PandemieGrippaleV1, Main, Exploration, bibRecordById, PMC:5854701

Exploring Ugi-Azide Four-Component Reaction Products for Broad-Spectrum Influenza Antivirals with a High Genetic Barrier to Drug Resistance

Identifieur interne : 000531 ( Main/Exploration ); précédent : 000530; suivant : 000532

Exploring Ugi-Azide Four-Component Reaction Products for Broad-Spectrum Influenza Antivirals with a High Genetic Barrier to Drug Resistance

Auteurs : Jiantao Zhang [États-Unis] ; Yanmei Hu [États-Unis] ; Christopher Foley [États-Unis] ; Yuanxiang Wang [États-Unis] ; Rami Musharrafieh [États-Unis] ; Shuting Xu [États-Unis] ; Yongtao Zhang [États-Unis] ; Chunlong Ma [États-Unis] ; Christopher Hulme [États-Unis] ; Jun Wang [États-Unis]

Source :

Scientific Reports [ 2045-2322 ] ; 2018.

RBID : PMC:5854701

Descripteurs français

KwdFr :
- Antiviraux (), Antiviraux (pharmacologie), Azotures (), Bibliothèques de petites molécules (), Bibliothèques de petites molécules (pharmacologie), Cellules A549, Découverte de médicament, Grippe humaine (génétique), Grippe humaine (traitement médicamenteux), Grippe humaine (virologie), Génome viral, Génotype, Humains, Relation structure-activité, Réplication virale (), Résistance virale aux médicaments (génétique), Simulation de docking moléculaire, Survie cellulaire, Virus de la grippe A (), Virus de la grippe A (génétique).
MESH :
- génétique : Grippe humaine, Résistance virale aux médicaments, Virus de la grippe A.
- pharmacologie : Antiviraux, Bibliothèques de petites molécules.
- traitement médicamenteux : Grippe humaine.
- virologie : Grippe humaine.
- Antiviraux, Azotures, Bibliothèques de petites molécules, Cellules A549, Découverte de médicament, Génome viral, Génotype, Humains, Relation structure-activité, Réplication virale, Simulation de docking moléculaire, Survie cellulaire, Virus de la grippe A.

English descriptors

KwdEn :
- A549 Cells, Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Azides (chemistry), Cell Survival, Drug Discovery, Drug Resistance, Viral (genetics), Genome, Viral, Genotype, Humans, Influenza A virus (drug effects), Influenza A virus (genetics), Influenza, Human (drug therapy), Influenza, Human (genetics), Influenza, Human (virology), Molecular Docking Simulation, Small Molecule Libraries (chemistry), Small Molecule Libraries (pharmacology), Structure-Activity Relationship, Virus Replication (drug effects).
MESH :
- chemical , chemistry : Antiviral Agents, Azides, Small Molecule Libraries.
- chemical , pharmacology : Antiviral Agents, Small Molecule Libraries.
- drug effects : Influenza A virus, Virus Replication.
- drug therapy : Influenza, Human.
- genetics : Drug Resistance, Viral, Influenza A virus, Influenza, Human.
- virology : Influenza, Human.
- A549 Cells, Cell Survival, Drug Discovery, Genome, Viral, Genotype, Humans, Molecular Docking Simulation, Structure-Activity Relationship.

Abstract

Influenza viruses are respiratory pathogens that are responsible for seasonal influenza and sporadic influenza pandemic. The therapeutic efficacy of current influenza vaccines and small molecule antiviral drugs is limited due to the emergence of multidrug-resistant influenza viruses. In response to the urgent need for the next generation of influenza antivirals, we utilized a fast-track drug discovery platform by exploring multi-component reaction products for antiviral drug candidates. Specifically, molecular docking was applied to screen a small molecule library derived from the Ugi-azide four-component reaction methodology for inhibitors that target the influenza polymerase PA_C-PB1_N interactions. One hit compound 5 was confirmed to inhibit PA_C-PB1_N interactions in an ELISA assay and had potent antiviral activity in an antiviral plaque assay. Subsequent structure-activity relationship studies led to the discovery of compound 12a, which had broad-spectrum antiviral activity and a higher in vitro genetic barrier to drug resistance than oseltamivir. Overall, the discovery of compound 12a as a broad-spectrum influenza antiviral with a high in vitro genetic barrier to drug resistance is significant, as it offers a second line of defense to combat the next influenza epidemics and pandemics if vaccines and oseltamivir fail to confine the disease outbreak.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854701

