SrasV1, Main, Exploration, bibRecord, 001297

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

Identifieur interne : 001297 ( Main/Exploration ); précédent : 001296; suivant : 001298

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

Auteurs : Hyun Lee [États-Unis] ; Hao Lei [États-Unis] ; Bernard D. Santarsiero [États-Unis] ; Joseph L. Gatuz [États-Unis] ; Shuyi Cao [États-Unis] ; Amy J. Rice [États-Unis] ; Kavankumar Patel [États-Unis] ; Michael Z. Szypulinski [États-Unis] ; Isabel Ojeda ; Arun K. Ghosh [États-Unis] ; Michael E. Johnson [États-Unis]

Source :

ACS chemical biology [ 1554-8937 ] ; 2015.

RBID : pubmed:25746232

Descripteurs français

English descriptors

KwdEn :
- Allosteric Regulation, Amino Acid Sequence, Antiviral Agents (chemistry), Catalytic Domain, Cysteine Endopeptidases (chemistry), Endopeptidases (chemistry), High-Throughput Screening Assays, Humans, Kinetics, Middle East Respiratory Syndrome Coronavirus (chemistry), Middle East Respiratory Syndrome Coronavirus (enzymology), Models, Molecular, Molecular Sequence Data, Protease Inhibitors (chemistry), Protein Binding, Protein Structure, Secondary, Recombinant Proteins (chemistry), SARS Virus (chemistry), SARS Virus (enzymology), Species Specificity, Surface Plasmon Resonance, Ubiquitin Thiolesterase (antagonists & inhibitors), Ubiquitin Thiolesterase (chemistry), Viral Proteins (antagonists & inhibitors), Viral Proteins (chemistry).
MESH :
- chemical , antagonists & inhibitors : Ubiquitin Thiolesterase, Viral Proteins.
- chemical , chemistry : Antiviral Agents, Cysteine Endopeptidases, Endopeptidases, Protease Inhibitors, Recombinant Proteins, Ubiquitin Thiolesterase, Viral Proteins.
- chemistry : Middle East Respiratory Syndrome Coronavirus, SARS Virus.
- enzymology : Middle East Respiratory Syndrome Coronavirus, SARS Virus.
- Allosteric Regulation, Amino Acid Sequence, Catalytic Domain, High-Throughput Screening Assays, Humans, Kinetics, Models, Molecular, Molecular Sequence Data, Protein Binding, Protein Structure, Secondary, Species Specificity, Surface Plasmon Resonance.

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).

DOI: 10.1021/cb500917m
PubMed: 25746232

Affiliations:

