Broad-spectrum inhibition of common respiratory RNA viruses by a pyrimidine synthesis inhibitor with involvement of the host antiviral response.
Identifieur interne : 000E67 ( Main/Exploration ); précédent : 000E66; suivant : 000E68Broad-spectrum inhibition of common respiratory RNA viruses by a pyrimidine synthesis inhibitor with involvement of the host antiviral response.
Auteurs : Nam Nam Cheung [République populaire de Chine] ; Kin Kui Lai [République populaire de Chine] ; Jun Dai [République populaire de Chine] ; Kin Hang Kok [République populaire de Chine] ; Honglin Chen [République populaire de Chine] ; Kwok-Hung Chan [République populaire de Chine] ; Kwok-Yung Yuen [République populaire de Chine] ; Richard Yi Tsun Kao [République populaire de Chine]Source :
- The Journal of general virology [ 1465-2099 ] ; 2017.
Descripteurs français
- KwdFr :
- Analyse de survie, Animaux, Antienzymes (isolement et purification), Antienzymes (pharmacologie), Antiviraux (isolement et purification), Antiviraux (pharmacologie), Coronavirus du syndrome respiratoire du Moyen-Orient, Humains, Infections à Orthomyxoviridae (anatomopathologie), Infections à Orthomyxoviridae (traitement médicamenteux), Interférons (métabolisme), Lignée cellulaire, Oxidoreductases acting on CH-CH group donors (antagonistes et inhibiteurs), Pyrimidines (biosynthèse), Souris de lignée BALB C, Virus à ARN (), Virus à ARN (croissance et développement), Virus à ARN (immunologie).
- MESH :
- anatomopathologie : Infections à Orthomyxoviridae.
- antagonistes et inhibiteurs : Oxidoreductases acting on CH-CH group donors.
- biosynthèse : Pyrimidines.
- croissance et développement : Virus à ARN.
- immunologie : Virus à ARN.
- isolement et purification : Antienzymes, Antiviraux.
- métabolisme : Interférons.
- pharmacologie : Antienzymes, Antiviraux.
- traitement médicamenteux : Infections à Orthomyxoviridae.
- Analyse de survie, Animaux, Coronavirus du syndrome respiratoire du Moyen-Orient, Humains, Lignée cellulaire, Souris de lignée BALB C, Virus à ARN.
English descriptors
- KwdEn :
- Animals, Antiviral Agents (isolation & purification), Antiviral Agents (pharmacology), Cell Line, Enzyme Inhibitors (isolation & purification), Enzyme Inhibitors (pharmacology), Humans, Interferons (metabolism), Mice, Inbred BALB C, Middle East Respiratory Syndrome Coronavirus, Orthomyxoviridae Infections (drug therapy), Orthomyxoviridae Infections (pathology), Oxidoreductases Acting on CH-CH Group Donors (antagonists & inhibitors), Pyrimidines (biosynthesis), RNA Viruses (drug effects), RNA Viruses (growth & development), RNA Viruses (immunology), Survival Analysis.
- MESH :
- chemical , antagonists & inhibitors : Oxidoreductases Acting on CH-CH Group Donors.
- chemical , biosynthesis : Pyrimidines.
- chemical , isolation & purification : Antiviral Agents, Enzyme Inhibitors.
- chemical , metabolism : Interferons.
- chemical , pharmacology : Antiviral Agents, Enzyme Inhibitors.
- drug effects : RNA Viruses.
- drug therapy : Orthomyxoviridae Infections.
- growth & development : RNA Viruses.
- immunology : RNA Viruses.
- pathology : Orthomyxoviridae Infections.
- Animals, Cell Line, Humans, Mice, Inbred BALB C, Middle East Respiratory Syndrome Coronavirus, Survival Analysis.
Abstract
Our previous screening of 50 240 structurally diverse compounds led to the identification of 39 influenza A virus infection inhibitors (Kao R.Y., Yang D., Lau L.S., Tsui W.H., Hu L. et al. Nat Biotechnol 2010;28:600-605). Further screening of these compounds against common respiratory viruses led to the discovery of compound FA-613. This inhibitor exhibited low micromolar antiviral activity against various influenza A and B virus strains, including the highly pathogenic influenza A strains H5N1 and H7N9, enterovirus A71, respiratory syncytial virus, human rhinovirus A, SARS- and MERS-coronavirus. No significant cellular toxicity was observed at the effective concentrations. Animal studies showed an improved survival rate in BALB/c mice that received intranasal FA-613 treatments against a lethal dose infection of A/HK/415742Md/2009 (H1N1). Further cell-based assays indicated that FA-613 interfer with the de novo pyrimidine biosynthesis pathway by targeting the dihydroorotate dehydrogenase. Surprisingly, FA-613 lost its antiviral potency in the interferon-deficient Vero cell line, while maintaining its inhibitory activity in an interferon-competent cell line which showed elevated expression of host antiviral genes when infected in the presence of FA-613. Further investigation of the specific connection between pyrimidine synthesis inhibition and the induction of host innate immunity might aid clinical development of this type of drug in antiviral therapies. Therefore, in acute cases of respiratory tract infections, when rapid diagnostics of the causative agent are not readily available, an antiviral drug with properties like FA-613 could prove to be very valuable.
