Session topic

13:45–14:00

Title: Cationic amphiphilic drugs inhibit glycoprotein-mediated entry of diverse enveloped viruses
ID: O 62
Type: Abstract talk
Talk time: 12 + 3 min
Session: Workshop 11
Antivirals and resistance II

Speaker: Antonia-Patricia Gunesch (Hannover/DE)


Abstract - Text

Abstract text (incl. references and figure legends)

Introduction 


Broadly acting antivirals are beneficial options in viral outbreaks that lack sufficient treatment and vaccines. Cationic amphiphilic drugs (CADs) have this potential as several members are known to be active against enveloped viruses, e.g. Ebola virus. Moreover, many CADs are licensed already against a variety of diseases. However, their full spectrum of antiviral activities and mechanism of action (MOA) are not known.


Objectives 


We aimed to assess the breadth of antiviral activity of CADs against diverse virus families including recent emerging viruses. Furthermore, we investigated their antiviral mode of action. 


Material and methods 


We used lentiviral and VSV-based pseudotyped virions for evaluation of entry inhibition of 17 virus species clustering into diverse enveloped viral families, including filoviruses, arenaviruses and coronaviruses. Furthermore, we tested CAD activity against authentic hepatitis C virus (HCV) and hepatitis D virus.


Results 


Dronedarone was found to be the broadest inhibiting CAD (inhibition ranged from 40-95 %). Moreover, pseudoparticle entry of filoviruses EBOV and MARV, arenaviruses guanarito virus (GTOV) and Junin virus (JUNV), HCV and severe acute respiratory syndrome-related coronavirus-1 (SARS-CoV-1) seemed the broadest inhibited. Importantly, we observed cell type dependent effects. In Huh-7.5 cells, dronedarone inhibited SARS-CoV-1 (73 %) and moderately MERS-CoV (27 %) glycoprotein (gp)-mediated entry whereas the effect was absent in Calu-3 cells. Furthermore, authentic HCV was inhibited by the CADs amiodarone, dronedarone, triparanol and clomifene up to 99 % but also a mutant resistant to the well characterised HCV inhibitor flunarizine up to 90 %. Surprisingly, flunarizine, also a CAD, in turn moderately inhibited entry of filovirus (60 %) and GTOV (60 %) gp-mediated entry. We could exclude that CADs operate viral infection by permanent binding to virus particles but rather suggest a cell-based MOA. Furthermore, we could show that the CADs MOA was not a modulation of endosomal acidification.


Conclusion 


We could show that CADs have broad antiviral potential. The contrasting effect of flunarizine to other CADs and first MOA investigations underscore that CADs might have both broad effects on host cells as well as drug- and virus-specific antiviral activities.