Remdesivir Metabolite GS-441524 Effectively Inhibits SARS-CoV-2 Infection in Mouse Models

被引:97
作者
Li, Yingjun [1 ,2 ]
Cao, Liu [3 ]
Li, Ge [4 ]
Cong, Feng [4 ]
Li, Yunfeng [4 ]
Sun, Jing [5 ]
Luo, Yinzhu [4 ]
Chen, Guijiang [4 ]
Li, Guanguan [1 ]
Wang, Ping [1 ]
Xing, Fan [3 ]
Ji, Yanxi [3 ]
Zhao, Jincun [5 ]
Zhang, Yu [4 ]
Guo, Deyin [3 ]
Zhang, Xumu [1 ,2 ]
机构
[1] Southern Univ Sci & Technol, Coll Sci, Dept Chem, Shenzhen Key Lab Small Mol Drug Discovery & Synth, Shenzhen 518055, Guangdong, Peoples R China
[2] Southern Univ Sci & Technol, Acad Adv Interdisciplinary Studies, Medi X, Shenzhen 518055, Guangdong, Peoples R China
[3] Sun Yat Sen Univ, Ctr Infect & Immun Studies, Sch Med, Shenzhen 518107, Peoples R China
[4] Guangdong Lab Anim Monitoring Inst, Guangdong Prov Key Lab Lab Anim, Guangzhou 510663, Guangdong, Peoples R China
[5] Guangzhou Med Univ, Natl Clin Res Ctr Resp Dis, Guangzhou Inst Resp Hlth, State Key Lab Resp Dis,Affiliated Hosp 1, Guangzhou 510182, Guangdong, Peoples R China
基金
中国国家自然科学基金;
关键词
ANTIVIRAL ACTIVITY; TISSUE-CULTURE; VIRUS; CORONAVIRUS; PRODRUG; MECHANISM; EFFICACY; GS-5734; EBOLA;
D O I
10.1021/acs.jmedchem.0c01929
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The outbreak of coronavirus disease 2019 (COVID-19) has resulted in a global pandemic due to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). At the time of this manuscript's publication, remdesivir is the only COVID-19 treatment approved by the United States Food and Drug Administration. However, its effectiveness is still under question due to the results of the large Solidarity Trial conducted by the World Health Organization. Herein, we report that the parent nucleoside of remdesivir, GS-441524, potently inhibits the replication of SARS-CoV-2 in Vero E6 and other cell lines. Challenge studies in both an AAV-hACE2 mouse model of SARS-CoV-2 and in mice infected with murine hepatitis virus, a closely related coronavirus, showed that GS-441524 was highly efficacious in reducing the viral titers in CoV-infected organs without notable toxicity. Our results support that GS-441524 is a promising and inexpensive drug candidate for treating of COVID-19 and other CoV diseases.
引用
收藏
页码:2785 / 2793
页数:9
相关论文
共 44 条
  • [31] Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis
    Pedersen, Niels C.
    Perron, Michel
    Bannasch, Michael
    Montgomery, Elizabeth
    Murakami, Eisuke
    Liepnieks, Molly
    Liu, Hongwei
    [J]. JOURNAL OF FELINE MEDICINE AND SURGERY, 2019, 21 (04) : 271 - 281
  • [32] Remdesivir Inhibits SARS-CoV-2 in Human Lung Cells and Chimeric SARS-CoV Expressing the SARS-CoV-2 RNA Polymerase in Mice
    Pruijssers, Andrea J.
    George, Amelia S.
    Schafer, Alexandra
    Leist, Sarah R.
    Gralinksi, Lisa E.
    Dinnon, Kenneth H., III
    Yount, Boyd L.
    Agostini, Maria L.
    Stevens, Laura J.
    Chappell, James D.
    Lu, Xiaotao
    Hughes, Tia M.
    Gully, Kendra
    Martinez, David R.
    Brown, Ariane J.
    Graham, Rachel L.
    Perry, Jason K.
    Du Pont, Venice
    Pitts, Jared
    Ma, Bin
    Babusis, Darius
    Murakami, Eisuke
    Feng, Joy Y.
    Bilello, John P.
    Porter, Danielle P.
    Cihlar, Tomas
    Baric, Ralph S.
    Denison, Mark R.
    Sheahan, Timothy P.
    [J]. CELL REPORTS, 2020, 32 (03):
  • [33] An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice
    Sheahan, Timothy P.
    Sims, Amy C.
    Zhou, Shuntai
    Graham, Rachel L.
    Pruijssers, Andrea J.
    Agostini, Maria L.
    Leist, Sarah R.
    Schafer, Alexandra
    Dinnon, Kenneth H., III
    Stevens, Laura J.
    Chappell, James D.
    Lu, Xiaotao
    Hughes, Tia M.
    George, Amelia S.
    Hill, Collin S.
    Montgomery, Stephanie A.
    Brown, Ariane J.
    Bluemling, Gregory R.
    Natchus, Michael G.
    Saindane, Manohar
    Kolykhalov, Alexander A.
    Painter, George
    Harcourt, Jennifer
    Tamin, Azaibi
    Thornburg, Natalie J.
    Swanstrom, Ronald
    Denison, Mark R.
    Baric, Ralph S.
    [J]. SCIENCE TRANSLATIONAL MEDICINE, 2020, 12 (541)
  • [34] Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo(2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses
    Siegel, Dustin
    Hui, Hon C.
    Doerffler, Edward
    Clarke, Michael O.
