Filovirus Antiviral Activity of Cationic Amphiphilic Drugs Is Associated with Lipophilicity and Ability To Induce Phospholipidosis
- 22 July 2020
- journal article
- research article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 64 (8)
- https://doi.org/10.1128/aac.00143-20
Abstract
Several 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 analyzed correlation of antiviral activity with four chemical properties: pKa, hydrophobicity (octanol/water partitioning coefficient; 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 structures (analogues) to those of 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 intramolecular 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 antiviral activity similar to that of the seed compound dronedarone. Overall, one-quarter of CADs inhibit MARVpp entry in vitro, and antiviral activity of CADs mostly relies on their hydrophobicity yet is promoted by the individual structure.Funding Information
- Deutsche Forschungsgemeinschaft (SFB738)
- Deutsches Zentrum für Infektionsforschung (05807)
This publication has 55 references indexed in Scilit:
- Multiple Cationic Amphiphiles Induce a Niemann-Pick C Phenotype and Inhibit Ebola Virus Entry and InfectionPLOS ONE, 2013
- Small molecule inhibitors reveal Niemann–Pick C1 is essential for Ebola virus infectionNature, 2011
- Impact of Intra- and Interspecies Variation of Occludin on Its Function as Coreceptor for Authentic Hepatitis C Virus ParticlesJournal of Virology, 2011
- A cell protection screen reveals potent inhibitors of multiple stages of the hepatitis C virus life cycleProceedings of the National Academy of Sciences of the United States of America, 2010
- Chemical combinations elucidate pathway interactions and regulation relevant to Hepatitis C replicationMolecular Systems Biology, 2010
- Unbiased probing of the entire hepatitis C virus life cycle identifies clinical compounds that target multiple aspects of the infectionProceedings of the National Academy of Sciences of the United States of America, 2009
- Intracellular sequestration of amiodarone: role of vacuolar ATPase and macroautophagic transition of the resulting vacuolar cytopathologyBritish Journal of Pharmacology, 2009
- Hexadecyloxypropyl-cidofovir, CMX001, prevents adenovirus-induced mortality in a permissive, immunosuppressed animal modelProceedings of the National Academy of Sciences of the United States of America, 2008
- Role of the Transmembrane Domain of Marburg Virus Surface Protein GP in Assembly of the Viral EnvelopeJournal of Virology, 2007
- Diverse CD81 Proteins Support Hepatitis C Virus InfectionJournal of Virology, 2006