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.

Learning from the Past: Possible Urgent Prevention and Treatment Options for Severe Acute Respiratory Infections Caused by 2019‐nCoV

“…[40][41][42][43][44][45] However,a few low-nm-range inhibitors have been identified that can be used in combination with other protease-inhibitor therapies to help combat the virus. Many of the inhibitors are in the micromolar range in terms of binding to and inhibiting the two proteases.…”

“…In a FRET-baseda ctivity assay,t he IC 50 value of GC376a gainst recombinant SARS 3CLpro was found to be 4.9 times that against FIPV 3CLpro( 4.35 vs. 0.72 mm,r espectively). Arepresentation of the top CoV protease inhibitors providing ascaffold to perform SAR studies in termsofdesigning novel small-molecule protease inhibitors for 2019-nCoV [40][41][42][43][44][45]49] .3 CLpro-1, the most potent inhibitor,ish ighlighted. Figure 7.…”

MERS-CoV spike protein: Targets for vaccines and therapeutics

“…Nonetheless, many antiviral agents have been identified, which have been summarized in several excellent reviews (Adedeji and Sarafianos, 2014;Keum and Jeong, 2012;Kumar et al, 2013;Liang, 2006;Ramajayam et al, 2011;Yang et al, 2006). Small molecules, such as 5chloropyridine ester, 6-mercaptopurine, and 6-thioguanine targeting MERS-CoV 3CL pro or PL pro have shown efficacy in inhibiting MERS-CoV replication in vitro (Chan et al, 2013;Cheng et al, 2015;Kilianski et al, 2013), though their activity and cytotoxicity needs to be further assessed in vivo. Small molecules, such as 5chloropyridine ester, 6-mercaptopurine, and 6-thioguanine targeting MERS-CoV 3CL pro or PL pro have shown efficacy in inhibiting MERS-CoV replication in vitro (Chan et al, 2013;Cheng et al, 2015;Kilianski et al, 2013), though their activity and cytotoxicity needs to be further assessed in vivo.…”

Middle East Respiratory Syndrome (MERS): The Emerging Zoonoses

“…Although, MERS-CoV has been shown to antagonize endogenous interferon (IFN) production, treatment with exogenous types I and III IFN (IFN-α and IFN-λ, respectively) have effectively reduced viral replication in vitro.When rhesus macaques were given interferon-α2b and ribavirin and exposed to MERS, they developed less pneumonia than control animals (Falzarano et al, 2013). Researchers are investigating a number of ways to combat the outbreak of Middle East respiratory syndrome coronavirus, including using interferon, chloroquine, chlorpromazine, loperamide and lopinavir as well as other agents such as mycophenolic acid and camostat (Chan et al, 2015;Cheng et al, 2015).…”