Broad-spectrum inhibition of common respiratory RNA viruses by a pyrimidine synthesis inhibitor with involvement of the host antiviral response.
Identifieur interne : 000C80 ( PubMed/Corpus ); précédent : 000C79; suivant : 000C81Broad-spectrum inhibition of common respiratory RNA viruses by a pyrimidine synthesis inhibitor with involvement of the host antiviral response.
Auteurs : Nam Nam Cheung ; Kin Kui Lai ; Jun Dai ; Kin Hang Kok ; Honglin Chen ; Kwok-Hung Chan ; Kwok-Yung Yuen ; Richard Yi Tsun KaoSource :
- The Journal of general virology [ 1465-2099 ] ; 2017.
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
Links to Exploration step
pubmed:28555543Le document en format XML
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HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.</nlm:affiliation></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><nlm:affiliation>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.</nlm:affiliation></affiliation></author><author><name sortKey="Chen, Honglin" sort="Chen, Honglin" uniqKey="Chen H" first="Honglin" last="Chen">Honglin Chen</name><affiliation><nlm:affiliation>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.</nlm:affiliation></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><nlm:affiliation>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.</nlm:affiliation></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><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></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><nlm:affiliation>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2017">2017</date><idno type="RBID">pubmed:28555543</idno><idno type="pmid">28555543</idno><idno 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China.</nlm:affiliation></affiliation></author><author><name sortKey="Dai, Jun" sort="Dai, Jun" uniqKey="Dai J" first="Jun" last="Dai">Jun Dai</name><affiliation><nlm:affiliation>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.</nlm:affiliation></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><nlm:affiliation>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.</nlm:affiliation></affiliation></author><author><name sortKey="Chen, Honglin" sort="Chen, Honglin" uniqKey="Chen H" first="Honglin" last="Chen">Honglin Chen</name><affiliation><nlm:affiliation>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.</nlm:affiliation></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><nlm:affiliation>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.</nlm:affiliation></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><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></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><nlm:affiliation>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.</nlm:affiliation></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="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="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="immunology" xml:lang="en"><term>RNA Viruses</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Orthomyxoviridae Infections</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></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><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">28555543</PMID><DateCompleted><Year>2017</Year><Month>07</Month><Day>11</Day></DateCompleted><DateRevised><Year>2019</Year><Month>12</Month><Day>09</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1465-2099</ISSN><JournalIssue CitedMedium="Internet"><Volume>98</Volume><Issue>5</Issue><PubDate><Year>2017</Year><Month>May</Month></PubDate></JournalIssue><Title>The Journal of general virology</Title><ISOAbbreviation>J. Gen. Virol.</ISOAbbreviation></Journal><ArticleTitle>Broad-spectrum inhibition of common respiratory RNA viruses by a pyrimidine synthesis inhibitor with involvement of the host antiviral response.</ArticleTitle><Pagination><MedlinePgn>946-954</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1099/jgv.0.000758</ELocationID><Abstract><AbstractText>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.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Cheung</LastName><ForeName>Nam Nam</ForeName><Initials>NN</Initials><AffiliationInfo><Affiliation>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lai</LastName><ForeName>Kin Kui</ForeName><Initials>KK</Initials><AffiliationInfo><Affiliation>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dai</LastName><ForeName>Jun</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kok</LastName><ForeName>Kin Hang</ForeName><Initials>KH</Initials><AffiliationInfo><Affiliation>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chen</LastName><ForeName>Honglin</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.</Affiliation></AffiliationInfo><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chan</LastName><ForeName>Kwok-Hung</ForeName><Initials>KH</Initials><AffiliationInfo><Affiliation>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yuen</LastName><ForeName>Kwok-Yung</ForeName><Initials>KY</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kao</LastName><ForeName>Richard Yi Tsun</ForeName><Initials>RYT</Initials><AffiliationInfo><Affiliation>Department of Microbiology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.</Affiliation></AffiliationInfo><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2017</Year><Month>05</Month><Day>30</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>J Gen Virol</MedlineTA><NlmUniqueID>0077340</NlmUniqueID><ISSNLinking>0022-1317</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000998">Antiviral Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004791">Enzyme Inhibitors</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011743">Pyrimidines</NameOfSubstance></Chemical><Chemical><RegistryNumber>9008-11-1</RegistryNumber><NameOfSubstance UI="D007372">Interferons</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 1.3.-</RegistryNumber><NameOfSubstance UI="D044925">Oxidoreductases Acting on CH-CH Group Donors</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 1.3.5.2</RegistryNumber><NameOfSubstance UI="C063014">dihydroorotate dehydrogenase</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000998" MajorTopicYN="N">Antiviral Agents</DescriptorName><QualifierName UI="Q000302" MajorTopicYN="Y">isolation & purification</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002460" MajorTopicYN="N">Cell Line</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004791" MajorTopicYN="N">Enzyme Inhibitors</DescriptorName><QualifierName UI="Q000302" MajorTopicYN="N">isolation & purification</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007372" MajorTopicYN="N">Interferons</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008807" MajorTopicYN="N">Mice, Inbred BALB C</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D065207" MajorTopicYN="N">Middle East Respiratory Syndrome Coronavirus</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009976" MajorTopicYN="N">Orthomyxoviridae Infections</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="N">drug therapy</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D044925" MajorTopicYN="N">Oxidoreductases Acting on CH-CH Group Donors</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="N">antagonists & inhibitors</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011743" MajorTopicYN="N">Pyrimidines</DescriptorName><QualifierName UI="Q000096" MajorTopicYN="Y">biosynthesis</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D012328" MajorTopicYN="N">RNA Viruses</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName><QualifierName UI="Q000254" MajorTopicYN="N">growth & development</QualifierName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016019" MajorTopicYN="N">Survival Analysis</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2017</Year><Month>5</Month><Day>31</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2017</Year><Month>7</Month><Day>14</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2017</Year><Month>5</Month><Day>31</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">28555543</ArticleId><ArticleId IdType="doi">10.1099/jgv.0.000758</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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