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

Svenja Sake (1) , Xiaoyu Zhang (1) , Manoj Kumar Rajak (2, 3) , Melanie Urbanek-Quaing (1) , Arnaud Carpentier (1) , Antonia Gunesch (1) , Christina Grethe (1) , Alina Matthaei (1) , Jessica Rückert (2) , Marie Galloux (4, 5) , Thibaut Larcher (6, 7) , Ronan Le Goffic (4, 5) , Fortune Hontonnou (4, 5) , Arnab Chatterjee (8) , Kristen Johnson (8) , Kaycie Morwood (8) , Katharina Rox (9, 10) , Walid Elgaher (11, 12, 13) , Jiabin Huang (14) , Martin Wetzke (13, 15, 16) , Gesine Hansen (13, 15, 16) , Nicole Fischer (14) , Jean-Francois Eléouët (4, 5) , Marie-Anne Rameix-Welti (4, 17) , Anna Hirsch (11, 12, 13, 9) , Elisabeth Herold (3) , Martin Empting (18, 11, 12, 13) , Chris Lauber (1, 13) , Thomas F. Schulz (2, 18, 13) , Thomas Krey (2, 3, 19, 20) , Sibylle Haid (1) , Thomas Pietschmann (1, 18, 13, 9)

1 TWINCORE - Centre for Experimental and Clinical Infection Research
2 Institute of Virology [Hannover]
3 Institute of Biochemistry, Center for Structural and Cell Biology in Medicine
4 Université Paris-Saclay
5 VIM (UR 0892) - Virologie et Immunologie Moléculaires
6 PAnTher - Physiopathologie Animale et bioThérapie du muscle et du système nerveux
7 APEX - Expertise en Anatomie Pathologique
8 California Institute for Biomedical Research - calibr
9 HZI - Helmholtz Centre for Infection Research
10 German Centre for Infection Research
11 HIPS - Helmholtz Institute for Pharmaceutical Research Saarland
12 Saarland University [Saarbrücken]
13 MHH - Medizinische Hochschule Hannover = Hannover Medical School
14 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
15 Department of Pediatric Pneumology, Allergy and Neonatology, Hannover Medical School, Hannover, Germany
16 German Center for Lung Research
17 2I - Infection et inflammation
18 DZIF - German Centre for Infection Research
19 Advanced Light and Fluorescence Microscopy Facility - Centre for Structural Systems Biology hamburg
20 DZIF - German Center for Infection Research - Partner Site Bonn-Cologne

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 (IC 50 : 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.

Domaines: Sciences du Vivant [q-bio]

Svenja Sake, Xiaoyu Zhang, Manoj Kumar Rajak, Melanie Urbanek-Quaing, Arnaud Carpentier, et al.. Drug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor. Nature Communications, 2024, 15 (1), pp.1173. ⟨10.1038/s41467-024-45241-y⟩. ⟨hal-04504093⟩