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dc.contributor.authorGunesch, Antonia P
dc.contributor.authorZapatero-Belinchon, Francisco J
dc.contributor.authorPinkert, Lukas
dc.contributor.authorSteinmann, Eike
dc.contributor.authorManns, Michael P
dc.contributor.authorSchneider, Gisbert
dc.contributor.authorPietschmann, Thomas
dc.contributor.authorBrönstrup, Mark
dc.contributor.authorvon Hahn, Thomas
dc.date.accessioned2020-06-29T09:16:05Z
dc.date.available2020-06-29T09:16:05Z
dc.date.issued2020-06-08
dc.identifier.citationAntimicrob Agents Chemother. 2020;AAC.00143-20. doi:10.1128/AAC.00143-20.en_US
dc.identifier.pmid32513799
dc.identifier.urihttp://hdl.handle.net/10033/622317
dc.description.abstractSeveral cationic amphiphilic drugs (CADs) have been found to inhibit cell entry of filoviruses and other enveloped viruses. Structurally unrelated CADs may have antiviral activity, yet the underlying common mechanism and structure-activity relationship are incompletely understood.We aimed to understand how widespread antiviral activity is among CADs and which structural and physico-chemical properties are linked to entry inhibition.We measured inhibition of Marburg virus pseudoparticle (MARVpp) cell entry by 45 heterogeneous and mostly FDA-approved CADs and cytotoxicity in EA.hy926 cells. We analysed correlation of antiviral activity with four chemical properties: pKa, ClogP, molecular weight and distance between the basic group and hydrophobic ring structures. Additionally, we quantified drug-induced phospholipidosis (DIPL) of a CAD subset by flow cytometry. Structurally similar compounds (derivatives) and those with similar chemical properties but unrelated structure (analogues) to strong inhibitors were obtained by two in silico similarity search approaches and tested for antiviral activity. Overall 11 out of 45 (24 %) CADs inhibited MARVpp by 40 % or more. The strongest antiviral compounds were dronedarone, triparanol and quinacrine. Structure-activity relationship studies revealed highly significant correlations between antiviral activity, hydrophobicity (ClogP>4), and DIPL. Moreover, pKa and intra-molecular distance between hydrophobic and hydrophilic moieties correlated with antiviral activity, but to a lesser extent. We also showed that in contrast to analogues, derivatives had similar antiviral activity as the seed compound dronedarone. Overall, one quarter of CADs inhibits MARVpp entry in vitro and antiviral activity of CADs mostly relies on their hydrophobicity, yet is promoted by the individual structure.en_US
dc.language.isoenen_US
dc.publisherASMen_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleFilovirus antiviral activity of cationic amphiphilic drugs is associated with lipophilicity and ability to induce phospholipidosis.en_US
dc.typeArticleen_US
dc.identifier.eissn1098-6596
dc.contributor.departmentHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.; TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.en_US
dc.identifier.journalAntimicrobial agents and chemotherapyen_US
dc.source.journaltitleAntimicrobial agents and chemotherapy
dc.source.countryUnited States


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