Isocyanides as Influenza A Virus Subtype H5N1 Wild‐Type M2 Channel Inhibitors
Identifieur interne : 001E15 ( Istex/Corpus ); précédent : 001E14; suivant : 001E16Isocyanides as Influenza A Virus Subtype H5N1 Wild‐Type M2 Channel Inhibitors
Auteurs : Shuwen Wu ; Jing Huang ; Sabrina Gazzarrini ; Si He ; Lihua Chen ; Jun Li ; Li Xing ; Chufang Li ; Ling Chen ; Constantinos G. Neochoritis ; George P. Liao ; Haibing Zhou ; Alexander Dömling ; Anna Moroni ; Wei WangSource :
- ChemMedChem [ 1860-7179 ] ; 2015-11.
Abstract
Basic bulky amines such as amantadine are well‐characterized M2 channel blockers, useful for treating influenza. Herein we report our surprising findings that charge‐neutral, bulky isocyanides exhibit activities similar to—or even higher than—that of amantadine. We also demonstrate that these isocyanides have potent growth inhibitory activity against the H5N1 virus. The −NH2 to −N≡C group replacement within current anti‐influenza drugs was found to give compounds with high activities at low‐micromolar concentrations. For example, a tenfold improvement in potency was observed for 1‐isocyanoadamantane (27), with an EC50 value of 0.487 μm against amantadine‐sensitive H5N1 virus as determined by both MTT and plaque‐reduction assays, without showing cytotoxicity. Furthermore, the isocyanide analogues synthesized in this study did not inhibit the V27A or S31N mutant M2 ion channels, according to electrophysiology experiments, and did not exhibit activity against amantadine‐resistant virus strains.
Charge‐neutral bulky isocyanides were found to exhibit antiviral activities similar to—or even higher than—that of amantadine. Moreover, we demonstrated that these isocyanides have potent growth inhibitory activity against the wild‐type H5N1 virus. The NH2 to N≡C group replacement within current anti‐influenza drugs was found to result in compounds with low‐micromolar activities.
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DOI: 10.1002/cmdc.201500318
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China</mods:affiliation></affiliation><affiliation><mods:affiliation>State Key Laboratory of Virology of China, Wuhan University, 430071, Wuhan, P.R. China</mods:affiliation></affiliation></author><author><name sortKey="Huang, Jing" sort="Huang, Jing" uniqKey="Huang J" first="Jing" last="Huang">Jing Huang</name><affiliation><mods:affiliation>Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, 430071, Wuhan, P.R. China</mods:affiliation></affiliation></author><author><name sortKey="Gazzarrini, Sabrina" sort="Gazzarrini, Sabrina" uniqKey="Gazzarrini S" first="Sabrina" last="Gazzarrini">Sabrina Gazzarrini</name><affiliation><mods:affiliation>Department of Biosciences, University of Milan and, Institute of Biophysics (IBF) Milan, National Research Council (CNR), Via Celoria 26, 20133, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="He, Si" sort="He, Si" uniqKey="He S" first="Si" last="He">Si He</name><affiliation><mods:affiliation>Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, 430071, Wuhan, P.R. China</mods:affiliation></affiliation></author><author><name sortKey="Chen, Lihua" sort="Chen, Lihua" uniqKey="Chen L" first="Lihua" last="Chen">Lihua Chen</name><affiliation><mods:affiliation>Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, 430071, Wuhan, P.R. China</mods:affiliation></affiliation></author><author><name sortKey="Li, Jun" sort="Li, Jun" uniqKey="Li J" first="Jun" last="Li">Jun Li</name><affiliation><mods:affiliation>Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, 430071, Wuhan, P.R. China</mods:affiliation></affiliation></author><author><name sortKey="Xing, Li" sort="Xing, Li" uniqKey="Xing L" first="Li" last="Xing">Li Xing</name><affiliation><mods:affiliation>Worldwide Research & Development, Pfizer Inc., 200 Cambridge Park Drive, MA, 02421, Cambridge, USA</mods:affiliation></affiliation></author><author><name sortKey="Li, Chufang" sort="Li, Chufang" uniqKey="Li C" first="Chufang" last="Li">Chufang Li</name><affiliation><mods:affiliation>Guangzhou Institute of Biomedicine & Health, Chinese Academy of Sciences, Guangdong, 510530, Guangzhou, P.R. China</mods:affiliation></affiliation></author><author><name sortKey="Chen, Ling" sort="Chen, Ling" uniqKey="Chen L" first="Ling" last="Chen">Ling Chen</name><affiliation><mods:affiliation>Guangzhou Institute of Biomedicine & Health, Chinese Academy of Sciences, Guangdong, 