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dc.contributor.authorKalbermatter, David-
dc.contributor.authorShrestha, Neeta-
dc.contributor.authorAder-Ebert, Nadine-
dc.contributor.authorHerren, Michael-
dc.contributor.authorMoll, Pascal-
dc.contributor.authorPlemper, Richard K.-
dc.contributor.authorAltmann, Karl-Heinz-
dc.contributor.authorLangedijk, Johannes P.-
dc.contributor.authorGall, Flavio-
dc.contributor.authorLindenmann, Urs-
dc.contributor.authorRiedl, Rainer-
dc.contributor.authorFotiadis, Dimitrios-
dc.contributor.authorPlattet, Philippe-
dc.date.accessioned2021-02-18T10:49:13Z-
dc.date.available2021-02-18T10:49:13Z-
dc.date.issued2018-10-05-
dc.identifier.issn0168-1702de_CH
dc.identifier.issn1872-7492de_CH
dc.identifier.urihttps://digitalcollection.zhaw.ch/handle/11475/21753-
dc.description.abstractMorbilliviruses (e.g. measles virus [MeV] or canine distemper virus [CDV]) employ the attachment (H) and fusion (F) envelope glycoproteins for cell entry. H protein engagement to a cognate receptor eventually leads to F-triggering. Upon activation, F proteins transit from a prefusion to a postfusion conformation; a refolding process that is associated with membrane merging. Small-molecule morbilliviral fusion inhibitors such as the compound 3G (a chemical analog in the AS-48 class) were previously generated and mechanistic studies revealed a stabilizing effect on morbilliviral prefusion F trimers. Here, we aimed at designing 3G-resistant CDV F mutants by introducing single cysteine residues at hydrophobic core positions of the helical stalk region. Covalently-linked F dimers were generated, which highlighted substantial conformational flexibility within the stalk to achieve those irregular F conformations. Our findings demonstrate that "top-stalk" CDV F cysteine mutants (F-V571C and F-L575C) remained functional and gained resistance to 3G. Conversely, although not all "bottom-stalk" F cysteine variants preserved proper bioactivity, those that remained functional exhibited 3G-sensitivity. According to the recently determined prefusion MeV F trimer/AS-48 co-crystal structure, CDV residues F-V571 and F-L575 may directly interact with 3G. A combination of conformation-specific anti-F antibodies and low-resolution electron microscopy structural analyses confirmed that 3G lost its stabilizing effect on "top-stalk" F cysteine mutants thus suggesting a primary resistance mechanism. Overall, our data suggest that the fusion inhibitor 3G stabilizes prefusion CDV F trimers by docking at the top of the stalk domain.de_CH
dc.language.isoende_CH
dc.publisherElsevierde_CH
dc.relation.ispartofVirus Researchde_CH
dc.rightsLicence according to publishing contractde_CH
dc.subjectFusion inhibitorsde_CH
dc.subjectFusion proteinde_CH
dc.subjectHead-stalk interfacede_CH
dc.subjectMorbillivirus cell entryde_CH
dc.subjectPrefusion state stabilizationde_CH
dc.subjectAmino acid sequencede_CH
dc.subjectAnimalde_CH
dc.subjectAntiviral agentde_CH
dc.subjectCell linede_CH
dc.subjectChlorocebus aethiopde_CH
dc.subjectDistemperde_CH
dc.subjectCanine distemper virusde_CH
dc.subjectMolecular modelde_CH
dc.subjectMutationde_CH
dc.subjectProtein conformationde_CH
dc.subjectVero cellsde_CH
dc.subjectViral fusion proteinsde_CH
dc.subjectViral drug resistancede_CH
dc.subject.ddc579: Mikrobiologiede_CH
dc.titlePrimary resistance mechanism of the canine distemper virus fusion protein against a small-molecule membrane fusion inhibitorde_CH
dc.typeBeitrag in wissenschaftlicher Zeitschriftde_CH
dcterms.typeTextde_CH
zhaw.departementLife Sciences und Facility Managementde_CH
zhaw.organisationalunitInstitut für Chemie und Biotechnologie (ICBT)de_CH
dc.identifier.doi10.1016/j.virusres.2018.10.003de_CH
dc.identifier.pmid30296457de_CH
zhaw.funding.euNode_CH
zhaw.originated.zhawYesde_CH
zhaw.pages.end37de_CH
zhaw.pages.start28de_CH
zhaw.publication.statuspublishedVersionde_CH
zhaw.volume259de_CH
zhaw.publication.reviewPeer review (Publikation)de_CH
zhaw.funding.snf183481de_CH
zhaw.webfeedCC Drug Discoveryde_CH
zhaw.author.additionalNode_CH
zhaw.display.portraitYesde_CH
Appears in collections:Publikationen Life Sciences und Facility Management

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Kalbermatter, D., Shrestha, N., Ader-Ebert, N., Herren, M., Moll, P., Plemper, R. K., Altmann, K.-H., Langedijk, J. P., Gall, F., Lindenmann, U., Riedl, R., Fotiadis, D., & Plattet, P. (2018). Primary resistance mechanism of the canine distemper virus fusion protein against a small-molecule membrane fusion inhibitor. Virus Research, 259, 28–37. https://doi.org/10.1016/j.virusres.2018.10.003
Kalbermatter, D. et al. (2018) ‘Primary resistance mechanism of the canine distemper virus fusion protein against a small-molecule membrane fusion inhibitor’, Virus Research, 259, pp. 28–37. Available at: https://doi.org/10.1016/j.virusres.2018.10.003.
D. Kalbermatter et al., “Primary resistance mechanism of the canine distemper virus fusion protein against a small-molecule membrane fusion inhibitor,” Virus Research, vol. 259, pp. 28–37, Oct. 2018, doi: 10.1016/j.virusres.2018.10.003.
KALBERMATTER, David, Neeta SHRESTHA, Nadine ADER-EBERT, Michael HERREN, Pascal MOLL, Richard K. PLEMPER, Karl-Heinz ALTMANN, Johannes P. LANGEDIJK, Flavio GALL, Urs LINDENMANN, Rainer RIEDL, Dimitrios FOTIADIS und Philippe PLATTET, 2018. Primary resistance mechanism of the canine distemper virus fusion protein against a small-molecule membrane fusion inhibitor. Virus Research. 5 Oktober 2018. Bd. 259, S. 28–37. DOI 10.1016/j.virusres.2018.10.003
Kalbermatter, David, Neeta Shrestha, Nadine Ader-Ebert, Michael Herren, Pascal Moll, Richard K. Plemper, Karl-Heinz Altmann, et al. 2018. “Primary Resistance Mechanism of the Canine Distemper Virus Fusion Protein against a Small-Molecule Membrane Fusion Inhibitor.” Virus Research 259 (October): 28–37. https://doi.org/10.1016/j.virusres.2018.10.003.
Kalbermatter, David, et al. “Primary Resistance Mechanism of the Canine Distemper Virus Fusion Protein against a Small-Molecule Membrane Fusion Inhibitor.” Virus Research, vol. 259, Oct. 2018, pp. 28–37, https://doi.org/10.1016/j.virusres.2018.10.003.


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