai

National Taiwan University - Department of Laboratory Medicine ( email )

1 Sec. 4, Roosevelt Road
Taipei 106, 106
Taiwan

Wen-Hau Lee

National Taiwan University - Department of Laboratory Medicine ( email )

1 Sec. 4, Roosevelt Road
Taipei 106, 106
Taiwan

Mi-Hua Tao

Academia Sinica - Institute of Biomedical Sciences ( email )

128 Academia Road, Section 2
Nankang, Taipei 11529
Taiwan

Tung-Ching Ho

National Taiwan University - Department of Microbiology ( email )

Taiwan

Ping-Yi Wu

Academia Sinica - Institute of Biomedical Sciences ( email )

128 Academia Road, Section 2
Nankang, Taipei 11529
Taiwan

Li-Ting Jang

National Taiwan University - Biomedical Resource Core at the First Core Labs ( email )

1 Sec. 4, Roosevelt Road
Taipei 106, 106
Taiwan

Pei-Jer Chen

National Taiwan University - Graduate Institute of Clinical Medicine

Taipei
Taiwan

Sui-Yuan Chang

National Taiwan University - Department of Laboratory Medicine ( email )

Shiou-Hwei Yeh (Contact Author)

National Taiwan University - Department of Microbiology ( email )

Taiwan

Click here to go to Cell.com

Paper statistics

Downloads
55
Abstract Views
2,112
PlumX Metrics