510530, Guangzhou, P.R. China</mods:affiliation></affiliation></author><author><name sortKey="Neochoritis, Constantinos G" sort="Neochoritis, Constantinos G" uniqKey="Neochoritis C" first="Constantinos G." last="Neochoritis">Constantinos G. Neochoritis</name><affiliation><mods:affiliation>Department of Drug Design, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Liao, George P" sort="Liao, George P" uniqKey="Liao G" first="George P." last="Liao">George P. Liao</name><affiliation><mods:affiliation>Department of Drug Design, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Zhou, Haibing" sort="Zhou, Haibing" uniqKey="Zhou H" first="Haibing" last="Zhou">Haibing Zhou</name><affiliation><mods:affiliation>Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, 430071, Wuhan, P.R. China</mods:affiliation></affiliation></author><author><name sortKey="Domling, Alexander" sort="Domling, Alexander" uniqKey="Domling A" first="Alexander" last="Dömling">Alexander Dömling</name><affiliation><mods:affiliation>Department of Drug Design, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Moroni, Anna" sort="Moroni, Anna" uniqKey="Moroni A" first="Anna" last="Moroni">Anna Moroni</name><affiliation><mods:affiliation>Department of Biosciences, University of Milan and, Institute of Biophysics (IBF) Milan, National Research Council (CNR), Via Celoria 26, 20133, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Wang, Wei" sort="Wang, Wei" uniqKey="Wang W" first="Wei" last="Wang">Wei Wang</name><affiliation><mods:affiliation>Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, 430071, Wuhan, P.R. China</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: waw6@whu.edu.cn</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">ChemMedChem</title><title level="j" type="alt">CHEMMEDCHEM</title><idno type="ISSN">1860-7179</idno><idno type="eISSN">1860-7187</idno><imprint><biblScope unit="vol">10</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="1837">1837</biblScope><biblScope unit="page" to="1845">1845</biblScope><biblScope unit="page-count">9</biblScope><date type="published" when="2015-11">2015-11</date></imprint><idno type="ISSN">1860-7179</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1860-7179</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Basic bulky amines such as amantadine are well‐characterized M2 channel blockers, useful for treating influenza. Herein we report our surprising findings that charge‐neutral, bulky isocyanides exhibit activities similar to—or even higher than—that of amantadine. We also demonstrate that these isocyanides have potent growth inhibitory activity against the H5N1 virus. The −NH2 to −N≡C group replacement within current anti‐influenza drugs was found to give compounds with high activities at low‐micromolar concentrations. For example, a tenfold improvement in potency was observed for 1‐isocyanoadamantane (27), with an EC50 value of 0.487 μm against amantadine‐sensitive H5N1 virus as determined by both MTT and plaque‐reduction assays, without showing cytotoxicity. Furthermore, the isocyanide analogues synthesized in this study did not inhibit the V27A or S31N mutant M2 ion channels, according to electrophysiology experiments, and did not exhibit activity against amantadine‐resistant virus strains.</div><div type="abstract" xml:lang="en">Charge‐neutral bulky isocyanides were found to exhibit antiviral activities similar to—or even higher than—that of amantadine. Moreover, we demonstrated that these isocyanides have potent growth inhibitory activity against the wild‐type H5N1 virus. The NH2 to N≡C group replacement within current anti‐influenza drugs was found to result in compounds with low‐micromolar activities.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Dr. Shuwen Wu</name><affiliations><json:string>Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, 430071, Wuhan, P.R. China</json:string><json:string>State Key Laboratory of Virology of China, Wuhan University, 430071, Wuhan, P.R. China</json:string></affiliations></json:item><json:item><name>Jing Huang</name><affiliations><json:string>Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, 430071, Wuhan, P.R. China</json:string></affiliations></json:item><json:item><name>Dr. Sabrina Gazzarrini</name><affiliations><json:string>Department of Biosciences, University of Milan and, Institute of Biophysics (IBF) Milan, National Research Council (CNR), Via Celoria 26, 20133, Milan, Italy</json:string></affiliations></json:item><json:item><name>Si