DOI: 10.1099/jgv.0.000758
PubMed: 28555543
Affiliations:
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xml:lang="en">Broad-spectrum inhibition of common respiratory RNA viruses by a pyrimidine synthesis inhibitor with involvement of the host antiviral response.</title><author><name sortKey="Cheung, Nam Nam" sort="Cheung, Nam Nam" uniqKey="Cheung N" first="Nam Nam" last="Cheung">Nam Nam Cheung</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong</wicri:regionArea><wicri:noRegion>Hong Kong</wicri:noRegion></affiliation></author><author><name sortKey="Lai, Kin Kui" sort="Lai, Kin Kui" uniqKey="Lai K" first="Kin Kui" last="Lai">Kin Kui Lai</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong</wicri:regionArea><wicri:noRegion>Hong Kong</wicri:noRegion></affiliation></author><author><name sortKey="Dai, Jun" sort="Dai, Jun" uniqKey="Dai J" first="Jun" last="Dai">Jun Dai</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong</wicri:regionArea><wicri:noRegion>Hong Kong</wicri:noRegion></affiliation></author><author><name sortKey="Kok, Kin Hang" sort="Kok, Kin Hang" uniqKey="Kok K" first="Kin Hang" last="Kok">Kin Hang Kok</name><affiliation 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Kong</wicri:noRegion></affiliation></author><author><name sortKey="Chan, Kwok Hung" sort="Chan, Kwok Hung" uniqKey="Chan K" first="Kwok-Hung" last="Chan">Kwok-Hung Chan</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong</wicri:regionArea><wicri:noRegion>Hong Kong</wicri:noRegion></affiliation></author><author><name sortKey="Yuen, Kwok Yung" sort="Yuen, Kwok Yung" uniqKey="Yuen K" first="Kwok-Yung" last="Yuen">Kwok-Yung Yuen</name><affiliation wicri:level="1"><nlm:affiliation>State Key Laboratory for Emerging Infectious Disease and the Research Centre of Infection and Immunology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory for Emerging Infectious Disease and the Research Centre of Infection and Immunology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong</wicri:regionArea><wicri:noRegion>Hong Kong</wicri:noRegion></affiliation></author><author><name sortKey="Kao, Richard Yi Tsun" sort="Kao, Richard Yi Tsun" uniqKey="Kao R" first="Richard Yi Tsun" last="Kao">Richard Yi Tsun Kao</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong</wicri:regionArea><wicri:noRegion>Hong Kong</wicri:noRegion></affiliation></author></analytic><series><title level="j">The Journal of general virology</title><idno type="eISSN">1465-2099</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Antiviral Agents (isolation & purification)</term><term>Antiviral Agents (pharmacology)</term><term>Cell Line</term><term>Enzyme Inhibitors (isolation & purification)</term><term>Enzyme Inhibitors (pharmacology)</term><term>Humans</term><term>Interferons (metabolism)</term><term>Mice, Inbred BALB C</term><term>Middle East Respiratory Syndrome Coronavirus</term><term>Orthomyxoviridae Infections (drug therapy)</term><term>Orthomyxoviridae Infections (pathology)</term><term>Oxidoreductases Acting on CH-CH Group Donors (antagonists & inhibitors)</term><term>Pyrimidines (biosynthesis)</term><term>RNA Viruses (drug effects)</term><term>RNA Viruses (growth & development)</term><term>RNA Viruses (immunology)</term><term>Survival Analysis</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Analyse de survie</term><term>Animaux</term><term>Antienzymes (isolement et purification)</term><term>Antienzymes (pharmacologie)</term><term>Antiviraux (isolement et purification)</term><term>Antiviraux (pharmacologie)</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term><term>Humains</term><term>Infections à Orthomyxoviridae (anatomopathologie)</term><term>Infections à Orthomyxoviridae (traitement médicamenteux)</term><term>Interférons (métabolisme)</term><term>Lignée cellulaire</term><term>Oxidoreductases acting on CH-CH group donors (antagonistes et inhibiteurs)</term><term>Pyrimidines (biosynthèse)</term><term>Souris de lignée BALB C</term><term>Virus à ARN ()</term><term>Virus à ARN (croissance et développement)</term><term>Virus à ARN (immunologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Oxidoreductases Acting on CH-CH Group Donors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="biosynthesis" xml:lang="en"><term>Pyrimidines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="isolation & purification" xml:lang="en"><term>Antiviral Agents</term><term>Enzyme Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Interferons</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term><term>Enzyme