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Inhibitor recognition specificity of MERS-CoV papain-like protease may differ from that of SARS-CoV.
ACS Chem Biol. 2015 Jun 19; 10(6):1456-65.AC

Abstract

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).

Authors+Show Affiliations

†Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, Chicago, Illinois 60607, United States.†Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, Chicago, Illinois 60607, United States.†Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, Chicago, Illinois 60607, United States.†Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, Chicago, Illinois 60607, United States.†Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, Chicago, Illinois 60607, United States.†Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, Chicago, Illinois 60607, United States.†Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, Chicago, Illinois 60607, United States.†Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, Chicago, Illinois 60607, United States.No affiliation info available‡Departments of Chemistry and Medicinal Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States.†Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, Chicago, Illinois 60607, United States.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

25746232

Citation

Lee, Hyun, et al. "Inhibitor Recognition Specificity of MERS-CoV Papain-like Protease May Differ From That of SARS-CoV." ACS Chemical Biology, vol. 10, no. 6, 2015, pp. 1456-65.
Lee H, Lei H, Santarsiero BD, et al. Inhibitor recognition specificity of MERS-CoV papain-like protease may differ from that of SARS-CoV. ACS Chem Biol. 2015;10(6):1456-65.
Lee, H., Lei, H., Santarsiero, B. D., Gatuz, J. L., Cao, S., Rice, A. J., Patel, K., Szypulinski, M. Z., Ojeda, I., Ghosh, A. K., & Johnson, M. E. (2015). Inhibitor recognition specificity of MERS-CoV papain-like protease may differ from that of SARS-CoV. ACS Chemical Biology, 10(6), 1456-65. https://doi.org/10.1021/cb500917m
Lee H, et al. Inhibitor Recognition Specificity of MERS-CoV Papain-like Protease May Differ From That of SARS-CoV. ACS Chem Biol. 2015 Jun 19;10(6):1456-65. PubMed PMID: 25746232.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibitor recognition specificity of MERS-CoV papain-like protease may differ from that of SARS-CoV. AU - Lee,Hyun, AU - Lei,Hao, AU - Santarsiero,Bernard D, AU - Gatuz,Joseph L, AU - Cao,Shuyi, AU - Rice,Amy J, AU - Patel,Kavankumar, AU - Szypulinski,Michael Z, AU - Ojeda,Isabel, AU - Ghosh,Arun K, AU - Johnson,Michael E, Y1 - 2015/03/16/ PY - 2015/3/10/entrez PY - 2015/3/10/pubmed PY - 2016/3/11/medline SP - 1456 EP - 65 JF - ACS chemical biology JO - ACS Chem. Biol. VL - 10 IS - 6 N2 - 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). SN - 1554-8937 UR - https://www.unboundmedicine.com/medline/citation/25746232/Inhibitor_recognition_specificity_of_MERS_CoV_papain_like_protease_may_differ_from_that_of_SARS_CoV_ L2 - https://dx.doi.org/10.1021/cb500917m DB - PRIME DP - Unbound Medicine ER -