Article: CL-385319 inhibits H5N1 avian influenza A virus infection by blocking viral entry

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TitleCL-385319 inhibits H5N1 avian influenza A virus infection by blocking viral entry
AuthorsLiu, S1
Li, R1
Zhang, R1
Chan, CCS2
Xi, B1
Zhu, Z1
Yang, J1
Poon, VKM2
Zhou, J2
Chen, M2
Münch, J5
Kirchhoff, F5
Pleschka, S4
Haarmann, T3
Dietrich, U3
Pan, C6
Du, L6
Jiang, S1 6
Zheng, B2
Issue Date2011
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/ejphar
CitationEuropean Journal Of Pharmacology, 2011, v. 660 n. 2-3, p. 460-467 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.ejphar.2011.04.013
AbstractCL-385319, an N-substituted piperidine, is effective in inhibiting infection of H1-, H2-, and to a lesser extent, H3-typed influenza A viruses by interfering with the fusogenic function of the viral hemagglutinin. Here we show that CL-385319 is effective in inhibiting infection of highly pathogenic H5N1 influenza A virus in Madin-Darby Canine Kidney (MDCK) cells with an IC 50 of 27.03 ± 2.54 μM. This compound with low cytotoxicity (CC 50 = 1.48 ± 0.01 mM) could also inhibit entry of pseudoviruses carrying hemagglutinins from H5N1 strains that were isolated from different places at different times, while it had no inhibitory activity on the entry of VSV-G pseudotyped particles. CL385319 could not inhibit N1-typed neuraminidase activity and the adsorption of H5-typed HA to chicken erythrocytes at the concentration as high as 1 mg/ml (2.8 mM). Computer-aid molecular docking analysis suggested that CL-385319 might bind to the cavity of HA2 stem region which was known to undergo significant rearrangement during membrane fusion. Pseudoviruses with M24A mutation in HA1 or F110S mutation in HA2 were resistant to CL-385319, indicating that these two residues in the cavity region may be critical for CL-385319 bindings. These findings suggest that CL-385319 can serve as a lead for development of novel virus entry inhibitors for preventing and treating H5N1 influenza A virus infection. © 2011 Elsevier B.V. All rights reserved.
ISSN0014-2999
2011 Impact Factor: 2.516
2011 SCImago Journal Rankings: 0.199
DOIhttp://dx.doi.org/10.1016/j.ejphar.2011.04.013
ISI Accession Number IDWOS:000291623600030
Funding AgencyGrant Number
Natural Science Foundation of China30772602
Ministry of EducationNCET-06-0753
German Research Foundation
Research Grants Council of Hong Kong SAR
European UnionSP5B-CT-2007-044098
Funding Information:

This work was supported by the Natural Science Foundation of China (30772602), the Ministry of Education's New Century Talent Program (NCET-06-0753), the German Research Foundation, the Research Grants Council of Hong Kong SAR and in parts by the 6th Framework Program (FP6) of the European Union (SP5B-CT-2007-044098, to S.P and U.D.).

