Simeprevir Potently Suppresses SARS-CoV-2 Replication and Synergizes with Remdesivir

被引：53

作者：

Lo, Ho Sing ^{[1
]}

Hui, Kenrie Pui Yan ^{[2
,3
]}

Lai, Hei-Ming ^{[4
,5
]}

He, Xu ^{[1
]}

Khan, Khadija Shahed ^{[1
]}

Kaur, Simranjeet ^{[6
]}

Huang, Junzhe ^{[5
,7
]}

Li, Zhongqi ^{[5
,7
]}

Chan, Anthony K. N. ^{[8
]}

Cheung, Hayley Hei-Yin ^{[9
]}

Ng, Ka-Chun ^{[2
]}

Ho, John Chi Wang ^{[2
]}

Chen, Yu Wai ^{[10
,11
]}

Ma, Bowen ^{[1
]}

Cheung, Peter Man-Hin ^{[12
]}

Shin, Donghyuk ^{[13
,14
]}

Wang, Kaidao ^{[15
]}

Lee, Meng-Hsuan ^{[16
]}

Selisko, Barbara ^{[17
]}

Eydoux, Cecilia ^{[17
]}

Guillemot, Jean-Claude ^{[17
]}

Canard, Bruno ^{[17
]}

Wu, Kuen-Phon ^{[16
]}

Liang, Po-Huang ^{[16
]}

Dikic, Ivan ^{[13
]}

Zuo, Zhong ^{[1
]}

Chan, Francis K. L. ^{[7
,18
]}

Hui, David S. C. ^{[7
,19
]}

Mok, Vincent C. T. ^{[7
,20
]}

Wong, Kam-Bo ^{[9
]}

Mok, Chris Ka Pun ^{[21
]}

Ko, Ho ^{[22
,23
]}

Aik, Wei Shen ^{[6
]}

Chan, Michael Chi Wai ^{[3
,24
]}

Ng, Wai-Lung ^{[1
]}

机构：

[1] Chinese Univ Hong Kong, Fac Med, Sch Pharm, Shatin, Hong Kong, Peoples R China

[2] Univ Hong Kong, Li Ka Shing Fac Med, Sch Publ Hlth, Pok Fu Lam, Hong Kong, Peoples R China

[3] Ctr Immunol & Infect C2I, Hong Kong Sci Pk, Hong Kong, Peoples R China

[4] Chinese Univ Hong Kong, Fac Med, Dept Med & Therapeut, Dept Psychiat,Shatin, Hong Kong, Peoples R China

[5] Chinese Univ Hong Kong, Fac Med, Li Ka Shing Inst Hlth Sci, Shatin, Hong Kong, Peoples R China

[6] Hong Kong Baptist Univ, Fac Sci, Dept Chem, Kowloon Tong, Hong Kong, Peoples R China

[7] Chinese Univ Hong Kong, Fac Med, Dept Med & Therapeut, Shatin, Hong Kong, Peoples R China

[8] City Hope Natl Med Ctr, Beckman Res Inst, Dept Syst Biol, Duarte, CA 91010 USA

[9] Chinese Univ Hong Kong, Fac Sci, Ctr Prot Sci & Crystallog, Sch Life Sci,State Key Lab Agrobiotechnol,Shatin, Hong Kong, Peoples R China

[10] Hong Kong Polytech Univ, Dept Appl Biol & Chem Technol, Hung Hom, Hong Kong, Peoples R China

[11] Hong Kong Polytech Univ, State Key Lab Chem Biol & Drug Discovery, Hung Hom, Hong Kong, Peoples R China

[12] Chinese Univ Hong Kong, Fac Med, Sch Publ Hlth, Shatin, Hong Kong, Peoples R China

[13] Goethe Univ, Buchmann Inst Mol Life Sci, D-60323 Frankfurt, Germany

[14] Yonsei Univ, Coll Life Sci & Biotechnol, Dept Syst Biol, Seoul 03722, South Korea

[15] GenScript Biotech Corp, Prot Prod Dept, Nanjing 211100, Jiangsu, Peoples R China

[16] Acad Sinica, Inst Biol Chem, Taipei 115, Taiwan

[17] Aix Marseille Univ, CNRS, Lab Architecture & Fonct Macromol Biol AFMB, F-13007 Marseille, France

[18] Chinese Univ Hong Kong, Fac Med, Inst Digest Dis, Shatin, Hong Kong, Peoples R China

[19] Chinese Univ Hong Kong, Stanley Ho Ctr Emerging Infect Dis, Fac Med, Shatin, Hong Kong, Peoples R China

[20] Chinese Univ Hong Kong, Fac Med, Margaret KL Cheung Res Ctr Management Parkinsonis, Gerald Choa Neurosci Ctr,Shatin, Hong Kong, Peoples R China

[21] Univ Hong Kong, Li Ka Shing Fac Med, Sch Publ Hlth, HKU Pasteur Res Pole,Shatin, Hong Kong, Peoples R China

[22] Chinese Univ Hong Kong, Margaret KL Cheung Res Ctr Management Parkinsonis, Fac Med,Dept Med & Therapeut,Dept Psychiat,Shatin, Sch Biomed Sci,Gerald Choa Neurosci Ctr,Li Ka Shi, Hong Kong, Peoples R China