DOI: 10.1038/s41598-018-22875-9
PubMed: 29545578
PubMed Central: 5854701

Affiliations:

Le document en format XML

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<term>Drug Resistance, Viral (genetics)</term>
<term>Genome, Viral</term>
<term>Genotype</term>
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<term>Influenza A virus (genetics)</term>
<term>Influenza, Human (drug therapy)</term>
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<term>Influenza, Human (virology)</term>
<term>Molecular Docking Simulation</term>
<term>Small Molecule Libraries (chemistry)</term>
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<term>Antiviraux (pharmacologie)</term>
<term>Azotures ()</term>
<term>Bibliothèques de petites molécules ()</term>
<term>Bibliothèques de petites molécules (pharmacologie)</term>
<term>Cellules A549</term>
<term>Découverte de médicament</term>
<term>Grippe humaine (génétique)</term>
<term>Grippe humaine (traitement médicamenteux)</term>
<term>Grippe humaine (virologie)</term>
<term>Génome viral</term>
<term>Génotype</term>
<term>Humains</term>
<term>Relation structure-activité</term>
<term>Réplication virale ()</term>
<term>Résistance virale aux médicaments (génétique)</term>
<term>Simulation de docking moléculaire</term>
<term>Survie cellulaire</term>
<term>Virus de la grippe A ()</term>
<term>Virus de la grippe A (génétique)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antiviral Agents</term>
<term>Azides</term>
<term>Small Molecule Libraries</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term>
<term>Small Molecule Libraries</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Influenza A virus</term>
<term>Virus Replication</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Influenza, Human</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Drug Resistance, Viral</term>
<term>Influenza A virus</term>
<term>Influenza, Human</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Grippe humaine</term>
<term>Résistance virale aux médicaments</term>
<term>Virus de la grippe A</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term>
<term>Bibliothèques de petites molécules</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Grippe humaine</term>
</keywords>
<keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Grippe humaine</term>
</keywords>
<keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Influenza, Human</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>A549 Cells</term>
<term>Cell Survival</term>
<term>Drug Discovery</term>
<term>Genome, Viral</term>
<term>Genotype</term>
<term>Humans</term>
<term>Molecular Docking Simulation</term>
<term>Structure-Activity Relationship</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Antiviraux</term>
<term>Azotures</term>
<term>Bibliothèques de petites molécules</term>
<term>Cellules A549</term>
<term>Découverte de médicament</term>
<term>Génome viral</term>
<term>Génotype</term>
<term>Humains</term>
<term>Relation structure-activité</term>
<term>Réplication virale</term>
<term>Simulation de docking moléculaire</term>
<term>Survie cellulaire</term>
<term>Virus de la grippe A</term>
</keywords>
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<front><div type="abstract" xml:lang="en"><p id="Par1">Influenza viruses are respiratory pathogens that are responsible for seasonal influenza and sporadic influenza pandemic. The therapeutic efficacy of current influenza vaccines and small molecule antiviral drugs is limited due to the emergence of multidrug-resistant influenza viruses. In response to the urgent need for the next generation of influenza antivirals, we utilized a fast-track drug discovery platform by exploring multi-component reaction products for antiviral drug candidates. Specifically, molecular docking was applied to screen a small molecule library derived from the Ugi-azide four-component reaction methodology for inhibitors that target the influenza polymerase PA<sub>C</sub>