Le document en format XML

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<country xml:lang="fr">États-Unis</country>
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<term>Amino Acid Sequence</term>
<term>Antiviral Agents (chemistry)</term>
<term>Catalytic Domain</term>
<term>Cysteine Endopeptidases (chemistry)</term>
<term>Endopeptidases (chemistry)</term>
<term>High-Throughput Screening Assays</term>
<term>Humans</term>
<term>Kinetics</term>
<term>Middle East Respiratory Syndrome Coronavirus (chemistry)</term>
<term>Middle East Respiratory Syndrome Coronavirus (enzymology)</term>
<term>Models, Molecular</term>
<term>Molecular Sequence Data</term>
<term>Protease Inhibitors (chemistry)</term>
<term>Protein Binding</term>
<term>Protein Structure, Secondary</term>
<term>Recombinant Proteins (chemistry)</term>
<term>SARS Virus (chemistry)</term>
<term>SARS Virus (enzymology)</term>
<term>Species Specificity</term>
<term>Surface Plasmon Resonance</term>
<term>Ubiquitin Thiolesterase (antagonists & inhibitors)</term>
<term>Ubiquitin Thiolesterase (chemistry)</term>
<term>Viral Proteins (antagonists & inhibitors)</term>
<term>Viral Proteins (chemistry)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Antiviraux ()</term>
<term>Cinétique</term>
<term>Coronavirus du syndrome respiratoire du Moyen-Orient ()</term>
<term>Coronavirus du syndrome respiratoire du Moyen-Orient (enzymologie)</term>
<term>Cysteine endopeptidases ()</term>
<term>Domaine catalytique</term>
<term>Données de séquences moléculaires</term>
<term>Endopeptidases ()</term>
<term>Humains</term>
<term>Inhibiteurs de protéases ()</term>
<term>Liaison aux protéines</term>
<term>Modèles moléculaires</term>
<term>Protéines recombinantes ()</term>
<term>Protéines virales ()</term>
<term>Protéines virales (antagonistes et inhibiteurs)</term>
<term>Régulation allostérique</term>
<term>Résonance plasmonique de surface</term>
<term>Spécificité d'espèce</term>
<term>Structure secondaire des protéines</term>
<term>Séquence d'acides aminés</term>
<term>Tests de criblage à haut débit</term>
<term>Ubiquitin thiolesterase ()</term>
<term>Ubiquitin thiolesterase (antagonistes et inhibiteurs)</term>
<term>Virus du SRAS ()</term>
<term>Virus du SRAS (enzymologie)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Ubiquitin Thiolesterase</term>
<term>Viral Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antiviral Agents</term>
<term>Cysteine Endopeptidases</term>
<term>Endopeptidases</term>
<term>Protease Inhibitors</term>
<term>Recombinant Proteins</term>
<term>Ubiquitin Thiolesterase</term>
<term>Viral Proteins</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines virales</term>
<term>Ubiquitin thiolesterase</term>
</keywords>
<keywords scheme="MESH" qualifier="chemistry" xml:lang="en"><term>Middle East Respiratory Syndrome Coronavirus</term>
<term>SARS Virus</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term>
<term>Virus du SRAS</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Middle East Respiratory Syndrome Coronavirus</term>
<term>SARS Virus</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Allosteric Regulation</term>
<term>Amino Acid Sequence</term>
<term>Catalytic Domain</term>
<term>High-Throughput Screening Assays</term>
<term>Humans</term>
<term>Kinetics</term>
<term>Models, Molecular</term>
<term>Molecular Sequence Data</term>
<term>Protein Binding</term>
<term>Protein Structure, Secondary</term>
<term>Species Specificity</term>
<term>Surface Plasmon Resonance</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Antiviraux</term>
<term>Cinétique</term>
<term>Coronavirus du syndrome respiratoire du Moyen-Orient</term>
<term>Cysteine endopeptidases</term>
<term>Domaine catalytique</term>
<term>Données de séquences moléculaires</term>
<term>Endopeptidases</term>
<term>Humains</term>
<term>Inhibiteurs de protéases</term>
<term>Liaison aux protéines</term>
<term>Modèles moléculaires</term>
<term>Protéines recombinantes</term>
<term>Protéines virales</term>
<term>Régulation allostérique</term>
<term>Résonance plasmonique de surface</term>
<term>Spécificité d'espèce</term>
<term>Structure secondaire des protéines</term>
<term>Séquence d'acides aminés</term>
<term>Tests de criblage à haut débit</term>
<term>Ubiquitin thiolesterase</term>
<term>Virus du SRAS</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">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). </div>
</front>
</TEI>
<affiliations><list><country><li>États-Unis</li>
</country>
<region><li>Illinois</li>
</region>
<settlement><li>Chicago</li>
</settlement>
<orgName><li>Université de l'Illinois à Chicago</li>
</orgName>
</list>
<tree><noCountry><name sortKey="Ojeda, Isabel" sort="Ojeda, Isabel" uniqKey="Ojeda I" first="Isabel" last="Ojeda">Isabel Ojeda</name>
</noCountry>
<country name="États-Unis"><region name="Illinois"><name sortKey="Lee, Hyun" sort="Lee, Hyun" uniqKey="Lee H" first="Hyun" last="Lee">Hyun Lee</name>
</region>
<name sortKey="Cao, Shuyi" sort="Cao, Shuyi" uniqKey="Cao S" first="Shuyi" last="Cao">Shuyi Cao</name>
<name sortKey="Gatuz, Joseph L" sort="Gatuz, Joseph L" uniqKey="Gatuz J" first="Joseph L" last="Gatuz">Joseph L. Gatuz</name>
<name sortKey="Ghosh, Arun K" sort="Ghosh, Arun K" uniqKey="Ghosh A" first="Arun K" last="Ghosh">Arun K. Ghosh</name>
<name sortKey="Johnson, Michael E" sort="Johnson, Michael E" uniqKey="Johnson M" first="Michael E" last="Johnson">Michael E. Johnson</name>
<name sortKey="Lei, Hao" sort="Lei, Hao" uniqKey="Lei H" first="Hao" last="Lei">Hao Lei</name>
<name sortKey="Patel, Kavankumar" sort="Patel, Kavankumar" uniqKey="Patel K" first="Kavankumar" last="Patel">Kavankumar Patel</name>
<name sortKey="Rice, Amy J" sort="Rice, Amy J" uniqKey="Rice A" first="Amy J" last="Rice">Amy J. Rice</name>
<name sortKey="Santarsiero, Bernard D" sort="Santarsiero, Bernard D" uniqKey="Santarsiero B" first="Bernard D" last="Santarsiero">Bernard D. Santarsiero</name>
<name sortKey="Szypulinski, Michael Z" sort="Szypulinski, Michael Z" uniqKey="Szypulinski M" first="Michael Z" last="Szypulinski">Michael Z. Szypulinski</name>
</country>
</tree>
</affiliations>
</record>

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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.

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