title: Targeting human respiratory syncytial virus transcription anti-termination factor M2-1 to inhibit in vivo viral replication.
abstract: Human respiratory syncytial virus (hRSV) is a leading cause of acute lower respiratory tract infection in infants, elderly and immunocompromised individuals. To date, no specific antiviral drug is available to treat or prevent this disease. Here, we report that the Smoothened receptor (Smo) antagonist cyclopamine acts as a potent and selective inhibitor of in vitro and in vivo hRSV replication. Cyclopamine inhibits hRSV through a novel, Smo-independent mechanism. It specifically impairs the function of the hRSV RNA-dependent RNA polymerase complex notably by reducing expression levels of the viral anti-termination factor M2-1. The relevance of these findings is corroborated by the demonstration that a single R151K mutation in M2-1 is sufficient to confer virus resistance to cyclopamine in vitro and that cyclopamine is able to reduce virus titers in a mouse model of hRSV infection. The results of our study open a novel avenue for the development of future therapies against hRSV infection.
authors.affiliation: Institut Pasteur of Shanghai - Chinese Academy of Sciences, Unit of anti-infective research, Shanghai, 200031, P.R. China.|Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD 4222, Australia.|Shandong University-Helmholtz Institute of Biotechnology, Qingdao, 266101, P.R. China.
authors.forename: B
authors.initials: B
authors.lastname: Bailly
authors.affiliation: INRA, Unité de Virologie et Immunologie Moléculaires (UR892), Jouy-en-Josas, 78352, France.
authors.forename: C-A
authors.initials: CA
authors.lastname: Richard
authors.affiliation: CombinatoRx-Singapore, 138667, Singapore.
authors.forename: G
authors.initials: G
authors.lastname: Sharma
authors.affiliation: Institut Pasteur of Shanghai - Chinese Academy of Sciences, Unit of anti-infective research, Shanghai, 200031, P.R. China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: CombinatoRx, Cambridge, MA 02142, USA.
authors.forename: L
authors.initials: L
authors.lastname: Johansen
authors.affiliation: Shandong University-Helmholtz Institute of Biotechnology, Qingdao, 266101, P.R. China.|Qingdao Municipal Center for Disease Control &Prevention, Qingdao, 266033, P.R. China.
authors.forename: J
authors.initials: J
authors.lastname: Cao
authors.affiliation: CombinatoRx-Singapore, 138667, Singapore.
authors.forename: V
authors.initials: V
authors.lastname: Pendharkar
authors.affiliation: CombinatoRx-Singapore, 138667, Singapore.
authors.forename: D-C
authors.initials: DC
authors.lastname: Sharma
authors.affiliation: INRA, Unité de Virologie et Immunologie Moléculaires (UR892), Jouy-en-Josas, 78352, France.
authors.forename: M
authors.initials: M
authors.lastname: Galloux
authors.affiliation: Institut Pasteur of Shanghai - Chinese Academy of Sciences, Unit of anti-infective research, Shanghai, 200031, P.R. China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institut Pasteur of Shanghai - Chinese Academy of Sciences, Unit of anti-infective research, Shanghai, 200031, P.R. China.
authors.forename: R
authors.initials: R
authors.lastname: Cui
authors.affiliation: Institut Pasteur of Shanghai - Chinese Academy of Sciences, Unit of anti-infective research, Shanghai, 200031, P.R. China.
authors.forename: G
authors.initials: G
authors.lastname: Zou
authors.affiliation: Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD 4222, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Guillon
authors.affiliation: Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD 4222, Australia.
authors.forename: M
authors.initials: M
authors.lastname: von Itzstein
authors.affiliation: INRA, Unité de Virologie et Immunologie Moléculaires (UR892), Jouy-en-Josas, 78352, France.
authors.forename: J-F
authors.initials: JF
authors.lastname: Eléouët
authors.affiliation: Institut Pasteur of Shanghai - Chinese Academy of Sciences, Unit of anti-infective research, Shanghai, 200031, P.R. China.|Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD 4222, Australia.|Shandong University-Helmholtz Institute of Biotechnology, Qingdao, 266101, P.R. China.|CombinatoRx-Singapore, 138667, Singapore.|CombinatoRx, Cambridge, MA 02142, USA.|Qingdao Municipal Center for Disease Control &Prevention, Qingdao, 266033, P.R. China.
authors.forename: R
authors.initials: R
authors.lastname: Altmeyer
mesh_terms: D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism; D004195:Disease Models, Animal; D024882:Drug Resistance, Viral / Q000187:drug effects; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D006801:Humans; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy / Q000821:virology; D018113:Respiratory Syncytial Virus, Human / Q000187:drug effects / Q000502:physiology*; D000072086:Smoothened Receptor / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014703:Veratrum / Q000737:chemistry; D014704:Veratrum Alkaloids / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014764:Viral Proteins / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
chemical_list: D000470:Alkaloids; D000072086:Smoothened Receptor; D014704:Veratrum Alkaloids; D014764:Viral Proteins; C010206:jervine; D012321:DNA-Directed RNA Polymerases; C000541:cyclopamine