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

Ho Sing Lo; Kenrie Pui Yan Hui; Hei Ming Lai; Xu He; Khadija Shahed Khan; Simranjeet Kaur; Junzhe Huang; Zhongqi Li; Anthony K.N. Chan; Hayley Hei Yin Cheung; Ka Chun Ng; John Chi Wang Ho; Yu Wai Chen; Bowen Ma; Peter Man Hin Cheung; Donghyuk Shin; Kaidao Wang; Meng Hsuan Lee; Barbara Selisko; Cecilia Eydoux; Jean Claude Guillemot; Bruno Canard; Kuen Phon Wu; Po Huang Liang; Ivan Dikic; Zhong Zuo; Francis K.L. Chan; David S.C. Hui; Vincent C.T. Mok; Kam Bo Wong; Chris Ka Pun Mok; Ho Ko; Wei Shen Aik; Michael Chi Wai Chan; Wai Lung Ng

doi:10.1021/acscentsci.0c01186

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

Ho Sing Lo, Kenrie Pui Yan Hui, Hei Ming Lai, Xu He, Khadija Shahed Khan, Simranjeet Kaur, Junzhe Huang, Zhongqi Li, Anthony K.N. Chan, Hayley Hei Yin Cheung, Ka Chun Ng, John Chi Wang Ho, Yu Wai Chen, Bowen Ma, Peter Man Hin Cheung, Donghyuk Shin, Kaidao Wang, Meng Hsuan Lee, Barbara Selisko, Cecilia EydouxJean Claude Guillemot, Bruno Canard, Kuen Phon Wu, Po Huang Liang, Ivan Dikic, Zhong Zuo, Francis K.L. Chan, David S.C. Hui, Vincent C.T. Mok, Kam Bo Wong, Chris Ka Pun Mok, Ho Ko, Wei Shen Aik, Michael Chi Wai Chan, Wai Lung Ng

Division of Life Sciences

Research output: Contribution to journal › Article › peer-review

28 Citations (Scopus)

Abstract

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 (Mpro) 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.

Original language	English
Pages (from-to)	792-802
Number of pages	11
Journal	ACS Central Science
Volume	7
Issue number	5
DOIs	https://doi.org/10.1021/acscentsci.0c01186
Publication status	Published - 2021 May 26

Bibliographical note

Funding Information:
W.L.N. acknowledges funding support from CUHK (“Improvement on competitiveness in hiring new faculties funding scheme”, a seed fund from the Faculty of Medicine and a PIEF grant [Ph2/COVID/19]) and the Croucher Foundation (start-up fund). M.C.W.C. acknowledges funding support by the Theme Based Research Scheme [T11-322 712/19-N], Research Grants Council, Hong Kong SAR, and the US National Institute of Allergy and Infectious Diseases (NIAID) under the Centers of Excellence for Influenza Research and Surveillance (CEIRS) [HHSN272201400006C]. W.S.A. acknowledges HKBU’s funding support through the Tier2 Start-up Grant (RC-SGT2/18-19/SCI/003). D.S. acknowledges the funding support of National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (no. 2021R1C1C1003961). The work of the BC group was supported by the Fondation pour la Recherche Médicale (Aide aux équipes), the SCORE project H2020 SC1-PHE-Coronavirus-2020 (grant #101003627) and the CARE project (grant #101005077) within IMI2 Europe’s partnership for health.

Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.

All Science Journal Classification (ASJC) codes

Chemistry(all)
Chemical Engineering(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acscentsci.0c01186

Cite this

Lo, H. S., Hui, K. P. Y., Lai, H. M., He, X., Khan, K. S., Kaur, S., Huang, J., Li, Z., Chan, A. K. N., Cheung, H. H. Y., Ng, K. C., Ho, J. C. W., Chen, Y. W., Ma, B., Cheung, P. M. H., Shin, D., Wang, K., Lee, M. H., Selisko, B., ... Ng, W. L. (2021). Simeprevir Potently Suppresses SARS-CoV-2 Replication and Synergizes with Remdesivir. ACS Central Science, 7(5), 792-802. https://doi.org/10.1021/acscentsci.0c01186

@article{4a2e52b0d8e54ae9adc32aa2f4c89cb9,

title = "Simeprevir Potently Suppresses SARS-CoV-2 Replication and Synergizes with Remdesivir",

abstract = "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 (Mpro) 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.",

author = "Lo, {Ho Sing} and Hui, {Kenrie Pui Yan} and Lai, {Hei Ming} and Xu He and Khan, {Khadija Shahed} and Simranjeet Kaur and Junzhe Huang and Zhongqi Li and Chan, {Anthony K.N.} and Cheung, {Hayley Hei Yin} and Ng, {Ka Chun} and Ho, {John Chi Wang} and Chen, {Yu Wai} and Bowen Ma and Cheung, {Peter Man Hin} and Donghyuk Shin and Kaidao Wang and Lee, {Meng Hsuan} and Barbara Selisko and Cecilia Eydoux and Guillemot, {Jean Claude} and Bruno Canard and Wu, {Kuen Phon} and Liang, {Po Huang} and Ivan Dikic and Zhong Zuo and Chan, {Francis K.L.} and Hui, {David S.C.} and Mok, {Vincent C.T.} and Wong, {Kam Bo} and Mok, {Chris Ka Pun} and Ho Ko and Aik, {Wei Shen} and Chan, {Michael Chi Wai} and Ng, {Wai Lung}",