He</name><affiliations><json:string>Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, 430071, Wuhan, P.R. China</json:string></affiliations></json:item><json:item><name>Lihua Chen</name><affiliations><json:string>Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, 430071, Wuhan, P.R. China</json:string></affiliations></json:item><json:item><name>Dr. Jun Li</name><affiliations><json:string>Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, 430071, Wuhan, P.R. China</json:string></affiliations></json:item><json:item><name>Dr. Li Xing</name><affiliations><json:string>Worldwide Research & Development, Pfizer Inc., 200 Cambridge Park Drive, MA, 02421, Cambridge, USA</json:string></affiliations></json:item><json:item><name>Dr. Chufang Li</name><affiliations><json:string>Guangzhou Institute of Biomedicine & Health, Chinese Academy of Sciences, Guangdong, 510530, Guangzhou, P.R. China</json:string></affiliations></json:item><json:item><name>Prof. Ling Chen</name><affiliations><json:string>Guangzhou Institute of Biomedicine & Health, Chinese Academy of Sciences, Guangdong, 510530, Guangzhou, P.R. China</json:string></affiliations></json:item><json:item><name>Dr. Constantinos G. Neochoritis</name><affiliations><json:string>Department of Drug Design, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands</json:string></affiliations></json:item><json:item><name>George P. Liao</name><affiliations><json:string>Department of Drug Design, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands</json:string></affiliations></json:item><json:item><name>Prof. Haibing Zhou</name><affiliations><json:string>Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, 430071, Wuhan, P.R. China</json:string></affiliations></json:item><json:item><name>Prof. Alexander Dömling</name><affiliations><json:string>Department of Drug Design, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands</json:string></affiliations></json:item><json:item><name>Prof. Anna Moroni</name><affiliations><json:string>Department of Biosciences, University of Milan and, Institute of Biophysics (IBF) Milan, National Research Council (CNR), Via Celoria 26, 20133, Milan, Italy</json:string></affiliations></json:item><json:item><name>Prof. Wei Wang</name><affiliations><json:string>Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, 430071, Wuhan, P.R. China</json:string><json:string>E-mail: waw6@whu.edu.cn</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>amantadines</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>antiviral agents</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>influenza</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>inhibitors</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>isocyanides</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>M2 channels</value></json:item></subject><articleId><json:string>CMDC201500318</json:string></articleId><arkIstex>ark:/67375/WNG-W6XL8Q3K-D</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><abstract>Basic bulky amines such as amantadine are well‐characterized M2 channel blockers, useful for treating influenza. Herein we report our surprising findings that charge‐neutral, bulky isocyanides exhibit activities similar to—or even higher than—that of amantadine. We also demonstrate that these isocyanides have potent growth inhibitory activity against the H5N1 virus. The −NH2 to −N≡C group replacement within current anti‐influenza drugs was found to give compounds with high activities at low‐micromolar concentrations. For example, a tenfold improvement in potency was observed for 1‐isocyanoadamantane (27), with an EC50 value of 0.487 μm against amantadine‐sensitive H5N1 virus as determined by both MTT and plaque‐reduction assays, without showing cytotoxicity. Furthermore, the isocyanide analogues synthesized in this study did not inhibit the V27A or S31N mutant M2 ion channels, according to electrophysiology experiments, and did not exhibit activity against amantadine‐resistant virus strains.