Drug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor
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 Universität des Saarlandes [Saarbrücken] = Saarland University [Saarbrücken]
13 MHH - Medizinische Hochschule Hannover = Hannover Medical School
14 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
15 German Center for Lung Research
16 2I - Infection et inflammation
17 DZIF - German Centre for Infection Research
18 Advanced Light and Fluorescence Microscopy Facility - Centre for Structural Systems Biology hamburg
19 DZIF - German Center for Infection Research - Partner Site Bonn-Cologne
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Résumé
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
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