Yeast-based assays for the high-throughput screening of inhibitors of coronavirus RNA cap guanine-N7-methyltransferase.
Identifieur interne : 001529 ( Main/Exploration ); précédent : 001528; suivant : 001530Yeast-based assays for the high-throughput screening of inhibitors of coronavirus RNA cap guanine-N7-methyltransferase.
Auteurs : Ying Sun [République populaire de Chine] ; Zidao Wang [République populaire de Chine] ; Jiali Tao [République populaire de Chine] ; Yi Wang [République populaire de Chine] ; Andong Wu [République populaire de Chine] ; Ziwen Yang [République populaire de Chine] ; Kaimei Wang [République populaire de Chine] ; Liqiao Shi [République populaire de Chine] ; Yu Chen [République populaire de Chine] ; Deyin Guo [République populaire de Chine]Source :
- Antiviral research [ 1872-9096 ] ; 2014.
Descripteurs français
- KwdFr :
- Activation enzymatique (), Antienzymes (pharmacologie), Antiviraux (pharmacologie), Coiffes des ARN (métabolisme), Concentration inhibitrice 50, Coronavirus (), Coronavirus (enzymologie), Guanine (métabolisme), Levures (), Levures (génétique), Levures (métabolisme), Methyltransferases (antagonistes et inhibiteurs), Produits biologiques (pharmacologie), Relation dose-effet des médicaments, Tests de criblage à haut débit, Virus du SRAS (), Virus du SRAS (enzymologie).
- MESH :
- antagonistes et inhibiteurs : Methyltransferases.
- enzymologie : Coronavirus, Virus du SRAS.
- génétique : Levures.
- métabolisme : Coiffes des ARN, Guanine, Levures.
- pharmacologie : Antienzymes, Antiviraux, Produits biologiques.
- Activation enzymatique, Concentration inhibitrice 50, Coronavirus, Levures, Relation dose-effet des médicaments, Tests de criblage à haut débit, Virus du SRAS.
English descriptors
- KwdEn :
- Antiviral Agents (pharmacology), Biological Products (pharmacology), Coronavirus (drug effects), Coronavirus (enzymology), Dose-Response Relationship, Drug, Enzyme Activation (drug effects), Enzyme Inhibitors (pharmacology), Guanine (metabolism), High-Throughput Screening Assays, Inhibitory Concentration 50, Methyltransferases (antagonists & inhibitors), RNA Caps (metabolism), SARS Virus (drug effects), SARS Virus (enzymology), Yeasts (drug effects), Yeasts (genetics), Yeasts (metabolism).
- MESH :
- chemical , antagonists & inhibitors : Methyltransferases.
- chemical , metabolism : Guanine, RNA Caps.
- chemical , pharmacology : Antiviral Agents, Biological Products, Enzyme Inhibitors.
- drug effects : Coronavirus, Enzyme Activation, SARS Virus, Yeasts.
- enzymology : Coronavirus, SARS Virus.
- genetics : Yeasts.
- metabolism : Yeasts.
- Dose-Response Relationship, Drug, High-Throughput Screening Assays, Inhibitory Concentration 50.
Abstract
The 5'-cap structure is a distinct feature of eukaryotic mRNAs and is important for RNA stability and protein translation by providing a molecular signature for the distinction of self or non-self mRNA. Eukaryotic viruses generally modify the 5'-end of their RNAs to mimic the cellular mRNA structure, thereby facilitating viral replication in host cells. However, the molecular organization and biochemical mechanisms of the viral capping apparatus typically differ from its cellular counterpart, which makes viral capping enzymes attractive targets for drug discovery. Our previous work showed that SARS coronavirus (SARS-CoV) non-structural protein 14 represents a structurally novel and unique guanine-N7-methyltransferase (N7-MTase) that is able to functionally complement yeast cellular N7-MTase. In the present study, we developed a yeast-based system for identifying and screening inhibitors against coronavirus N7-MTase using both 96-well and 384-well microtiter plates. The MTase inhibitors previously identified by in vitro biochemical assays were tested, and some, such as sinefungin, effectively suppressed N7-MTase in the yeast system. However, other compounds, such as ATA and AdoHcy, did not exert an inhibitory effect within a cellular context. These results validated the yeast assay system for inhibitor screening yet also demonstrated the difference between cell-based and in vitro biochemical assays. The yeast system was applied to the screening of 3000 natural product extracts, and three were observed to more potently inhibit the activity of coronavirus than human N7-MTase.
