Primary resistance mechanism of the canine distemper virus fusion protein against a small-molecule membrane fusion inhibitor

Kalbermatter, David; Shrestha, Neeta; Ader-Ebert, Nadine; Herren, Michael; Moll, Pascal; Plemper, Richard K.; Altmann, Karl-Heinz; Langedijk, Johannes P.; Gall, Flavio; Lindenmann, Urs; Riedl, Rainer; Fotiadis, Dimitrios; Plattet, Philippe

doi:10.1016/j.virusres.2018.10.003

Publication type:	Article in scientific journal
Type of review:	Peer review (publication)
Title:	Primary resistance mechanism of the canine distemper virus fusion protein against a small-molecule membrane fusion inhibitor
Authors:	Kalbermatter, David Shrestha, Neeta Ader-Ebert, Nadine Herren, Michael Moll, Pascal Plemper, Richard K. Altmann, Karl-Heinz Langedijk, Johannes P. Gall, Flavio Lindenmann, Urs Riedl, Rainer Fotiadis, Dimitrios Plattet, Philippe
et. al:	No
DOI:	10.1016/j.virusres.2018.10.003
Published in:	Virus Research
Volume(Issue):	259
Page(s):	28
Pages to:	37
Issue Date:	5-Oct-2018
Publisher / Ed. Institution:	Elsevier
ISSN:	0168-1702 1872-7492
Language:	English
Subjects:	Fusion inhibitors; Fusion protein; Head-stalk interface; Morbillivirus cell entry; Prefusion state stabilization; Amino acid sequence; Animal; Antiviral agent; Cell line; Chlorocebus aethiop; Distemper; Canine distemper virus; Molecular model; Mutation; Protein conformation; Vero cells; Viral fusion proteins; Viral drug resistance
Subject (DDC):	579: Microbiology
Abstract:	Morbilliviruses (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.
URI:	https://digitalcollection.zhaw.ch/handle/11475/21753
Fulltext version:	Published version
License (according to publishing contract):	Licence according to publishing contract
Departement:	Life Sciences and Facility Management
Organisational Unit:	Institute of Chemistry and Biotechnology (ICBT)
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.