ReferencesReferences in Scopus
DC Field
Value
dc.contributor.authorLiu, S
dc.contributor.authorLi, R
dc.contributor.authorZhang, R
dc.contributor.authorChan, CCS
dc.contributor.authorXi, B
dc.contributor.authorZhu, Z
dc.contributor.authorYang, J
dc.contributor.authorPoon, VKM
dc.contributor.authorZhou, J
dc.contributor.authorChen, M
dc.contributor.authorMünch, J
dc.contributor.authorKirchhoff, F
dc.contributor.authorPleschka, S
dc.contributor.authorHaarmann, T
dc.contributor.authorDietrich, U
dc.contributor.authorPan, C
dc.contributor.authorDu, L
dc.contributor.authorJiang, S
dc.contributor.authorZheng, B
dc.date.accessioned2011-07-27T01:31:20Z
dc.date.available2011-07-27T01:31:20Z
dc.date.issued2011
dc.description.abstractCL-385319, an N-substituted piperidine, is effective in inhibiting infection of H1-, H2-, and to a lesser extent, H3-typed influenza A viruses by interfering with the fusogenic function of the viral hemagglutinin. Here we show that CL-385319 is effective in inhibiting infection of highly pathogenic H5N1 influenza A virus in Madin-Darby Canine Kidney (MDCK) cells with an IC 50 of 27.03 ± 2.54 μM. This compound with low cytotoxicity (CC 50 = 1.48 ± 0.01 mM) could also inhibit entry of pseudoviruses carrying hemagglutinins from H5N1 strains that were isolated from different places at different times, while it had no inhibitory activity on the entry of VSV-G pseudotyped particles. CL385319 could not inhibit N1-typed neuraminidase activity and the adsorption of H5-typed HA to chicken erythrocytes at the concentration as high as 1 mg/ml (2.8 mM). Computer-aid molecular docking analysis suggested that CL-385319 might bind to the cavity of HA2 stem region which was known to undergo significant rearrangement during membrane fusion. Pseudoviruses with M24A mutation in HA1 or F110S mutation in HA2 were resistant to CL-385319, indicating that these two residues in the cavity region may be critical for CL-385319 bindings. These findings suggest that CL-385319 can serve as a lead for development of novel virus entry inhibitors for preventing and treating H5N1 influenza A virus infection. © 2011 Elsevier B.V. All rights reserved.
dc.description.natureLink_to_subscribed_fulltext
dc.identifier.citationEuropean Journal Of Pharmacology, 2011, v. 660 n. 2-3, p. 460-467 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.ejphar.2011.04.013
dc.identifier.citeulike9230718
dc.identifier.doihttp://dx.doi.org/10.1016/j.ejphar.2011.04.013
dc.identifier.epage467
dc.identifier.hkuros188645
dc.identifier.isiWOS:000291623600030
Funding AgencyGrant Number
Natural Science Foundation of China30772602
Ministry of EducationNCET-06-0753
German Research Foundation
Research Grants Council of Hong Kong SAR
European UnionSP5B-CT-2007-044098
Funding Information:

This work was supported by the Natural Science Foundation of China (30772602), the Ministry of Education's New Century Talent Program (NCET-06-0753), the German Research Foundation, the Research Grants Council of Hong Kong SAR and in parts by the 6th Framework Program (FP6) of the European Union (SP5B-CT-2007-044098, to S.P and U.D.).

dc.identifier.issn0014-2999
2011 Impact Factor: 2.516
2011 SCImago Journal Rankings: 0.199
dc.identifier.issue2-3
dc.identifier.pmid21536025
dc.identifier.scopuseid_2-s2.0-79956103650
dc.identifier.spage460
dc.identifier.urihttp://hdl.handle.net/10722/135284
dc.identifier.volume660
dc.languageeng
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/ejphar
dc.publisher.placeNetherlands
dc.relation.ispartofEuropean Journal of Pharmacology
dc.relation.referencesReferences in Scopus
dc.subject.meshAnimals
dc.subject.meshAntiviral Agents - metabolism - pharmacology - toxicity
dc.subject.meshDogs
dc.subject.meshHEK293 Cells
dc.subject.meshHemagglutinin Glycoproteins, Influenza Virus - chemistry - metabolism
dc.subject.meshHumans
dc.subject.meshHydrocarbons, Fluorinated - metabolism - pharmacology - toxicity
dc.subject.meshInfluenza A Virus, H5N1 Subtype - drug effects - metabolism - physiology
dc.subject.meshModels, Molecular
dc.subject.meshPiperidines - metabolism - pharmacology - toxicity
dc.subject.meshProtein Conformation
dc.subject.meshVirus Internalization - drug effects
dc.titleCL-385319 inhibits H5N1 avian influenza A virus infection by blocking viral entry
dc.typeArticle
Author Affiliations
  1. Southern Medical University
  2. The University of Hong Kong
  3. Georg-Speyer-Haus
  4. null
  5. Universitätsklinikum Ulm
  6. New York Blood Center