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

TY - JOUR

T1 - Drug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor

AU - Sake, Svenja M

AU - Zhang, Xiaoyu

AU - Rajak, Manoj Kumar

AU - Urbanek-Quaing, Melanie

AU - Carpentier, Arnaud

AU - Gunesch, Antonia P

AU - Grethe, Christina

AU - Matthaei, Alina

AU - Rückert, Jessica

AU - Galloux, Marie

AU - Larcher, Thibaut

AU - Le Goffic, Ronan

AU - Hontonnou, Fortune

AU - Chatterjee, Arnab K

AU - Johnson, Kristen

AU - Morwood, Kaycie

AU - Rox, Katharina

AU - Elgaher, Walid A M

AU - Huang, Jiabin

AU - Wetzke, Martin

AU - Hansen, Gesine

AU - Fischer, Nicole

AU - Eléouët, Jean-Francois

AU - Rameix-Welti, Marie-Anne

AU - Hirsch, Anna K H

AU - Herold, Elisabeth

AU - Empting, Martin

AU - Lauber, Chris

AU - Krey, Thomas

AU - Haid, Sibylle

AU - Pietschmann, Thomas

N1 - © 2024. The Author(s).

PY - 2024/2/8

Y1 - 2024/2/8

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-024-45241-y

DO - 10.1038/s41467-024-45241-y

M3 - SCORING: Journal article

C2 - 38332002

VL - 15

SP - 1173

JO - NAT COMMUN

JF - NAT COMMUN

SN - 2041-1723

IS - 1

ER -