DOI: 10.1016/j.antiviral.2014.02.002
PubMed: 24530452
Affiliations:
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Le document en format XML
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<front><div type="abstract" xml:lang="en">The 5'-cap structure is a distinct feature of eukaryotic mRNAs and is important for RNA stability and protein translation by providing a molecular signature for the distinction of self or non-self mRNA. Eukaryotic viruses generally modify the 5'-end of their RNAs to mimic the cellular mRNA structure, thereby facilitating viral replication in host cells. However, the molecular organization and biochemical mechanisms of the viral capping apparatus typically differ from its cellular counterpart, which makes viral capping enzymes attractive targets for drug discovery. Our previous work showed that SARS coronavirus (SARS-CoV) non-structural protein 14 represents a structurally novel and unique guanine-N7-methyltransferase (N7-MTase) that is able to functionally complement yeast cellular N7-MTase. In the present study, we developed a yeast-based system for identifying and screening inhibitors against coronavirus N7-MTase using both 96-well and 384-well microtiter plates. The MTase inhibitors previously identified by in vitro biochemical assays were tested, and some, such as sinefungin, effectively suppressed N7-MTase in the yeast system. However, other compounds, such as ATA and AdoHcy, did not exert an inhibitory effect within a cellular context. These results validated the yeast assay system for inhibitor screening yet also demonstrated the difference between cell-based and in vitro biochemical assays. The yeast system was applied to the screening of 3000 natural product extracts, and three were observed to more potently inhibit the activity of coronavirus than human N7-MTase. </div>
</front>
</TEI>
<affiliations><list><country><li>République populaire de Chine</li>
</country>
<region><li>Hubei</li>
</region>
<settlement><li>Wuhan</li>
</settlement>
<orgName><li>Université de Wuhan</li>
</orgName>
</list>
<tree><country name="République populaire de Chine"><region name="Hubei"><name sortKey="Sun, Ying" sort="Sun, Ying" uniqKey="Sun Y" first="Ying" last="Sun">Ying Sun</name>
</region>
<name sortKey="Chen, Yu" sort="Chen, Yu" uniqKey="Chen Y" first="Yu" last="Chen">Yu Chen</name>
<name sortKey="Guo, Deyin" sort="Guo, Deyin" uniqKey="Guo D" first="Deyin" last="Guo">Deyin Guo</name>
<name sortKey="Shi, Liqiao" sort="Shi, Liqiao" uniqKey="Shi L" first="Liqiao" last="Shi">Liqiao Shi</name>
<name sortKey="Tao, Jiali" sort="Tao, Jiali" uniqKey="Tao J" first="Jiali" last="Tao">Jiali Tao</name>
<name sortKey="Wang, Kaimei" sort="Wang, Kaimei" uniqKey="Wang K" first="Kaimei" last="Wang">Kaimei Wang</name>
<name sortKey="Wang, Yi" sort="Wang, Yi" uniqKey="Wang Y" first="Yi" last="Wang">Yi Wang</name>
<name sortKey="Wang, Zidao" sort="Wang, Zidao" uniqKey="Wang Z" first="Zidao" last="Wang">Zidao Wang</name>
<name sortKey="Wu, Andong" sort="Wu, Andong" uniqKey="Wu A" first="Andong" last="Wu">Andong Wu</name>
<name sortKey="Yang, Ziwen" sort="Yang, Ziwen" uniqKey="Yang Z" first="Ziwen" last="Yang">Ziwen Yang</name>
</country>
</tree>
</affiliations>
</record>
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