-PB1<sub>N</sub>
 interactions. One hit compound <bold>5</bold>
 was confirmed to inhibit PA<sub>C</sub>
-PB1<sub>N</sub>
 interactions in an ELISA assay and had potent antiviral activity in an antiviral plaque assay. Subsequent structure-activity relationship studies led to the discovery of compound <bold>12a</bold>
, which had broad-spectrum antiviral activity and a higher <italic>in vitro</italic>
 genetic barrier to drug resistance than oseltamivir. Overall, the discovery of compound <bold>12a</bold>
 as a broad-spectrum influenza antiviral with a high <italic>in vitro</italic>
 genetic barrier to drug resistance is significant, as it offers a second line of defense to combat the next influenza epidemics and pandemics if vaccines and oseltamivir fail to confine the disease outbreak.</p>
</div>
</front>
<back><div1 type="bibliography"><listBibl><biblStruct></biblStruct>
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<biblStruct><analytic><author><name sortKey="Zhu, H" uniqKey="Zhu H">H Zhu</name>
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<biblStruct><analytic><author><name sortKey="Domling, A" uniqKey="Domling A">A Dömling</name>
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<author><name sortKey="Miranda, Ld" uniqKey="Miranda L">LD Miranda</name>
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<biblStruct><analytic><author><name sortKey="Brauch, S" uniqKey="Brauch S">S Brauch</name>
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<biblStruct><analytic><author><name sortKey="Pflug, A" uniqKey="Pflug A">A Pflug</name>
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</listBibl>
</div1>
</back>
</TEI>
<affiliations><list><country><li>États-Unis</li>
</country>
<region><li>Arizona</li>
</region>
</list>
<tree><country name="États-Unis"><region name="Arizona"><name sortKey="Zhang, Jiantao" sort="Zhang, Jiantao" uniqKey="Zhang J" first="Jiantao" last="Zhang">Jiantao Zhang</name>
</region>
<name sortKey="Foley, Christopher" sort="Foley, Christopher" uniqKey="Foley C" first="Christopher" last="Foley">Christopher Foley</name>
<name sortKey="Hu, Yanmei" sort="Hu, Yanmei" uniqKey="Hu Y" first="Yanmei" last="Hu">Yanmei Hu</name>
<name sortKey="Hulme, Christopher" sort="Hulme, Christopher" uniqKey="Hulme C" first="Christopher" last="Hulme">Christopher Hulme</name>
<name sortKey="Ma, Chunlong" sort="Ma, Chunlong" uniqKey="Ma C" first="Chunlong" last="Ma">Chunlong Ma</name>
<name sortKey="Musharrafieh, Rami" sort="Musharrafieh, Rami" uniqKey="Musharrafieh R" first="Rami" last="Musharrafieh">Rami Musharrafieh</name>
<name sortKey="Wang, Jun" sort="Wang, Jun" uniqKey="Wang J" first="Jun" last="Wang">Jun Wang</name>
<name sortKey="Wang, Jun" sort="Wang, Jun" uniqKey="Wang J" first="Jun" last="Wang">Jun Wang</name>
<name sortKey="Wang, Yuanxiang" sort="Wang, Yuanxiang" uniqKey="Wang Y" first="Yuanxiang" last="Wang">Yuanxiang Wang</name>
<name sortKey="Xu, Shuting" sort="Xu, Shuting" uniqKey="Xu S" first="Shuting" last="Xu">Shuting Xu</name>
<name sortKey="Zhang, Yongtao" sort="Zhang, Yongtao" uniqKey="Zhang Y" first="Yongtao" last="Zhang">Yongtao Zhang</name>
</country>
</tree>
</affiliations>
</record>

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Exploring Ugi-Azide Four-Component Reaction Products for Broad-Spectrum Influenza Antivirals with a High Genetic Barrier to Drug Resistance

Exploring Ugi-Azide Four-Component Reaction Products for Broad-Spectrum Influenza Antivirals with a High Genetic Barrier to Drug Resistance

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