Labyrinthopeptins as virolytic inhibitors of respiratory syncytial virus cell entry.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
Sake, Svenja M
Le Goffic, Ronan
Duprex, W Paul
MetadataShow full item record
AbstractAcute 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.
CitationAntiviral Res. 2020;177:104774. doi:10.1016/j.antiviral.2020.104774.
AffiliationTWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
The following license files are associated with this item:
- Creative Commons
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-ShareAlike 4.0 International
- Labyrinthopeptins Exert Broad-Spectrum Antiviral Activity through Lipid-Binding-Mediated Virolysis.
- Authors: Prochnow H, Rox K, Birudukota NVS, Weichert L, Hotop SK, Klahn P, Mohr K, Franz S, Banda DH, Blockus S, Schreiber J, Haid S, Oeyen M, Martinez JP, Süssmuth RD, Wink J, Meyerhans A, Goffinet C, Messerle M, Schulz TF, Kröger A, Schols D, Pietschmann T, Brönstrup M
- Issue date: 2020 Jan 6
- Cross-resistance mechanism of respiratory syncytial virus against structurally diverse entry inhibitors.
- Authors: Yan D, Lee S, Thakkar VD, Luo M, Moore ML, Plemper RK
- Issue date: 2014 Aug 19
- Induction and Antagonism of Antiviral Responses in Respiratory Syncytial Virus-Infected Pediatric Airway Epithelium.
- Authors: Villenave R, Broadbent L, Douglas I, Lyons JD, Coyle PV, Teng MN, Tripp RA, Heaney LG, Shields MD, Power UF
- Issue date: 2015 Dec
- Characterization of novel respiratory syncytial virus inhibitors identified by high throughput screen.
- Authors: Laganas VA, Dunn EF, McLaughlin RE, Tiong-Yip CL, Yuzhakov O, Isabella VM, Hill P, Yu Q
- Issue date: 2015 Mar
- Respiratory syncytial virus (RSV) entry is inhibited by serine protease inhibitor AEBSF when present during an early stage of infection.
- Authors: Van der Gucht W, Leemans A, De Schryver M, Heykers A, Caljon G, Maes L, Cos P, Delputte PL
- Issue date: 2017 Aug 17