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

Autor: Sake SM; Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany., Zhang X; Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany., Rajak MK; Institute of Virology, Hannover Medical School, Hannover, Germany.; Center of Structural and Cell Biology in Medicine, Institute of Biochemistry, University of Luebeck, Luebeck, Germany., Urbanek-Quaing M; Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany., Carpentier A; Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany., Gunesch AP; Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany., Grethe C; Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany., Matthaei A; Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany., Rückert J; Institute of Virology, Hannover Medical School, Hannover, Germany., Galloux M; Université Paris-Saclay, INRAE, UVSQ, VIM, Jouy-en-Josas, France., Larcher T; INRAE Oniris, PAnTher, APEX, Oniris, Nantes, France., Le Goffic R; Université Paris-Saclay, INRAE, UVSQ, VIM, Jouy-en-Josas, France., Hontonnou F; Université Paris-Saclay, INRAE, UVSQ, VIM, Jouy-en-Josas, France., Chatterjee AK; Calibr, Scripps Research, La Jolla, CA, USA., Johnson K; Calibr, Scripps Research, La Jolla, CA, USA., Morwood K; Calibr, Scripps Research, La Jolla, CA, USA., Rox K; Department of Chemical Biology, Helmholtz Center of Infection Research, Braunschweig, Germany.; German Centre for Infection Research, Partner site Braunschweig-Hannover, Braunschweig, Germany., Elgaher WAM; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)-HZI, Saarbrücken, Germany.; Department of Pharmacy, Saarland University, Saarbrücken, Germany.; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany., Huang J; Insitute for Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Wetzke M; Department for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.; German Center for Lung Research, Partner Site Hannover, BREATH, Hannover, Germany., Hansen G; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.; Department for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.; German Center for Lung Research, Partner Site Hannover, BREATH, Hannover, Germany., Fischer N; Insitute for Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Eléouët JF; Université Paris-Saclay, INRAE, UVSQ, VIM, Jouy-en-Josas, France., Rameix-Welti MA; Université Paris-Saclay, Université de Versailles St. Quentin; UMR 1173 (2I), INSERM; Assistance Publique des Hôpitaux de Paris, Hôpital Ambroise Paré, Laboratoire de Microbiologie, DMU15, Versailles, France., Hirsch AKH; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)-HZI, Saarbrücken, Germany.; Department of Pharmacy, Saarland University, Saarbrücken, Germany.; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.; Helmholtz International Lab for Anti-infectives, HZI, Braunschweig, Germany., Herold E; Center of Structural and Cell Biology in Medicine, Institute of Biochemistry, University of Luebeck, Luebeck, Germany., Empting M; German Centre for Infection Research, Partner site Braunschweig-Hannover, Braunschweig, Germany.; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)-HZI, Saarbrücken, Germany.; Department of Pharmacy, Saarland University, Saarbrücken, Germany.; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany., Lauber C; Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany.; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany., Schulz TF; Institute of Virology, Hannover Medical School, Hannover, Germany.; German Centre for Infection Research, Partner site Braunschweig-Hannover, Braunschweig, Germany.; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany., Krey T; Institute of Virology, Hannover Medical School, Hannover, Germany.; Center of Structural and Cell Biology in Medicine, Institute of Biochemistry, University of Luebeck, Luebeck, Germany.; Centre for Structural Systems Biology (CSSB), Hamburg, Germany.; German Center for Infection Research, Partner Site Hamburg-Luebeck-Borstel-Riems, Luebeck, Germany., Haid S; Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany. sibylle.haid@twincore.de., Pietschmann T; Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany. thomas.pietschmann@twincore.de.; German Centre for Infection Research, Partner site Braunschweig-Hannover, Braunschweig, Germany. thomas.pietschmann@twincore.de.; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany. thomas.pietschmann@twincore.de.; Helmholtz International Lab for Anti-infectives, HZI, Braunschweig, Germany. thomas.pietschmann@twincore.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Feb 08; Vol. 15 (1), pp. 1173. Date of Electronic Publication: 2024 Feb 08.
DOI: 10.1038/s41467-024-45241-y
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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