Interferon-β and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays

被引:172
作者
Hart, Brit J. [1 ]
Dyall, Julie [1 ]
Postnikova, Elena [1 ]
Zhou, Huanying [1 ]
Kindrachuk, Jason [1 ]
Johnson, Reed F. [2 ]
Olinger, Gene G., Jr. [1 ]
Frieman, Matthew B. [3 ]
Holbrook, Michael R. [1 ]
Jahrling, Peter B. [1 ,2 ]
Hensley, Lisa [1 ]
机构
[1] NIAID, Integrated Res Facil, NIH, Frederick, MD 21703 USA
[2] NIAID, Emerging Viral Pathogens Sect, NIH, Frederick, MD USA
[3] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA
关键词
IN-VITRO; C VIRUS; ANTIVIRAL ACTIVITY; CYCLOSPORINE-A; RIBAVIRIN; COV; REPLICATION;
D O I
10.1099/vir.0.061911-0
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
The Middle East respiratory syndrome coronavirus (MERS-CoV) presents a novel emerging threat to public health worldwide. Several treatments for infected individuals have been suggested including IFN, ribavirin and passive immunotherapy with convalescent plasma. Administration of IFN-alpha 2b and ribavirin has improved outcomes of MERS-CoV infection in rhesus macaques when administered within 8 h post-challenge. However, detailed and systematic evidence on the activity of other clinically available drugs is limited. Here we compared the susceptibility of MERS-CoV with different IFN products (IFN-alpha 2b, IFN-gamma, IFN-universal, IFN-alpha 2a and IFN-beta), as well as with two antivirals, ribavirin and mycophenolic acid (MPA), against MERS-CoV (Hu/Jordan-N3/2012) in vitro. Of all the IFNs tested, IFN-beta showed the strongst inhibition of MERS-CoV in vitro, with an IC50 of 1.37 U ml(-1), 41 times lower than the previously reported IC50 (56.08 U ml(-1)) of IFN-alpha 2b. IFN-beta inhibition was confirmed in the virus yield reduction assay, with an IC90 of 38.8 U ml(-1). Ribavirin did not inhibit viral replication in vitro at a dose that would be applicable to current treatment protocols in humans. In contrast, MPA showed strong inhibition, with an IC50 of 2.87 mu M. This drug has not been previously tested against MERS-CoV and may provide an alternative to ribavirin for treatment of MERS-CoV. In conclusion, IFN-beta, MPA or a combination of the two may be beneficial in the treatment of MERS-CoV or as a post-exposure intervention in high-risk patients with known exposures to MERS-CoV.
引用
收藏
页码:571 / 577
页数:7
相关论文
共 21 条
[1]  
[Anonymous], CLIN DEC MAK TOOL TR
[2]   Enhancement of the infectivity of SARS-CoV in BALB/c mice by IMP dehydrogenase inhibitors, including ribavirin [J].
Barnard, Dale L. ;
Day, Craig W. ;
Bailey, Kevin ;
Heiner, Matthew ;
Montgomery, Robert ;
Lauridsen, Larry ;
Winslow, Scott ;
Hoopes, Justin ;
Li, Joseph K. -K. ;
Lee, Jongdae ;
Carson, Dennis A. ;
Cottam, Howard B. ;
Sidwell, Robert W. .
ANTIVIRAL RESEARCH, 2006, 71 (01) :53-63
[3]  
Brown C., 2013, TREATMENT MERS COV D
[4]   Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus [J].
Chan, Jasper F. W. ;
Chan, Kwok-Hung ;
Kao, Richard Y. T. ;
To, Kelvin K. W. ;
Zheng, Bo-Jian ;
Li, Clara P. Y. ;
Li, Patrick T. W. ;
Dai, Jun ;
Mok, Florence K. Y. ;
Chen, Honglin ;
Hayden, Frederick G. ;
Yuen, Kwok-Yung .
JOURNAL OF INFECTION, 2013, 67 (06) :606-616
[5]   Tropism of and Innate Immune Responses to the Novel Human Betacoronavirus Lineage C Virus in Human Ex Vivo Respiratory Organ Cultures [J].
Chan, Renee W. Y. ;
Chan, Michael C. W. ;
Agnihothram, Sudhakar ;
Chan, Louisa L. Y. ;
Kuok, Denise I. T. ;
Fong, Joanne H. M. ;
Guan, Y. ;
Poon, Leo L. M. ;
Baric, Ralph S. ;
Nicholls, John M. ;
Peiris, J. S. Malik .
JOURNAL OF VIROLOGY, 2013, 87 (12) :6604-6614
[6]   Middle East Respiratory Syndrome Coronavirus (MERS-CoV): Announcement of the Coronavirus Study Group [J].
de Groot, Raoul J. ;
Baker, Susan C. ;
Baric, Ralph S. ;
Brown, Caroline S. ;
Drosten, Christian ;
Enjuanes, Luis ;
Fouchier, Ron A. M. ;
Galiano, Monica ;
Gorbalenya, Alexander E. ;
Memish, Ziad A. ;
Perlman, Stanley ;
Poon, Leo L. M. ;
Snijder, Eric J. ;
Stephens, Gwen M. ;
Woo, Patrick C. Y. ;
Zaki, Ali M. ;
Zambon, Maria ;
Ziebuhr, John .
JOURNAL OF VIROLOGY, 2013, 87 (14) :7790-7792
[7]   MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-α treatment [J].
de Wilde, Adriaan H. ;
Raj, V. Stalin ;
Oudshoorn, Diede ;
Bestebroer, Theo M. ;
van Nieuwkoop, Stefan ;
Limpens, Ronald W. A. L. ;
Posthuma, Clara C. ;
van der Meer, Yvonne ;
Barcena, Montserrat ;
Haagmans, Bart L. ;
Snijder, Eric J. ;
van den Hoogen, Bernadette G. .
JOURNAL OF GENERAL VIROLOGY, 2013, 94 :1749-1760
[8]   Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques [J].
Falzarano, Darryl ;
de Wit, Emmie ;
Rasmussen, Angela L. ;
Feldmann, Friederike ;
Okumura, Atsushi ;
Scott, Dana P. ;
Brining, Doug ;
Bushmaker, Trenton ;
Martellaro, Cynthia ;
Baseler, Laura ;
Benecke, Arndt G. ;
Katze, Michael G. ;
Munster, Vincent J. ;
Feldmann, Heinz .
NATURE MEDICINE, 2013, 19 (10) :1313-+
[9]   Mycophenolic acid inhibits hepatitis C virus replication and acts in synergy with cyclosporin A and interferon-α [J].
Henry, Scot D. ;
Metselaar, Herold J. ;
Lonsdale, Richard C. B. ;
Kok, Alice ;
Haagmans, Bart L. ;
Tilanus, Hugo W. ;
Van der Laan, Luc J. W. .
GASTROENTEROLOGY, 2006, 131 (05) :1452-1462
[10]   Gene Expression Signature-Based Screening Identifies New Broadly Effective Influenza A Antivirals [J].
Josset, Laurence ;
Textoris, Julien ;
Loriod, Beatrice ;
Ferraris, Olivier ;
Moules, Vincent ;
Lina, Bruno ;
N'Guyen, Catherine ;
Diaz, Jean-Jacques ;
Rosa-Calatrava, Manuel .
PLOS ONE, 2010, 5 (10)