Synergistic Inhibitor Binding to the Papain‐Like Protease of Human SARS Coronavirus: Mechanistic and Inhibitor Design Implications

Lee, Hyun; Cao, Shuyi; Hevener, Kirk E.; Truong, Lena; Gatuz, Joseph L.; Patel, Kavankumar; Ghosh, Arun K.; Johnson, Michael E.

doi:10.1002/cmdc.201300134

Cited by 21 publications

(20 citation statements)

References 45 publications

(37 reference statements)

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“…Mechanism of inhibition studies revealed that these compounds are mixed-type inhibitors with α values greater than 1, indicating that they bind to an allosteric site other than its catalytic site, but behave as if they are competitive inhibitors 35 . As noted above, these lead inhibitors bind to the flexible BL2 region and induce conformational changes to block substrate access to the catalytic site of the enzyme 27, 28 .…”

Section: Resultsmentioning

confidence: 99%

Inhibitor Recognition Specificity of MERS-CoV Papain-like Protease May Differ from That of SARS-CoV

et al. 2015

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The Middle East Respiratory Syndrome coronavirus (MERS-CoV) papain-like protease (PLpro) blocking loop 2 (BL2) structure differs significantly from that of SARS-CoV PLpro, where it has been proven to play a crucial role in SARS-CoV PLpro inhibitor binding. Four SARS-CoV PLpro lead inhibitors were tested against MERS-CoV PLpro, none of which were effective against MERS-CoV PLpro. Structure and sequence alignments revealed that two residues, Y269 and Q270, responsible for inhibitor binding to SARS-CoV PLpro were replaced by T274 and A275 in MERS-CoV PLpro, making critical binding interactions difficult to form for similar types of inhibitors. High-throughput screening (HTS) of 25,000 compounds against both PLpro enzymes identified a small fragment-like noncovalent dual inhibitor. Mode of inhibition studies by enzyme kinetics and competition surface plasmon resonance (SPR) analyses suggested that this compound acts as a competitive inhibitor with an IC50 of 6 µM against MERS-CoV PLpro, indicating that it binds to the active site, whereas it acts as an allosteric inhibitor against SARS-CoV PLpro with an IC50 of 11 µM. These results raised the possibility that inhibitor recognition specificity of MERS-CoV PLpro may differ from that of SARS-CoV PLpro. In addition, inhibitory activity of this compound was selective for SARS-CoV and MERS-CoV PLpro enzymes over two human homologues, the ubiquitin C-terminal hydrolases 1 and 3 (hUCH-L1 and hUCH-L3).

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Section: Resultsmentioning

confidence: 99%

Inhibitor Recognition Specificity of MERS-CoV Papain-like Protease May Differ from That of SARS-CoV

et al. 2015

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“…GRL-0617, a highly effective SARS-CoV PL pro inhibitor whose binding site is in the S3-S4 site, also has a noncompetitive inhibition mechanism (Lee et al, 2013). As there are significant differences in the S3 subsite, as well as in the BL2 loop, between the SARS-CoV and MERS-CoV PL pro s, it is unlikely that GRL0617 and its derivatives will also inhibit MERS-CoV PL pro (Lei et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus

Cheng¹,

et al. 2015

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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.

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“…The involvement of PL pro in the maturation of the viral polyprotein and its role in counteracting cellular antiviral signaling pathways have contributed to its recognition as a promising target for therapeutic intervention, and the availability of X-ray crystallographic data [135,140], along with work describing the substrate specificity of PL pro at its cognate subsites [145,146], has contributed to such efforts. Highthroughput screening of small-molecule libraries and rational structure-guided design have led to the identification and development of several lead compounds capable of inhibiting the proteolytic activities of SARS-CoV PL pro [147][148][149][150][151][152][153][154].…”

Section: Sars-cov Pl Promentioning

confidence: 99%

Structure and Function of Viral Deubiquitinating Enzymes

Bailey-Elkin

Knaap

Kikkert

et al. 2017

Journal of Molecular Biology

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Post-translational modification of cellular proteins by ubiquitin regulates numerous cellular processes, including innate and adaptive immune responses. Ubiquitin-mediated control over these processes can be reversed by cellular deubiquitinating enzymes (DUBs), which remove ubiquitin from cellular targets and depolymerize polyubiquitin chains. The importance of protein ubiquitination to host immunity has been underscored by the discovery of viruses that encode proteases with deubiquitinating activity, many of which have been demonstrated to actively corrupt cellular ubiquitin-dependent processes to suppress innate antiviral responses and promote viral replication. DUBs have now been identified in diverse viral lineages, and their characterization is providing valuable insights into virus biology and the role of the ubiquitin system in host antiviral mechanisms. Here, we provide an overview of the structural biology of these fascinating viral enzymes and their role innate immune evasion and viral replication.

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Synergistic Inhibitor Binding to the Papain‐Like Protease of Human SARS Coronavirus: Mechanistic and Inhibitor Design Implications

Cited by 21 publications

References 45 publications

Inhibitor Recognition Specificity of MERS-CoV Papain-like Protease May Differ from That of SARS-CoV

Inhibitor Recognition Specificity of MERS-CoV Papain-like Protease May Differ from That of SARS-CoV

Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus

Structure and Function of Viral Deubiquitinating Enzymes

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