Details
| Original language | English |
|---|---|
| Article number | 104774 |
| Journal | Antiviral Research |
| Volume | 177 |
| Publication status | Published - May 2020 |
| Externally published | Yes |
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.
Keywords
- Antiviral activity, Human respiratory syncytial virus (hRSV), Labyrinthopeptin, Lanthipeptide, Virolytic, Virus entry
ASJC Scopus subject areas
- Pharmacology, Toxicology and Pharmaceutics(all)
- Pharmacology
- Immunology and Microbiology(all)
- Virology
Sustainable Development Goals
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In: Antiviral Research, Vol. 177, 104774, 05.2020.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Labyrinthopeptins as virolytic inhibitors of respiratory syncytial virus cell entry
AU - Blockus, Sebastian
AU - Sake, Svenja M.
AU - Wetzke, Martin
AU - Grethe, Christina
AU - Graalmann, Theresa
AU - Pils, Marina
AU - Le Goffic, Ronan
AU - Galloux, Marie
AU - Prochnow, Hans
AU - Rox, Katharina
AU - Hüttel, Stephan
AU - Rupcic, Zeljka
AU - Wiegmann, Bettina
AU - Dijkman, Ronald
AU - Rameix-Welti, Marie Anne
AU - Eléouët, Jean François
AU - Duprex, W. Paul
AU - Thiel, Volker
AU - Hansen, Gesine
AU - Brönstrup, Mark
AU - Haid, Sibylle
AU - Pietschmann, Thomas
N1 - Funding Information: This work was supported by the Innovation Fonds of the Helmholtz Association, by the Pre-4D-Fonds of the Helmholtz Centre for Infection Research, and by the Helmholtz-Alberta Initiative for Infectious Disease Research (HAI-IDR). T.P. and G.H. are funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy – EXC 2155 “RESIST” – Project ID 39087428 . M.W. received a clinical leave scholarship from the German Centre for Infection Research (DZIF) and was funded by a scholarship from the Young Academy of Hannover Medical School . R.D. and V.T. were supported by the Swiss National Science Foundation (grants 310030_179260 (R.D.) and 310030_173085 (V.T.). We are grateful to Richard Karl Plemper for gift of BMS-433771. We thank all members of the Institute for Experimental Virology at TWINCORE-Centre of Experimental and Clinical Infection Research for helpful comments and discussion of this work. TWINCORE is a joint venture of the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research, Braunschweig (HZI). Funding Information: This work was supported by the Innovation Fonds of the Helmholtz Association, by the Pre-4D-Fonds of the Helmholtz Centre for Infection Research, and by the Helmholtz-Alberta Initiative for Infectious Disease Research (HAI-IDR). T.P. and G.H. are funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy ? EXC 2155 ?RESIST? ? Project ID 39087428. M.W. received a clinical leave scholarship from the German Centre for Infection Research (DZIF) and was funded by a scholarship from the Young Academy of Hannover Medical School. R.D. and V.T. were supported by the Swiss National Science Foundation (grants 310030_179260 (R.D.) and 310030_173085 (V.T.). We are grateful to Richard Karl Plemper for gift of BMS-433771. We thank all members of the Institute for Experimental Virology at TWINCORE-Centre of Experimental and Clinical Infection Research for helpful comments and discussion of this work. TWINCORE is a joint venture of the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research, Braunschweig (HZI).
PY - 2020/5
Y1 - 2020/5
N2 - 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.
AB - 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.
KW - Antiviral activity
KW - Human respiratory syncytial virus (hRSV)
KW - Labyrinthopeptin
KW - Lanthipeptide
KW - Virolytic
KW - Virus entry
UR - http://www.scopus.com/inward/record.url?scp=85082126932&partnerID=8YFLogxK
U2 - 10.1016/j.antiviral.2020.104774
DO - 10.1016/j.antiviral.2020.104774
M3 - Article
C2 - 32197980
AN - SCOPUS:85082126932
VL - 177
JO - Antiviral Research
JF - Antiviral Research
SN - 0166-3542
M1 - 104774
ER -