</abstract><qualityIndicators><score>8.62</score><pdfWordCount>6557</pdfWordCount><pdfCharCount>36310</pdfCharCount><pdfVersion>1.4</pdfVersion><pdfPageCount>9</pdfPageCount><pdfPageSize>595.276 x 841.89 pts (A4)</pdfPageSize><pdfWordsPerPage>729</pdfWordsPerPage><pdfText>true</pdfText><refBibsNative>true</refBibsNative><abstractWordCount>135</abstractWordCount><abstractCharCount>1006</abstractCharCount><keywordCount>6</keywordCount></qualityIndicators><title>Isocyanides as Influenza A Virus Subtype H5N1 Wild‐Type M2 Channel Inhibitors</title><genre><json:string>article</json:string></genre><host><title>ChemMedChem</title><language><json:string>unknown</json:string></language><doi><json:string>10.1002/(ISSN)1860-7187</json:string></doi><issn><json:string>1860-7179</json:string></issn><eissn><json:string>1860-7187</json:string></eissn><publisherId><json:string>CMDC</json:string></publisherId><volume>10</volume><issue>11</issue><pages><first>1837</first><last>1845</last><total>9</total></pages><genre><json:string>journal</json:string></genre><subject><json:item><value>Full Paper</value></json:item><json:item><value>Full Papers</value></json:item></subject></host><ark><json:string>ark:/67375/WNG-W6XL8Q3K-D</json:string></ark><categories><wos><json:string>1 - science</json:string><json:string>2 - pharmacology & pharmacy</json:string><json:string>2 - chemistry, medicinal</json:string></wos><scienceMetrix><json:string>1 - natural sciences</json:string><json:string>2 - chemistry</json:string><json:string>3 - medicinal & biomolecular chemistry</json:string></scienceMetrix><scopus><json:string>1 - Physical Sciences</json:string><json:string>2 - Chemistry</json:string><json:string>3 - Organic Chemistry</json:string><json:string>1 - Life Sciences</json:string><json:string>2 - Pharmacology, Toxicology and Pharmaceutics</json:string><json:string>3 - General Pharmacology, Toxicology and Pharmaceutics</json:string><json:string>1 - Life Sciences</json:string><json:string>2 - Biochemistry, Genetics and Molecular Biology</json:string><json:string>3 - Molecular Medicine</json:string></scopus><inist><json:string>1 - sciences appliquees, technologies et medecines</json:string><json:string>2 - sciences biologiques et medicales</json:string><json:string>3 - sciences medicales</json:string><json:string>4 - pathologie infectieuse</json:string></inist></categories><publicationDate>2015</publicationDate><copyrightDate>2015</copyrightDate><doi><json:string>10.1002/cmdc.201500318</json:string></doi><id>CE54FBD52BF61A4E559CBAB1F771F3F06CDD3F57</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/ark:/67375/WNG-W6XL8Q3K-D/fulltext.pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/ark:/67375/WNG-W6XL8Q3K-D/bundle.zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/ark:/67375/WNG-W6XL8Q3K-D/fulltext.tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main">Isocyanides as Influenza A Virus Subtype H5N1 Wild‐Type M2 Channel Inhibitors</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher ref="https://scientific-publisher.data.istex.fr/ark:/67375/H02-QW5Q88H5-V">Wiley Publishing Ltd</publisher><availability><licence>© 2015 WILEY‐VCH Verlag GmbH & Co. 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University</orgName><address><settlement>Wuhan</settlement><postCode>430071</postCode><country key="CN" xml:lang="en">CHINA</country></address></affiliation><affiliation><orgName type="division">State Key Laboratory of Virology of China</orgName><orgName type="institution">Wuhan University</orgName><address><settlement>Wuhan</settlement><postCode>430071</postCode><country key="CN" xml:lang="en">CHINA</country></address></affiliation></author><author xml:id="author-0001"><persName><forename type="first">Jing</forename><surname>Huang</surname></persName><affiliation><orgName type="division">Key Laboratory of Combinatorial Biosynthesis & Drug Discovery</orgName><orgName type="division">Ministry of Education</orgName><orgName type="division">School of Pharmaceutical Sciences</orgName><orgName type="institution">Wuhan University</orgName><address><settlement>Wuhan</settlement><postCode>430071</postCode><country key="CN" xml:lang="en">CHINA</country></address></affiliation></author><author xml:id="author-0002"><persName><addName>Dr.</addName><forename type="first">Sabrina</forename><surname>Gazzarrini</surname></persName><affiliation><orgName type="division">Department of Biosciences</orgName><orgName type="institution">University of Milan and</orgName><orgName type="institution">Institute of Biophysics (IBF) Milan, National Research Council (CNR)</orgName><address><street>Via Celoria 26</street><postCode>20133</postCode><settlement>Milan</settlement><country key="IT" xml:lang="en">ITALY</country></address></affiliation></author><author xml:id="author-0003"><persName><forename type="first">Si</forename><surname>He</surname></persName><affiliation><orgName type="division">Key Laboratory of Combinatorial Biosynthesis & Drug Discovery</orgName><orgName type="division">Ministry of Education</orgName><orgName type="division">School of Pharmaceutical Sciences</orgName><orgName type="institution">Wuhan 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type="division">School of Pharmaceutical Sciences</orgName><orgName type="institution">Wuhan University</orgName><address><settlement>Wuhan</settlement><postCode>430071</postCode><country key="CN" xml:lang="en">CHINA</country></address></affiliation></author><author xml:id="author-0012"><persName><addName>Prof.