    Chun, Kwon
    Zhang, Lijun
    Neville, Sean
    Carra, Ernest
    Lew, Willard
    Ross, Bruce
    Wang, Queenie
    Wolfe, Lydia
    Jordan, Robert
    Soloveva, Veronica
    Knox, John
    Perry, Jason
    Perron, Michel
    Stray, Kirsten M.
    Barauskas, Ona
    Feng, Joy Y.
    Xu, Yili
    Lee, Gary
    Rheingold, Arnold L.
    Ray, Adrian S.
    Bannister, Roy
    Strickley, Robert
    Swaminathan, Swami
    Lee, William A.
    Bavari, Sina
    Cihlar, Tomas
    Lo, Michael K.
    Warren, Travis K.
    Mackman, Richard L.
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2017, 60 (05) : 1648 - 1661
  • [35] COVID-19 treatment: close to a cure? A rapid review of pharmacotherapies for the novel coronavirus (SARS-CoV-2)
    Song, Yang
    Zhang, Min
    Yin, Ling
    Wang, Kunkun
    Zhou, Yiyi
    Zhou, Mi
    Lu, Yun
    [J]. INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, 2020, 56 (02)
  • [36] Generation of a Broadly Useful Model for COVID-19 Pathogenesis, Vaccination, and Treatment
    Sun, Jing
    Zhuang, Zhen
    Zheng, Jian
    Li, Kun
    Wong, Roy Lok-Yin
    Liu, Donglan
    Huang, Jicheng
    He, Jiangping
    Zhu, Airu
    Zhao, Jingxian
    Li, Xiaobo
    Xi, Yin
    Chen, Rongchang
    Alshukairi, Abeer N.
    Chen, Zhao
    Zhang, Zhaoyong
    Chen, Chunke
    Huang, Xiaofang
    Li, Fang
    Lai, Xiaomin
    Chen, Dingbin
    Wen, Liyan
    Zhuo, Jianfen
    Zhang, Yanjun
    Wang, Yanqun
    Huang, Shuxiang
    Dai, Jun
    Shi, Yongxia
    Zheng, Kui
    Leidinger, Mariah R.
    Chen, Jiekai
    Li, Yimin
    Zhong, Nanshan
    Meyerholz, David K.
    McCray, Paul B., Jr.
    Perlman, Stanley
    Zhao, Jincun
    [J]. CELL, 2020, 182 (03) : 734 - +
  • [37] Pharmacokinetics of remdesivir and GS-441524 in two critically ill patients who recovered from COVID-19
    Tempestilli, Massimo
    Caputi, Priscilla
    Avataneo, Valeria
    Notari, Stefanie
    Forini, Olinda
    Scorzolini, Laura
    Marchioni, Luisa
    Bartoli, Tommaso Ascoli
    Castilletti, Concetta
    Lalle, Eleanore
    Capobianchi, Maria R.
    Nicastri, Emanuele
    D'Avolio, Antonio
    Ippolito, Giuseppe
    Agrati, Chiara
    [J]. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 2020, 75 (10) : 2977 - 2980
  • [38] Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro
    Wang, Manli
    Cao, Ruiyuan
    Zhang, Leike
    Yang, Xinglou
    Liu, Jia
    Xu, Mingyue
    Shi, Zhengli
    Hu, Zhihong
    Zhong, Wu
    Xiao, Gengfu
    [J]. CELL RESEARCH, 2020, 30 (03) : 269 - 271
  • [39] Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase
    Wang, Quan
    Wu, Jiqin
    Wang, Haofeng
    Gao, Yan
    Liu, Qiaojie
    Mu, An
    Ji, Wenxin
    Yan, Liming
    Zhu, Yan
    Zhu, Chen
    Fang, Xiang
    Yang, Xiaobao
    Huang, Yucen
    Gao, Hailong
    Liu, Fengjiang
    Ge, Ji
    Sun, Qianqian
    Yang, Xiuna
    Xu, Wenqing
    Liu, Zhijie
    Yang, Haitao
    Lou, Zhiyong
    Jiang, Biao
    Guddat, Luke W.
    Gong, Peng
    Rao, Zihe
    [J]. CELL, 2020, 182 (02) : 417 - +
  • [40] Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys
    Warren, Travis K.
    Jordan, Robert
    Lo, Michael K.
    Ray, Adrian S.
    Mackman, Richard L.
    Soloveva, Veronica
    Siegel, Dustin
    Perron, Michel
    Bannister, Roy
    Hui, Hon C.
    Larson, Nate
    Strickley, Robert
    Wells, Jay
    Stuthman, Kelly S.
    Van Tongeren, Sean A.
    Garza, Nicole L.
    Donnelly, Ginger
    Shurtleff, Amy C.
    Retterer, Cary J.
    Gharaibeh, Dima
    Zamani, Rouzbeh
    Kenny, Tara
    Eaton, Brett P.
    Grimes, Elizabeth
    Welch, Lisa S.
    Gomba, Laura
    Wilhelmsen, Catherine L.
    Nichols, Donald K.
    Nuss, Jonathan E.
    Nagle, Elyse R.
    Kugelman, Jeffrey R.
    Palacios, Gustavo
    Doerffler, Edward
    Neville, Sean
    Carra, Ernest
    Clarke, Michael O.
    Zhang, Lijun
    Lew, Willard
    Ross, Bruce
    Wang, Queenie
    Chun, Kwon
    Wolfe, Lydia
    Babusis, Darius
    Park, Yeojin
    Stray, Kirsten M.
    Trancheva, Iva
    Feng, Joy Y.
    Barauskas, Ona
    Xu, Yili
    Wong, Pamela
    [J]. NATURE, 2016, 531 (7594) : 381 - +