Inhibitors</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Infections à Orthomyxoviridae</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Oxidoreductases acting on CH-CH group donors</term></keywords><keywords scheme="MESH" qualifier="biosynthèse" xml:lang="fr"><term>Pyrimidines</term></keywords><keywords scheme="MESH" qualifier="croissance et développement" xml:lang="fr"><term>Virus à ARN</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>RNA Viruses</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Orthomyxoviridae Infections</term></keywords><keywords scheme="MESH" qualifier="growth & development" xml:lang="en"><term>RNA Viruses</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Virus à ARN</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>RNA Viruses</term></keywords><keywords scheme="MESH" qualifier="isolement et purification" xml:lang="fr"><term>Antienzymes</term><term>Antiviraux</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Interférons</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Orthomyxoviridae Infections</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antienzymes</term><term>Antiviraux</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Infections à Orthomyxoviridae</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Line</term><term>Humans</term><term>Mice, Inbred BALB C</term><term>Middle East Respiratory Syndrome Coronavirus</term><term>Survival Analysis</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Analyse de survie</term><term>Animaux</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term><term>Humains</term><term>Lignée cellulaire</term><term>Souris de lignée BALB C</term><term>Virus à ARN</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Our previous screening of 50 240 structurally diverse compounds led to the identification of 39 influenza A virus infection inhibitors (Kao R.Y., Yang D., Lau L.S., Tsui W.H., Hu L. et al. Nat Biotechnol 2010;28:600-605). Further screening of these compounds against common respiratory viruses led to the discovery of compound FA-613. This inhibitor exhibited low micromolar antiviral activity against various influenza A and B virus strains, including the highly pathogenic influenza A strains H5N1 and H7N9, enterovirus A71, respiratory syncytial virus, human rhinovirus A, SARS- and MERS-coronavirus. No significant cellular toxicity was observed at the effective concentrations. Animal studies showed an improved survival rate in BALB/c mice that received intranasal FA-613 treatments against a lethal dose infection of A/HK/415742Md/2009 (H1N1). Further cell-based assays indicated that FA-613 interfer with the de novo pyrimidine biosynthesis pathway by targeting the dihydroorotate dehydrogenase. Surprisingly, FA-613 lost its antiviral potency in the interferon-deficient Vero cell line, while maintaining its inhibitory activity in an interferon-competent cell line which showed elevated expression of host antiviral genes when infected in the presence of FA-613. Further investigation of the specific connection between pyrimidine synthesis inhibition and the induction of host innate immunity might aid clinical development of this type of drug in antiviral therapies. Therefore, in acute cases of respiratory tract infections, when rapid diagnostics of the causative agent are not readily available, an antiviral drug with properties like FA-613 could prove to be very valuable.</div></front></TEI><affiliations><list><country><li>République populaire de Chine</li></country></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Cheung, Nam Nam" sort="Cheung, Nam Nam" uniqKey="Cheung N" first="Nam Nam" last="Cheung">Nam Nam Cheung</name></noRegion><name sortKey="Chan, Kwok Hung" sort="Chan, Kwok Hung" uniqKey="Chan K" first="Kwok-Hung" last="Chan">Kwok-Hung Chan</name><name sortKey="Chen, Honglin" sort="Chen, Honglin" uniqKey="Chen H" first="Honglin" last="Chen">Honglin Chen</name><name sortKey="Dai, Jun" sort="Dai, Jun" uniqKey="Dai J" first="Jun" last="Dai">Jun Dai</name><name sortKey="Kao, Richard Yi Tsun" sort="Kao, Richard Yi Tsun" uniqKey="Kao R" first="Richard Yi Tsun" last="Kao">Richard Yi Tsun Kao</name><name sortKey="Kok, Kin Hang" sort="Kok, Kin Hang" uniqKey="Kok K" first="Kin Hang" last="Kok">Kin Hang Kok</name><name sortKey="Lai, Kin Kui" sort="Lai, Kin Kui" uniqKey="Lai K" first="Kin Kui" last="Lai">Kin Kui Lai</name><name sortKey="Yuen, Kwok Yung" sort="Yuen, Kwok Yung" uniqKey="Yuen K" first="Kwok-Yung" last="Yuen">Kwok-Yung Yuen</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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