</addName><forename type="first">Alexander</forename><surname>Dömling</surname></persName><affiliation><orgName type="division">Department of Drug Design</orgName><orgName type="institution">University of Groningen</orgName><address><street>Antonius Deusinglaan 1</street><postCode>9713 AV</postCode><settlement>Groningen</settlement><country key="NL" xml:lang="en">THE NETHERLANDS</country></address></affiliation></author><author xml:id="author-0013"><persName><addName>Prof.</addName><forename type="first">Anna</forename><surname>Moroni</surname></persName><affiliation><orgName type="division">Department of Biosciences</orgName><orgName type="institution">University of Milan 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KGaA, Weinheim</copyright><numberingGroup><numbering type="journalVolume" number="10">10</numbering><numbering type="journalIssue">11</numbering></numberingGroup><coverDate startDate="2015-11">November 2015</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="120" status="forIssue"><doi origin="wiley">10.1002/cmdc.201500318</doi><idGroup><id type="unit" value="CMDC201500318"></id></idGroup><countGroup><count type="pageTotal" number="9"></count></countGroup><titleGroup><title type="articleCategory">Full Paper</title><title type="tocHeading1">Full Papers</title></titleGroup><copyright ownership="publisher">© 2015 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim</copyright><eventGroup><event type="manuscriptReceived" date="2015-07-21"></event><event type="xmlConverted" agent="Triltsch" date="2015-10-27"></event><event type="publishedOnlineEarlyUnpaginated" date="2015-09-07"></event><event type="firstOnline" date="2015-09-07"></event><event type="publishedOnlineFinalForm" date="2015-10-27"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.6.8 mode:FullText" date="2015-10-27"></event></eventGroup><numberingGroup><numbering type="pageFirst">1837</numbering><numbering type="pageLast">1845</numbering></numberingGroup><selfCitationGroup><citation type="self" xml:id="cmdc201500318-self">S. Wu, J. Huang, S. Gazzarrini, S. He, L. Chen, J. Li, L. Xing, C. Li, L. Chen, C. G. Neochoritis, G. P. Liao, H. Zhou, A. Dömling, A. Moroni, W. Wang, <i>ChemMedChem</i> <b>2015</b>, <i>10</i>, 1837.</citation></selfCitationGroup><objectNameGroup><objectName elementName="figure">Figure</objectName><objectName elementName="figure">Scheme</objectName></objectNameGroup><linkGroup><link type="toTypesetVersion" href="file:CMDC.CMDC201500318.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="22"></count><count type="tableTotal" number="1"></count><count type="referenceTotal" number="62"></count></countGroup><titleGroup><title type="main" xml:lang="en">Isocyanides as Influenza A Virus Subtype H5N1 Wild‐Type M2 Channel Inhibitors</title></titleGroup><creators><creator xml:id="cmdc201500318-cr-0001" creatorRole="author" affiliationRef="#cmdc201500318-aff-0001 #cmdc201500318-aff-0002" noteRef="#cmdc201500318-note-1001"><personName><honorifics>Dr.</honorifics><givenNames>Shuwen</givenNames><familyName>Wu</familyName></personName></creator><creator xml:id="cmdc201500318-cr-0002" creatorRole="author" affiliationRef="#cmdc201500318-aff-0001" noteRef="#cmdc201500318-note-1001"><personName><givenNames>Jing</givenNames><familyName>Huang</familyName></personName></creator><creator xml:id="cmdc201500318-cr-0003" creatorRole="author" affiliationRef="#cmdc201500318-aff-0003" noteRef="#cmdc201500318-note-1001"><personName><honorifics>Dr.</honorifics><givenNames>Sabrina</givenNames><familyName>Gazzarrini</familyName></personName></creator><creator xml:id="cmdc201500318-cr-0004" creatorRole="author" affiliationRef="#cmdc201500318-aff-0001"><personName><givenNames>Si</givenNames><familyName>He</familyName></personName></creator><creator xml:id="cmdc201500318-cr-0005" creatorRole="author" affiliationRef="#cmdc201500318-aff-0001"><personName><givenNames>Lihua</givenNames><familyName>Chen</familyName></personName></creator><creator xml:id="cmdc201500318-cr-0006" creatorRole="author" affiliationRef="#cmdc201500318-aff-0001"><personName><honorifics>Dr.