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 WetzkeGesine 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, Thomas Pietschmann

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.

Original languageEnglish
Article number1173
JournalNature Communications
Volume15
Issue number1
Pages (from-to)1173
Number of pages1
ISSN1751-8628
DOIs
Publication statusPublished - 08.02.2024

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)

DFG Research Classification Scheme

  • 204-04 Virology
  • 201-01 Biochemistry
  • 205-31 Clinical Infectiology and Tropical Medicine

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