Labyrinthopeptins as virolytic inhibitors of respiratory syncytial virus cell entry

verfasst von

Sebastian Blockus, Svenja M. Sake, Martin Wetzke, Christina Grethe, Theresa Graalmann, Marina Pils, Ronan Le Goffic, Marie Galloux, Hans Prochnow, Katharina Rox, Stephan Hüttel, Zeljka Rupcic, Bettina Wiegmann, Ronald Dijkman, Marie Anne Rameix-Welti, Jean François Eléouët, W. Paul Duprex, Volker Thiel, Gesine Hansen, Mark Brönstrup, Sibylle Haid, Thomas Pietschmann

Abstract

Acute lower respiratory tract infections (ALRI) caused by respiratory syncytial virus (RSV) are associated with a severe disease burden among infants and elderly patients. Treatment options are limited. While numerous drug candidates with different viral targets are under development, the utility of RSV entry inhibitors is challenged by a low resistance barrier and by single mutations causing cross-resistance against a wide spectrum of fusion inhibitor chemotypes. We developed a cell-based screening assay for discovery of compounds inhibiting infection with primary RSV isolates. Using this system, we identified labyrinthopeptin A1 and A2 (Laby A1/A2), lantibiotics isolated from Actinomadura namibiensis, as effective RSV cell entry inhibitors with IC₅₀s of 0.39 μM and 4.97 μM, respectively, and with favourable therapeutic index (>200 and > 20, respectively). Both molecules were active against multiple RSV strains including primary isolates and their antiviral activity against RSV was confirmed in primary human airway cells ex vivo and a murine model in vivo. Laby A1/A2 were antiviral in prophylactic and therapeutic treatment regimens and displayed synergistic activity when applied in combination with each other. Mechanistic studies showed that Laby A1/A2 exert virolytic activity likely by binding to phosphatidylethanolamine moieties within the viral membrane and by disrupting virus particle membrane integrity. Probably due to its specific mode of action, Laby A1/A2 antiviral activity was not affected by common resistance mutations to known RSV entry inhibitors. Taken together, Laby A1/A2 represent promising candidates for development as RSV inhibitors. Moreover, the cell-based screening system with primary RSV isolates described here should be useful to identify further antiviral agents.

Externe Organisation(en)

TWINCORE Zentrum für Experimentelle und Klinische Infektionsforschung GmbH
Medizinische Hochschule Hannover (MHH)
Deutsches Zentrum für Infektionsforschung (DZIF)
Helmholtz-Zentrum für Infektionsforschung GmbH (HZI)
Universität Paris-Saclay
Deutsches Zentrum für Lungenforschung (DZL)
Institut für Virologie und Immunologie (IVI)
University of Bern
Universite de Versailles
University of Pittsburgh

Typ

Artikel

Journal

Antiviral Research

Band

177

ISSN

0166-3542

Publikationsdatum

05.2020

Publikationsstatus

Veröffentlicht

Peer-reviewed

Ja

ASJC Scopus Sachgebiete

Pharmakologie, Virologie

Ziele für nachhaltige Entwicklung

SDG 3 – Gute Gesundheit und Wohlergehen

Elektronische Version(en)

https://doi.org/10.1016/j.antiviral.2020.104774 (Zugang: Offen)