Inhibitor recognition specificity of MERS-CoV papain-like protease may differ from that of SARS-CoV.

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ID: 100779
2015
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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).
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lee2015inhibitoracs Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Lee, Hyun;Lei, Hao;Santarsiero, Bernard D;Gatuz, Joseph L;Cao, Shuyi;Rice, Amy J;Patel, Kavankumar;Szypulinski, Michael Z;Ojeda, Isabel;Ghosh, Arun K;Johnson, Michael E;
Journal ACS chemical biology
Year 2015
DOI
10.1021/cb500917m
URL
Keywords Keywords not found

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