</honorifics><givenNames>Jun</givenNames><familyName>Li</familyName></personName></creator><creator xml:id="cmdc201500318-cr-0007" creatorRole="author" affiliationRef="#cmdc201500318-aff-0004"><personName><honorifics>Dr.</honorifics><givenNames>Li</givenNames><familyName>Xing</familyName></personName></creator><creator xml:id="cmdc201500318-cr-0008" creatorRole="author" affiliationRef="#cmdc201500318-aff-0005"><personName><honorifics>Dr.</honorifics><givenNames>Chufang</givenNames><familyName>Li</familyName></personName></creator><creator xml:id="cmdc201500318-cr-0009" creatorRole="author" affiliationRef="#cmdc201500318-aff-0005"><personName><honorifics>Prof.</honorifics><givenNames>Ling</givenNames><familyName>Chen</familyName></personName></creator><creator xml:id="cmdc201500318-cr-0010" creatorRole="author" affiliationRef="#cmdc201500318-aff-0006"><personName><honorifics>Dr.</honorifics><givenNames>Constantinos G.</givenNames><familyName>Neochoritis</familyName></personName></creator><creator xml:id="cmdc201500318-cr-0011" creatorRole="author" affiliationRef="#cmdc201500318-aff-0006"><personName><givenNames>George P.</givenNames><familyName>Liao</familyName></personName></creator><creator xml:id="cmdc201500318-cr-0012" creatorRole="author" affiliationRef="#cmdc201500318-aff-0001"><personName><honorifics>Prof.</honorifics><givenNames>Haibing</givenNames><familyName>Zhou</familyName></personName></creator><creator xml:id="cmdc201500318-cr-0013" creatorRole="author" affiliationRef="#cmdc201500318-aff-0006"><personName><honorifics>Prof.</honorifics><givenNames>Alexander</givenNames><familyName>Dömling</familyName></personName></creator><creator xml:id="cmdc201500318-cr-0014" creatorRole="author" affiliationRef="#cmdc201500318-aff-0003"><personName><honorifics>Prof.</honorifics><givenNames>Anna</givenNames><familyName>Moroni</familyName></personName></creator><creator xml:id="cmdc201500318-cr-0015" creatorRole="author" affiliationRef="#cmdc201500318-aff-0001" corresponding="yes"><personName><honorifics>Prof.</honorifics><givenNames>Wei</givenNames><familyName>Wang</familyName></personName><contactDetails><email>waw6@whu.edu.cn</email></contactDetails></creator></creators><affiliationGroup><affiliation xml:id="cmdc201500318-aff-0001" countryCode="CN" type="organization"><orgDiv>Key Laboratory of Combinatorial Biosynthesis & Drug Discovery</orgDiv><orgDiv>Ministry of Education</orgDiv><orgDiv>School of Pharmaceutical Sciences</orgDiv><orgName>Wuhan University</orgName><address><city>Wuhan</city><postCode>430071</postCode><country>P.R. 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China</country></address></affiliation><affiliation xml:id="cmdc201500318-aff-0003" countryCode="IT" type="organization"><orgDiv>Department of Biosciences</orgDiv><orgName>University of Milan and</orgName><orgName>Institute of Biophysics (IBF) Milan, National Research Council (CNR)</orgName><address><street>Via Celoria 26</street><postCode>20133</postCode><city>Milan</city><country>Italy</country></address></affiliation><affiliation xml:id="cmdc201500318-aff-0004" countryCode="US" type="organization"><orgDiv>Worldwide Research & Development</orgDiv><orgName>Pfizer Inc.</orgName><address><street>200 Cambridge Park Drive</street><city>Cambridge</city><countryPart>MA</countryPart><postCode>02421</postCode><country>USA</country></address></affiliation><affiliation xml:id="cmdc201500318-aff-0005" countryCode="CN" type="organization"><orgDiv>Guangzhou Institute of Biomedicine & Health</orgDiv><orgName>Chinese Academy of Sciences</orgName><address><city>Guangzhou</city><countryPart>Guangdong</countryPart><postCode>510530</postCode><country>P.R. China</country></address></affiliation><affiliation xml:id="cmdc201500318-aff-0006" countryCode="NL" type="organization"><orgDiv>Department of Drug Design</orgDiv><orgName>University of Groningen</orgName><address><street>Antonius Deusinglaan 1</street><postCode>9713 AV</postCode><city>Groningen</city><country>The Netherlands</country></address></affiliation></affiliationGroup><keywordGroup xml:lang="en" type="author"><keyword xml:id="cmdc201500318-kwd-0001">amantadines</keyword><keyword xml:id="cmdc201500318-kwd-0002">antiviral agents</keyword><keyword