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

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 Larcher, Ronan Le Goffic, Fortune Hontonnou, Arnab K. Chatterjee, Kristen Johnson, Kaycie Morwood, Katharina Rox, Walid A. M. Elgaher, Jiabin Huang, Martin Wetzke, Gesine Hansen, Nicole Fischer, Jean-Francois Eléouët, Marie-Anne Rameix-Welti, Anna K. H. Hirsch, Elisabeth Herold, Martin Empting, Chris Lauber, Thomas F. Schulz, Thomas Krey, Sibylle Haid () and Thomas Pietschmann ()
Additional contact information
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
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
Walid A. M. Elgaher: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)—HZI
Jiabin Huang: University Medical Center Hamburg-Eppendorf
Martin Wetzke: Allergology and Neonatology, Hannover Medical School
Gesine Hansen: Hannover Medical School
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
Elisabeth Herold: University of Luebeck
Martin Empting: Partner site Braunschweig-Hannover
Chris Lauber: Centre for Experimental and Clinical Infection Research
Thomas F. Schulz: Hannover Medical School
Thomas Krey: Hannover Medical School
Sibylle Haid: Centre for Experimental and Clinical Infection Research
Thomas Pietschmann: Centre for Experimental and Clinical Infection Research

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45241-y

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