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dc.contributor.author
Stadelmann, Thomas
dc.contributor.author
Subramanian, Govindan
dc.contributor.author
Menon, Sanjay
dc.contributor.author
Townsend, Chad E.
dc.contributor.author
Lokey, R. Scott
dc.contributor.author
Ebert, Marc-Olivier
dc.contributor.author
Riniker, Sereina
dc.date.accessioned
2020-09-30T09:47:49Z
dc.date.available
2020-09-29T14:56:35Z
dc.date.available
2020-09-30T09:47:49Z
dc.date.issued
2020-09-28
dc.identifier.issn
1477-0520
dc.identifier.issn
1477-0539
dc.identifier.other
10.1039/d0ob01447h
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/443546
dc.identifier.doi
10.3929/ethz-b-000443546
dc.description.abstract
Cyclic octadepsipeptides such as PF1022A and its synthetic derivative emodepside exhibit anthelmintic activity with the latter sold as a commercial drug treatment against gastrointestinal nematodes for animal health use. The structure–permeability relationship of these cyclic depsipeptides that could ultimately provide insights into the compound bioavailability is not yet well understood. The fully N-methylated amide backbone and apolar sidechain residues do not allow for the formation of intramolecular hydrogen bonds, normally observed in the membrane-permeable conformations of cyclic peptides. Hence, any understanding gained on these depsipeptides would serve as a prototype for future design strategies. In previous nuclear magnetic resonance (NMR) studies, two macrocyclic core conformers of emodepside were detected, one with all backbone amides in trans-configuration (hereon referred as the symmetric conformer) and the other with one amide in cis-configuration (hereon referred as the asymmetric conformer). In addition, these depsipeptides were also reported to be ionophores with a preference of potassium over sodium. In this study, we relate the conformational behavior of PF1022A, emodepside, and closely related analogs with their ionophoric characteristic probed using NMR and molecular dynamics (MD) simulations and finally evaluated their passive membrane permeability using PAMPA. We find that the equilibrium between the two core conformers shifts more towards the symmetric conformer upon addition of monovalent cations with selectivity for potassium over sodium. Both the NMR experiments and the theoretical Markov state models based on extensive MD simulations indicate a more rigid backbone for the asymmetric conformation, whereas the symmetric conformation shows greater flexibility. The experimental results further advocate for the symmetric conformation binding the cation. The PAMPA results suggest that the investigated depsipeptides are retained in the membrane, which may be advantageous for the likely target, a membrane-bound potassium channel.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
Royal Society of Chemistry
en_US
dc.rights.uri
http://creativecommons.org/licenses/by/3.0/
dc.title
Connecting the conformational behavior of cyclic octadepsipeptides with their ionophoric property and membrane permeability
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution 3.0 Unported
dc.date.published
2020-08-12
ethz.journal.title
Organic & biomolecular chemistry
ethz.journal.volume
18
en_US
ethz.journal.issue
36
en_US
ethz.journal.abbreviated
Org. biomol. chem.
ethz.pages.start
7110
en_US
ethz.pages.end
7126
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.grant
Passive Membrane-Permeability Prediction for Peptides and Peptidomimetics Using Computational Methods
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
Cambridge
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.::02543 - Inst. f. Molekulare Physikalische Wiss. / Institute of Molecular Physical Science::09458 - Riniker, Sereina Z. / Riniker, Sereina Z.
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.::02514 - Laboratorium für Organische Chemie / Laboratory of Organic Chemistry::08663 - NMR-Service LOC
en_US
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.::02543 - Inst. f. Molekulare Physikalische Wiss. / Institute of Molecular Physical Science::09458 - Riniker, Sereina Z. / Riniker, Sereina Z.
en_US
ethz.grant.agreementno
178762
ethz.grant.fundername
SNF
ethz.grant.funderDoi
10.13039/501100001711
ethz.grant.program
Projekte MINT
ethz.date.deposited
2020-09-29T14:56:45Z
ethz.source
FORM
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2020-09-30T09:48:01Z
ethz.rosetta.lastUpdated
2024-02-02T12:12:22Z
ethz.rosetta.versionExported
true
ethz.COinS
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