8PHI

Crystal structure of prefusion-stabilized RSV F Variant DS-Cav1 in complex with Lonafarnib

Summary for 8PHI

• Entry DOI: 10.2210/pdb8phi/pdb
• Descriptor: Fusion glycoprotein F0, 4-{2-[4-(3,10-DIBROMO-8-CHLORO-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-B]PYRIDIN-11-YL)PIPERIDIN-1-YL]-2-OXOETHYL}PIPERIDINE-1-CARBOXAMIDE, SULFATE ION, ... (6 entities in total)
• Functional Keywords: rsv f glycoprotein, inhibitor, viral protein
• Biological source: Human respiratory syncytial virus A2
• Total number of polymer chains: 1
• Total formula weight: 62596.40

Authors

Rajak, M.,Krey, T. (deposition date: 2023-06-19, release date: 2024-02-21, Last modification date: 2024-11-20)

Primary citation

Sake, S.M.,Zhang, X.,Rajak, M.K.,Urbanek-Quaing, M.,Carpentier, A.,Gunesch, A.P.,Grethe, C.,Matthaei, A.,Ruckert, J.,Galloux, M.,Larcher, T.,Le Goffic, R.,Hontonnou, F.,Chatterjee, A.K.,Johnson, K.,Morwood, K.,Rox, K.,Elgaher, W.A.M.,Huang, J.,Wetzke, M.,Hansen, G.,Fischer, N.,Eleouet, J.F.,Rameix-Welti, M.A.,Hirsch, A.K.H.,Herold, E.,Empting, M.,Lauber, C.,Schulz, T.F.,Krey, T.,Haid, S.,Pietschmann, T.
Drug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor.
Nat Commun, 15:1173-1173, 2024

PubMed 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: 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.

PubMed: 38332002
DOI: 10.1038/s41467-024-45241-y

Experimental method

X-RAY DIFFRACTION (2.289 Å)