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An In vitro Model to Study Immune Responses of Human Peripheral Blood Mononuclear Cells to Human Respiratory Syncytial Virus Infection
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Labyrinthopeptins as virolytic inhibitors of respiratory syncytial virus cell entry

Sebastian Blockus1, Svenja M Sake1, Martin Wetzke2

  • 1Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany.

Antiviral Research
|March 22, 2020
PubMed

Insights

New lantibiotics, labyrinthopeptin A1 and A2, show promise as respiratory syncytial virus (RSV) inhibitors. These compounds effectively block RSV entry and demonstrate low resistance, offering a potential new treatment for severe infant and elderly infections.

Area of Science:

  • Virology
  • Microbiology
  • Drug Discovery

Background:

  • Acute lower respiratory tract infections (ALRI) caused by respiratory syncytial virus (RSV) pose a significant health burden, particularly for infants and the elderly.
  • Current treatment options for RSV infections are limited, and existing antiviral drug candidates face challenges like low resistance barriers.

Purpose of the Study:

  • To identify novel compounds that inhibit respiratory syncytial virus (RSV) cell entry.
  • To evaluate the efficacy and mechanism of action of lantibiotics labyrinthopeptin A1 and A2 (Laby A1/A2) as potential RSV inhibitors.

Main Methods:

  • Development of a cell-based screening assay to discover compounds inhibiting infection with primary RSV isolates.
  • In vitro testing of Laby A1/A2 for antiviral activity, including IC50 determination and assessment of therapeutic index.
  • Ex vivo and in vivo validation of Laby A1/A2 efficacy in human airway cells and a murine model, respectively.
  • Mechanistic studies to elucidate the mode of action of Laby A1/A2.

Main Results:

  • Labyrinthopeptin A1 and A2 (Laby A1/A2) were identified as potent RSV cell entry inhibitors with favorable therapeutic indices.
  • Laby A1/A2 demonstrated activity against multiple RSV strains, including primary isolates, and were effective in prophylactic and therapeutic settings.
  • The compounds exhibited synergistic activity when used in combination and their antiviral activity was not impacted by common resistance mutations.
  • Mechanistic studies suggest Laby A1/A2 disrupt viral membrane integrity by binding to phosphatidylethanolamine.

Conclusions:

  • Laby A1/A2 represent promising candidates for the development of novel respiratory syncytial virus (RSV) inhibitors due to their unique mechanism of action and low resistance potential.
  • The developed cell-based screening system is valuable for identifying new antiviral agents against RSV using primary isolates.
Keywords:
Antiviral activityHuman respiratory syncytial virus (hRSV)LabyrinthopeptinLanthipeptideVirolyticVirus entry

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