note = "Funding Information: W.L.N. acknowledges funding support from CUHK (“Improvement on competitiveness in hiring new faculties funding scheme”, a seed fund from the Faculty of Medicine and a PIEF grant [Ph2/COVID/19]) and the Croucher Foundation (start-up fund). M.C.W.C. acknowledges funding support by the Theme Based Research Scheme [T11-322 712/19-N], Research Grants Council, Hong Kong SAR, and the US National Institute of Allergy and Infectious Diseases (NIAID) under the Centers of Excellence for Influenza Research and Surveillance (CEIRS) [HHSN272201400006C]. W.S.A. acknowledges HKBU{\textquoteright}s funding support through the Tier2 Start-up Grant (RC-SGT2/18-19/SCI/003). D.S. acknowledges the funding support of National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (no. 2021R1C1C1003961). The work of the BC group was supported by the Fondation pour la Recherche M{\'e}dicale (Aide aux {\'e}quipes), the SCORE project H2020 SC1-PHE-Coronavirus-2020 (grant #101003627) and the CARE project (grant #101005077) within IMI2 Europe{\textquoteright}s partnership for health. Publisher Copyright: {\textcopyright} 2021 The Authors. Published by American Chemical Society.",

year = "2021",

month = may,

day = "26",

doi = "10.1021/acscentsci.0c01186",

language = "English",

volume = "7",

pages = "792--802",

journal = "ACS Central Science",

issn = "2374-7943",

publisher = "American Chemical Society",

number = "5",

}

Lo, HS, Hui, KPY, Lai, HM, He, X, Khan, KS, Kaur, S, Huang, J, Li, Z, Chan, AKN, Cheung, HHY, Ng, KC, Ho, JCW, Chen, YW, Ma, B, Cheung, PMH, Shin, D, Wang, K, Lee, MH, Selisko, B, Eydoux, C, Guillemot, JC, Canard, B, Wu, KP, Liang, PH, Dikic, I, Zuo, Z, Chan, FKL, Hui, DSC, Mok, VCT, Wong, KB, Mok, CKP, Ko, H, Aik, WS, Chan, MCW & Ng, WL 2021, 'Simeprevir Potently Suppresses SARS-CoV-2 Replication and Synergizes with Remdesivir', ACS Central Science, vol. 7, no. 5, pp. 792-802. https://doi.org/10.1021/acscentsci.0c01186

TY - JOUR

T1 - Simeprevir Potently Suppresses SARS-CoV-2 Replication and Synergizes with Remdesivir

AU - Lo, Ho Sing

AU - Hui, Kenrie Pui Yan

AU - Lai, Hei Ming

AU - He, Xu

AU - Khan, Khadija Shahed

AU - Kaur, Simranjeet

AU - Huang, Junzhe

AU - Li, Zhongqi

AU - Chan, Anthony K.N.

AU - Cheung, Hayley Hei Yin

AU - Ng, Ka Chun

AU - Ho, John Chi Wang

AU - Chen, Yu Wai

AU - Ma, Bowen

AU - Cheung, Peter Man Hin

AU - Shin, Donghyuk

AU - Wang, Kaidao

AU - Lee, Meng Hsuan

AU - Selisko, Barbara

AU - Eydoux, Cecilia

AU - Guillemot, Jean Claude

AU - Canard, Bruno

AU - Wu, Kuen Phon

AU - Liang, Po Huang

AU - Dikic, Ivan

AU - Zuo, Zhong

AU - Chan, Francis K.L.

AU - Hui, David S.C.

AU - Mok, Vincent C.T.

AU - Wong, Kam Bo

AU - Mok, Chris Ka Pun

AU - Ko, Ho

AU - Aik, Wei Shen

AU - Chan, Michael Chi Wai

AU - Ng, Wai Lung

N1 - Funding Information: W.L.N. acknowledges funding support from CUHK (“Improvement on competitiveness in hiring new faculties funding scheme”, a seed fund from the Faculty of Medicine and a PIEF grant [Ph2/COVID/19]) and the Croucher Foundation (start-up fund). M.C.W.C. acknowledges funding support by the Theme Based Research Scheme [T11-322 712/19-N], Research Grants Council, Hong Kong SAR, and the US National Institute of Allergy and Infectious Diseases (NIAID) under the Centers of Excellence for Influenza Research and Surveillance (CEIRS) [HHSN272201400006C]. W.S.A. acknowledges HKBU’s funding support through the Tier2 Start-up Grant (RC-SGT2/18-19/SCI/003). D.S. acknowledges the funding support of National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (no. 2021R1C1C1003961). The work of the BC group was supported by the Fondation pour la Recherche Médicale (Aide aux équipes), the SCORE project H2020 SC1-PHE-Coronavirus-2020 (grant #101003627) and the CARE project (grant #101005077) within IMI2 Europe’s partnership for health. Publisher Copyright: © 2021 The Authors. Published by American Chemical Society.

PY - 2021/5/26

Y1 - 2021/5/26

N2 - 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 (Mpro) 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.

AB - 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 (Mpro) 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=85105116950&partnerID=8YFLogxK

U2 - 10.1021/acscentsci.0c01186

DO - 10.1021/acscentsci.0c01186

M3 - Article

AN - SCOPUS:85105116950

SN - 2374-7943

VL - 7

SP - 792

EP - 802

JO - ACS Central Science

JF - ACS Central Science

IS - 5

ER -

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

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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