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

TitleCL-385319 inhibits H5N1 avian influenza A virus infection by blocking viral entry
Authors
Issue Date2011
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/ejphar
Citation
European Journal Of Pharmacology, 2011, v. 660 n. 2-3, p. 460-467 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/135284
ISSN
2014 Impact Factor: 2.532
2014 SCImago Journal Rankings: 0.871
ISI Accession Number ID
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.).

References

 

DC FieldValueLanguage
dc.contributor.authorLiu, Sen_HK
dc.contributor.authorLi, Ren_HK
dc.contributor.authorZhang, Ren_HK
dc.contributor.authorChan, CCSen_HK
dc.contributor.authorXi, Ben_HK
dc.contributor.authorZhu, Zen_HK
dc.contributor.authorYang, Jen_HK
dc.contributor.authorPoon, VKMen_HK
dc.contributor.authorZhou, Jen_HK
dc.contributor.authorChen, Men_HK
dc.contributor.authorMünch, Jen_HK
dc.contributor.authorKirchhoff, Fen_HK
dc.contributor.authorPleschka, Sen_HK
dc.contributor.authorHaarmann, Ten_HK
dc.contributor.authorDietrich, Uen_HK
dc.contributor.authorPan, Cen_HK
dc.contributor.authorDu, Len_HK
dc.contributor.authorJiang, Sen_HK
dc.contributor.authorZheng, Ben_HK
dc.date.accessioned2011-07-27T01:31:20Z-
dc.date.available2011-07-27T01:31:20Z-
dc.date.issued2011en_HK
dc.identifier.citationEuropean Journal Of Pharmacology, 2011, v. 660 n. 2-3, p. 460-467en_HK
dc.identifier.issn0014-2999en_HK
dc.identifier.urihttp://hdl.handle.net/10722/135284-
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.en_HK
dc.languageengen_US
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/ejpharen_HK
dc.relation.ispartofEuropean Journal of Pharmacologyen_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshAntiviral Agents - metabolism - pharmacology - toxicityen_HK
dc.subject.meshDogsen_HK
dc.subject.meshHEK293 Cellsen_HK
dc.subject.meshHemagglutinin Glycoproteins, Influenza Virus - chemistry - metabolismen_HK
dc.subject.meshHumansen_HK
dc.subject.meshHydrocarbons, Fluorinated - metabolism - pharmacology - toxicityen_HK
dc.subject.meshInfluenza A Virus, H5N1 Subtype - drug effects - metabolism - physiologyen_HK
dc.subject.meshModels, Molecularen_HK
dc.subject.meshPiperidines - metabolism - pharmacology - toxicityen_HK
dc.subject.meshProtein Conformationen_HK
dc.subject.meshVirus Internalization - drug effectsen_HK
dc.titleCL-385319 inhibits H5N1 avian influenza A virus infection by blocking viral entryen_HK
dc.typeArticleen_HK
dc.identifier.emailZhou, J:jiezhou@hku.hken_HK
dc.identifier.emailZheng, B:bzheng@hkucc.hku.hken_HK
dc.identifier.authorityZhou, J=rp01412en_HK
dc.identifier.authorityZheng, B=rp00353en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.ejphar.2011.04.013en_HK
dc.identifier.pmid21536025en_HK
dc.identifier.scopuseid_2-s2.0-79956103650en_HK
dc.identifier.hkuros188645en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79956103650&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume660en_HK
dc.identifier.issue2-3en_HK
dc.identifier.spage460en_HK
dc.identifier.epage467en_HK
dc.identifier.isiWOS:000291623600030-
dc.publisher.placeNetherlandsen_HK
dc.identifier.scopusauthoridLiu, S=35253814900en_HK
dc.identifier.scopusauthoridLi, R=37104400100en_HK
dc.identifier.scopusauthoridZhang, R=35226856000en_HK
dc.identifier.scopusauthoridChan, CCS=16021156900en_HK
dc.identifier.scopusauthoridXi, B=7005575394en_HK
dc.identifier.scopusauthoridZhu, Z=36083826700en_HK
dc.identifier.scopusauthoridYang, J=35331454800en_HK
dc.identifier.scopusauthoridPoon, VKM=6603703384en_HK
dc.identifier.scopusauthoridZhou, J=7405550443en_HK
dc.identifier.scopusauthoridChen, M=35168778400en_HK
dc.identifier.scopusauthoridMünch, J=7102005157en_HK
dc.identifier.scopusauthoridKirchhoff, F=7005249256en_HK
dc.identifier.scopusauthoridPleschka, S=6602999462en_HK
dc.identifier.scopusauthoridHaarmann, T=8585718100en_HK
dc.identifier.scopusauthoridDietrich, U=7006163144en_HK
dc.identifier.scopusauthoridPan, C=24491970300en_HK
dc.identifier.scopusauthoridDu, L=8686996200en_HK
dc.identifier.scopusauthoridJiang, S=35198433300en_HK
dc.identifier.scopusauthoridZheng, B=7201780588en_HK
dc.identifier.citeulike9230718-

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