xml:id="cmdc201500318-kwd-0003">influenza</keyword><keyword xml:id="cmdc201500318-kwd-0004">inhibitors</keyword><keyword xml:id="cmdc201500318-kwd-0005">isocyanides</keyword><keyword xml:id="cmdc201500318-kwd-0006">M2 channels</keyword></keywordGroup><fundingInfo><fundingAgency>National Natural Science Foundation of China</fundingAgency><fundingNumber>21202125</fundingNumber><fundingNumber>31300060</fundingNumber></fundingInfo><fundingInfo><fundingAgency>Hubei Province Natural Science Foundation</fundingAgency><fundingNumber>2014CFB241</fundingNumber></fundingInfo><fundingInfo><fundingAgency>Scientific Research Foundation for the Returned Overseas Chinese Scholars</fundingAgency></fundingInfo><fundingInfo><fundingAgency>Fundamental Research Funds for the Central Universities</fundingAgency></fundingInfo><supportingInformation><p>As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.</p><supportingInfoItem><mediaResource alt="supplementary_material" rendition="webOriginal" href="urn-x:wiley:18607179:media:cmdc201500318:cmdc201500318-sup-0001-misc_information"></mediaResource><caption>Supplementary</caption></supportingInfoItem></supportingInformation><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>Basic bulky amines such as amantadine are well‐characterized M2 channel blockers, useful for treating influenza. Herein we report our surprising findings that charge‐neutral, bulky isocyanides exhibit activities similar to—or even higher than—that of amantadine. We also demonstrate that these isocyanides have potent growth inhibitory activity against the H5N1 virus. The −NH<sub>2</sub> to −N≡C group replacement within current anti‐influenza drugs was found to give compounds with high activities at low‐micromolar concentrations. For example, a tenfold improvement in potency was observed for 1‐isocyanoadamantane (<b>27</b>), with an EC<sub>50</sub> value of 0.487 μ<sc>m</sc> against amantadine‐sensitive H5N1 virus as determined by both MTT and plaque‐reduction assays, without showing cytotoxicity. Furthermore, the isocyanide analogues synthesized in this study did not inhibit the V27A or S31N mutant M2 ion channels, according to electrophysiology experiments, and did not exhibit activity against amantadine‐resistant virus strains.</p></abstract><abstract type="graphical" xml:lang="en"><p><b>Charge‐neutral bulky isocyanides</b> were found to exhibit antiviral activities similar to—or even higher than—that of amantadine. Moreover, we demonstrated that these isocyanides have potent growth inhibitory activity against the wild‐type H5N1 virus. The NH<sub>2</sub> to N≡C group replacement within current anti‐influenza drugs was found to result in compounds with low‐micromolar activities.<blockFixed type="graphic"><mediaResourceGroup><mediaResource alt="image" href="urn:x-wiley:18607179:media:cmdc201500318:cmdc201500318-toc-0001"></mediaResource></mediaResourceGroup></blockFixed></p></abstract></abstractGroup></contentMeta><noteGroup xml:id="cmdc201500318-ntgp-0001"><note xml:id="cmdc201500318-note-1001"><p>These authors contributed equally to this work.</p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Isocyanides as Influenza A Virus Subtype H5N1 Wild‐Type M2 Channel Inhibitors</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Isocyanides as Influenza A Virus Subtype H5N1 Wild‐Type M2 Channel Inhibitors</title></titleInfo><name type="personal"><namePart type="termsOfAddress">Dr.</namePart><namePart type="given">Shuwen</namePart><namePart type="family">Wu</namePart><affiliation>Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, 430071, Wuhan, P.R. China</affiliation><affiliation>State Key Laboratory of Virology of China, Wuhan University, 430071, Wuhan, P.R. China</affiliation><description>These authors contributed equally to this work.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jing</namePart><namePart type="family">Huang</namePart><affiliation>Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, 430071, Wuhan, P.R. China</affiliation><description>These authors contributed equally to this work.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="termsOfAddress">Dr.</namePart><namePart type="given">Sabrina</namePart><namePart type="family">Gazzarrini</namePart><affiliation>Department of Biosciences, University of Milan and, Institute of Biophysics (IBF) Milan, National Research Council (CNR), Via Celoria 26, 20133, Milan, Italy</affiliation><description>These authors contributed equally to this work.