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Drug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor

Author

Listed:
  • Svenja M. Sake

    (Centre for Experimental and Clinical Infection Research)

  • Xiaoyu Zhang

    (Centre for Experimental and Clinical Infection Research)

  • Manoj Kumar Rajak

    (Hannover Medical School
    University of Luebeck)

  • Melanie Urbanek-Quaing

    (Centre for Experimental and Clinical Infection Research)

  • Arnaud Carpentier

    (Centre for Experimental and Clinical Infection Research)

  • Antonia P. Gunesch

    (Centre for Experimental and Clinical Infection Research)

  • Christina Grethe

    (Centre for Experimental and Clinical Infection Research)

  • Alina Matthaei

    (Centre for Experimental and Clinical Infection Research)

  • Jessica Rückert

    (Hannover Medical School)

  • Marie Galloux

    (Université Paris-Saclay, INRAE, UVSQ, VIM)

  • Thibaut Larcher

    (INRAE Oniris, PAnTher, APEX, Oniris)

  • Ronan Le Goffic

    (Université Paris-Saclay, INRAE, UVSQ, VIM)

  • Fortune Hontonnou

    (Université Paris-Saclay, INRAE, UVSQ, VIM)

  • Arnab K. Chatterjee

    (Calibr, Scripps Research)

  • Kristen Johnson

    (Calibr, Scripps Research)

  • Kaycie Morwood

    (Calibr, Scripps Research)

  • Katharina Rox

    (Helmholtz Center of Infection Research
    Partner site Braunschweig-Hannover)

  • Walid A. M. Elgaher

    (Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)—HZI
    Saarland University
    Hannover Medical School)

  • Jiabin Huang

    (University Medical Center Hamburg-Eppendorf)

  • Martin Wetzke

    (Allergology and Neonatology, Hannover Medical School
    Partner Site Hannover, BREATH)

  • Gesine Hansen

    (Hannover Medical School
    Allergology and Neonatology, Hannover Medical School
    Partner Site Hannover, BREATH)

  • Nicole Fischer

    (University Medical Center Hamburg-Eppendorf)

  • Jean-Francois Eléouët

    (Université Paris-Saclay, INRAE, UVSQ, VIM)

  • Marie-Anne Rameix-Welti

    (Université Paris-Saclay, Université de Versailles St. Quentin; UMR 1173 (2I), INSERM; Assistance Publique des Hôpitaux de Paris, Hôpital Ambroise Paré, Laboratoire de Microbiologie, DMU15)

  • Anna K. H. Hirsch

    (Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)—HZI
    Saarland University
    Hannover Medical School
    Helmholtz International Lab for Anti-infectives, HZI)

  • Elisabeth Herold

    (University of Luebeck)

  • Martin Empting

    (Partner site Braunschweig-Hannover
    Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)—HZI
    Saarland University
    Hannover Medical School)

  • Chris Lauber

    (Centre for Experimental and Clinical Infection Research
    Hannover Medical School)

  • Thomas F. Schulz

    (Hannover Medical School
    Partner site Braunschweig-Hannover
    Hannover Medical School)

  • Thomas Krey

    (Hannover Medical School
    University of Luebeck
    Centre for Structural Systems Biology (CSSB)
    Partner Site Hamburg-Luebeck-Borstel-Riems)

  • Sibylle Haid

    (Centre for Experimental and Clinical Infection Research)

  • Thomas Pietschmann

    (Centre for Experimental and Clinical Infection Research
    Partner site Braunschweig-Hannover
    Hannover Medical School
    Helmholtz International Lab for Anti-infectives, HZI)

Abstract

Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infection in infants, older adults and the immunocompromised. Effective directly acting antivirals are not yet available for clinical use. To address this, we screen the ReFRAME drug-repurposing library consisting of 12,000 small molecules against RSV. We identify 21 primary candidates including RSV F and N protein inhibitors, five HSP90 and four IMPDH inhibitors. We select lonafarnib, a licensed farnesyltransferase inhibitor, and phase III candidate for hepatitis delta virus (HDV) therapy, for further follow-up. Dose-response analyses and plaque assays confirm the antiviral activity (IC50: 10-118 nM). Passaging of RSV with lonafarnib selects for phenotypic resistance and fixation of mutations in the RSV fusion protein (T335I and T400A). Lentiviral pseudotypes programmed with variant RSV fusion proteins confirm that lonafarnib inhibits RSV cell entry and that these mutations confer lonafarnib resistance. Surface plasmon resonance reveals RSV fusion protein binding of lonafarnib and co-crystallography identifies the lonafarnib binding site within RSV F. Oral administration of lonafarnib dose-dependently reduces RSV virus load in a murine infection model using female mice. Collectively, this work provides an overview of RSV drug repurposing candidates and establishes lonafarnib as a bona fide fusion protein inhibitor.

Suggested Citation

  • Svenja M. Sake & Xiaoyu Zhang & Manoj Kumar Rajak & Melanie Urbanek-Quaing & Arnaud Carpentier & Antonia P. Gunesch & Christina Grethe & Alina Matthaei & Jessica Rückert & Marie Galloux & Thibaut Larc, 2024. "Drug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45241-y
    DOI: 10.1038/s41467-024-45241-y
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    References listed on IDEAS

    as
    1. Laura Riva & Shuofeng Yuan & Xin Yin & Laura Martin-Sancho & Naoko Matsunaga & Lars Pache & Sebastian Burgstaller-Muehlbacher & Paul D. Jesus & Peter Teriete & Mitchell V. Hull & Max W. Chang & Jasper, 2020. "Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing," Nature, Nature, vol. 586(7827), pages 113-119, October.
    2. Jennifer Risso-Ballester & Marie Galloux & Jingjing Cao & Ronan Goffic & Fortune Hontonnou & Aude Jobart-Malfait & Aurore Desquesnes & Svenja M. Sake & Sibylle Haid & Miaomiao Du & Xiumei Zhang & Huan, 2021. "A condensate-hardening drug blocks RSV replication in vivo," Nature, Nature, vol. 595(7868), pages 596-599, July.
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