title: Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus.
abstract: Middle East respiratory syndrome coronavirus (MERS-CoV) is a new highly pathogenic human coronaviruses that emerged in Jeddah and Saudi Arabia and has quickly spread to other countries in Middle East, Europe and North Africa since 2012. Up to 17 December 2014, it has infected at least 938 people with a fatality rate of about 36% globally. This has resulted in an urgent need to identify antiviral drugs that are active against MERS-CoV. The papain-like protease (PL(pro)) of MERS-CoV represents an important antiviral target as it is not only essential for viral maturation, but also antagonizes interferon stimulation of the host via its deubiquitination activity. Here, we report the discovery that two SARS-CoV PL(pro) inhibitors, 6-mercaptopurine (6MP) and 6-thioguanine (6TG), as well as the immunosuppressive drug mycophenolic acid, are able to inhibit MERS-CoV PL(pro). Their inhibition mechanisms and mutually binding synergistic effect were also investigated. Our results identify for the first time three inhibitors targeting MERS-CoV PL(pro) and these can now be used as lead compounds for further antiviral drug development.
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Kai-Wen
authors.initials: KW
authors.lastname: Cheng
authors.affiliation: Department of Nephrology, Chang-Gung Memorial Hospital, Keelung 204, Taiwan.
authors.forename: Shu-Chun
authors.initials: SC
authors.lastname: Cheng
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Chen
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Min-Han
authors.initials: MH
authors.lastname: Lin
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Shang-Ju
authors.initials: SJ
authors.lastname: Chuang
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: I-Hsin
authors.initials: IH
authors.lastname: Cheng
authors.affiliation: Department of Nephrology, Chang-Gung Memorial Hospital, Keelung 204, Taiwan. Electronic address: fish3970@gmail.com.
authors.forename: Chiao-Yin
authors.initials: CY
authors.lastname: Sun
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan. Electronic address: cychou@ym.edu.tw.
authors.forename: Chi-Yuan
authors.initials: CY
authors.lastname: Chou
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D000086782:Coronavirus 3C Proteases; D003546:Cysteine Endopeptidases; D057056:Cysteine Proteases / Q000737:chemistry / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D015122:Mercaptopurine / Q000494:pharmacology*; D065207:Middle East Respiratory Syndrome Coronavirus / Q000187:drug effects* / Q000201:enzymology; D008958:Models, Molecular; D009173:Mycophenolic Acid / Q000494:pharmacology*; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects / Q000201:enzymology; D013866:Thioguanine / Q000494:pharmacology*; D014764:Viral Proteins / Q000037:antagonists & inhibitors
chemical_list: D000998:Antiviral Agents; D015853:Cysteine Proteinase Inhibitors; D014764:Viral Proteins; D015122:Mercaptopurine; D057056:Cysteine Proteases; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases; D013866:Thioguanine; D009173:Mycophenolic Acid
keywords: 6-Mercaptopurine; 6-Thioguanine; MERS-CoV papain-like protease; Mycophenolic acid; Synergistic inhibition