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Si</namePart><namePart type="family">He</namePart><affiliation>Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, 430071, Wuhan, P.R. China</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Lihua</namePart><namePart type="family">Chen</namePart><affiliation>Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, 430071, Wuhan, P.R. China</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="termsOfAddress">Dr.</namePart><namePart type="given">Jun</namePart><namePart type="family">Li</namePart><affiliation>Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, 430071, Wuhan, P.R. China</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="termsOfAddress">Dr.</namePart><namePart type="given">Li</namePart><namePart type="family">Xing</namePart><affiliation>Worldwide Research & Development, Pfizer Inc., 200 Cambridge Park Drive, MA, 02421, Cambridge, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="termsOfAddress">Dr.</namePart><namePart type="given">Chufang</namePart><namePart type="family">Li</namePart><affiliation>Guangzhou Institute of Biomedicine & Health, Chinese Academy of Sciences, Guangdong, 510530, Guangzhou, P.R. China</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="termsOfAddress">Prof.</namePart><namePart type="given">Ling</namePart><namePart type="family">Chen</namePart><affiliation>Guangzhou Institute of Biomedicine & Health, Chinese Academy of Sciences, Guangdong, 510530, Guangzhou, P.R. 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China</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="termsOfAddress">Prof.</namePart><namePart type="given">Alexander</namePart><namePart type="family">Dömling</namePart><affiliation>Department of Drug Design, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="termsOfAddress">Prof.</namePart><namePart type="given">Anna</namePart><namePart type="family">Moroni</namePart><affiliation>Department of Biosciences, University of Milan and, Institute of Biophysics (IBF) Milan, National Research Council (CNR), Via Celoria 26, 20133, Milan, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="termsOfAddress">Prof.</namePart><namePart type="given">Wei</namePart><namePart type="family">Wang</namePart><affiliation>Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, 430071, Wuhan, P.R. China</affiliation><affiliation>E-mail: waw6@whu.edu.cn</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-6N5SZHKN-D">article</genre><originInfo><publisher>Blackwell Publishing Ltd</publisher><dateIssued encoding="w3cdtf">2015-11</dateIssued><dateCaptured encoding="w3cdtf">2015-07-21</dateCaptured><edition>S. Wu, J. Huang, S. Gazzarrini, S. He, L. Chen, J. Li, L. Xing, C. Li, L. Chen, C. G. Neochoritis, G. P. Liao, H. Zhou, A. Dömling, A. Moroni, W. Wang, ChemMedChem 2015, 10, 1837.</edition><copyrightDate encoding="w3cdtf">2015</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><extent unit="figures">22</extent><extent unit="tables">1</extent><extent unit="references">62</extent></physicalDescription><abstract lang="en">Basic bulky amines such as amantadine are well‐characterized M2 channel blockers, useful for treating influenza. Herein we report our surprising findings that charge‐neutral, bulky isocyanides exhibit activities similar to—or even higher than—that of amantadine. We also demonstrate that these isocyanides have potent growth inhibitory activity against the H5N1 virus. The −NH2 to −N≡C group replacement within current anti‐influenza drugs was found to give compounds with high activities at low‐micromolar concentrations. For example, a tenfold improvement in potency was observed for 1‐isocyanoadamantane (27), with an EC50 value of 0.487 μm against amantadine‐sensitive H5N1 virus as determined by both MTT and plaque‐reduction assays, without showing cytotoxicity. Furthermore, the isocyanide analogues synthesized in this study did not inhibit the V27A or S31N mutant M2 ion channels, according to electrophysiology experiments, and did not exhibit activity against amantadine‐resistant virus strains.</abstract><abstract type="graphical" lang="en">Charge‐neutral bulky isocyanides were found to exhibit antiviral activities similar to—or even higher than—that of amantadine. Moreover, we demonstrated that these isocyanides have potent growth inhibitory activity against the wild‐type H5N1 virus. 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