[23] Chinese Univ Hong Kong, Fac Med, Peter Hung Pain Res Inst, Shatin, Hong Kong, Peoples R China

[24] Univ Hong Kong, Li Ka Shing Fac Med, Sch Publ Hlth, Hong Kong, Peoples R China

来源：

ACS CENTRAL SCIENCE | 2021年 / 7卷 / 05期

基金：

欧盟地平线“2020”; 新加坡国家研究基金会;

关键词：

DISCOVERY;

D O I：

10.1021/acscentsci.0c01186

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

The outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global threat to human health. Using a multidisciplinary approach, we identified and validated the hepatitis C virus (HCV) protease inhibitor simeprevir as an especially promising repurposable drug for treating COVID-19. Simeprevir potently reduces SARS-CoV-2 viral load by multiple orders of magnitude and synergizes with remdesivir in vitro. Mechanistically, we showed that simeprevir not only inhibits the main protease (M-pro) and unexpectedly the RNA-dependent RNA polymerase (RdRp) but also modulates host immune responses. Our results thus reveal the possible anti-SARS-CoV-2 mechanism of simeprevir and highlight the translational potential of optimizing simeprevir as a therapeutic agent for managing COVID-19 and future outbreaks of CoV.

引用

页码：792 / 802

页数：11

共 64 条

[1] Repurposing simeprevir, calpain inhibitor IV and a cathepsin F inhibitor against SARS-CoV-2 and insights into their interactions with Mpro [J].

Abhithaj, J. ;

Francis, Dileep ;

Sharanya, C. S. ;

Arun, K. G. ;

Sadasivan, C. ;

Variyar, E. Jayadevi .

JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, 2022, 40 (01) :325-336

[2]

Acton T. B., 2020, HEPATITIS C VIRUS DR, DOI [10.1101/2020.12.13.422511, DOI 10.1101/2020.12.13.422511]

[3]

[Anonymous], 2021, WEEKLY EPIDEMIOLOGIC

[4] Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19 [J].

Blanco-Melo, Daniel ;

Nilsson-Payant, Benjamin E. ;

Liu, Wen-Chun ;

Uhl, Skyler ;

Hoagland, Daisy ;

Moller, Rasmus ;

Jordan, Tristan X. ;

Oishi, Kohei ;

Panis, Maryline ;

Sachs, David ;

Wang, Taia T. ;

Schwartz, Robert E. ;

Lim, Jean K. ;

Albrecht, Randy A. ;

tenOever, Benjamin R. .

CELL, 2020, 181 (05) :1036-+

[5] Molecular Investigation of SARS-CoV-2 Proteins and Their Interactions with Antiviral Drugs [J].

Calligari, Paolo ;

Bobone, Sara ;

Ricci, Giorgio ;

Bocedi, Alessio .

VIRUSES-BASEL, 2020, 12 (04)

[6]

Cao B, 2020, NEW ENGL J MED, V382, P1787, DOI [10.1056/NEJMoa2001282, 10.1056/NEJMc2008043]

[7] QT interval prolongation and torsade de pointes in patients with COVID-19 treated with hydroxychloroquine/azithromycin [J].

Chorin, Ehud ;

Wadhwani, Lalit ;

Magnani, Silvia ;

Dai, Matthew ;

Shulman, Eric ;

Nadeau-Routhier, Charles ;

Knotts, Robert ;

Bar-Cohen, Roi ;

Kogan, Edward ;

Barbhaiya, Chirag ;

Aizer, Anthony ;

Holmes, Douglas ;

Bernstein, Scott ;

Spinelli, Michael ;

Park, David S. ;

Stefano, Carugo ;

Chinitz, Larry A. ;

Jankelson, Lior .

HEART RHYTHM, 2020, 17 (09) :1425-1433

[8] Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro [J].

Choy, Ka-Tim ;

Wong, Alvina Yin-Lam ;

Kaewpreedee, Prathanporn ;

Sia, Sin Fun ;

Chen, Dongdong ;

Hui, Kenrie Pui Yan ;

Chu, Daniel Ka Wing ;

Chan, Michael Chi Wai ;

Cheung, Peter Pak-Hang ;

Huang, Xuhui ;

Peiris, Malik ;

Yen, Hui-Ling .

ANTIVIRAL RESEARCH, 2020, 178

[9] Design, synthesis and crystallographic analysis of nitrile-based broad-spectrum peptidomimetic inhibitors for coronavirus 3C-like proteases [J].

Chuck, Chi-Pang ;

Chen, Chao ;

Ke, Zhihai ;

Wan, David Chi-Cheong ;

Chow, Hak-Fun ;

Wong, Kam-Bo .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2013, 59 :1-6

[10] Profiling of Substrate Specificity of SARS-CoV 3CLpro [J].

Chuck, Chi-Pang ;

Chong, Lin-Tat ;

Chen, Chao ;

Chow, Hak-Fun ;

Wan, David Chi-Cheong ;

Wong, Kam-Bo .

PLOS ONE, 2010, 5 (10)

← 1 2 3 4 5 6 7 →