title: Antiviral and lung protective activity of a novel respiratory syncytial virus fusion inhibitor in a mouse model.
abstract: Respiratory syncytial virus (RSV) causes bronchiolitis in young children and common colds in adults. There is no licensed vaccine, and prophylactic treatment with palivizumab is very expensive and limited to high-risk infants. Ribavirin is used as an antiviral treatment in infants and immunosuppressed patients, and its use is limited due to side-effects, toxicity to the recipient and staff, and evidence of marginal clinical efficacy. Therefore, we studied the in vivo kinetics, and the antiviral and protective properties of a novel candidate for RSV disease treatment. The drug is a small molecule (TMC353121) discovered by screening for fusion inhibitory properties against RSV in a cellular infection model. The pharmacokinetics of TMC353121 was studied in BALB/c mice and antiviral effects determined by testing viral loads in lung tissue by quantitative RT-PCR and plaque assay after intranasal RSV infection. At doses of 0.25-10 mg · kg(-1), TMC353121 significantly reduced viral load, bronchoalveolar lavage cell accumulation and the severity of lung histopathological change after infection. Treatment remained effective if started within 48 h of infection, but was ineffective thereafter. Therefore, TMC353121 is a novel potent antiviral drug, in vivo reducing RSV replication and inhibiting consequential lung inflammation, with a great potential for further clinical development.
authors.affiliation: Centre for Respiratory Infection Imperial College London, St Mary's Campus, Norfolk Place, Paddington, W2 1PG, London, UK. w.olszewska@medrescom.co.uk
authors.forename: W
authors.initials: W
authors.lastname: Olszewska
authors.forename: G
authors.initials: G
authors.lastname: Ispas
authors.forename: C
authors.initials: C
authors.lastname: Schnoeller
authors.forename: D
authors.initials: D
authors.lastname: Sawant
authors.forename: T
authors.initials: T
authors.lastname: Van de Casteele
authors.forename: D
authors.initials: D
authors.lastname: Nauwelaers
authors.forename: B
authors.initials: B
authors.lastname: Van Kerckhove
authors.forename: D
authors.initials: D
authors.lastname: Roymans
authors.forename: M
authors.initials: M
authors.lastname: De Meulder
authors.forename: M C
authors.initials: MC
authors.lastname: Rouan
authors.forename: P
authors.initials: P
authors.lastname: Van Remoortere
authors.forename: J F
authors.initials: JF
authors.lastname: Bonfanti
authors.forename: F
authors.initials: F
authors.lastname: Van Velsen
authors.forename: A
authors.initials: A
authors.lastname: Koul
authors.forename: M
authors.initials: M
authors.lastname: Vanstockem
authors.forename: K
authors.initials: K
authors.lastname: Andries
authors.forename: P
authors.initials: P
authors.lastname: Sowinski
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.forename: P
authors.initials: P
authors.lastname: Openshaw
authors.forename: R
authors.initials: R
authors.lastname: Verloes
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use*; D001992:Bronchoalveolar Lavage Fluid / Q000821:virology; D005260:Female; D008168:Lung / Q000187:drug effects* / Q000821:virology; D008171:Lung Diseases / Q000188:drug therapy / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D011725:Pyridines / Q000627:therapeutic use*; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy; D012136:Respiratory Syncytial Viruses / Q000187:drug effects*; D016896:Treatment Outcome; D019562:Viral Load / Q000187:drug effects; D053586:Virus Internalization / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
chemical_list: C528854:2-(6-((2-(3-hydroxypropyl)-5-methylphenylamino)methyl)-2-(3-morpholin-4-ylpropylamino)benzoimidazol-1-ylmethyl)-6-methylpyridin-3-ol; D000998:Antiviral Agents; D001562:Benzimidazoles; D011725:Pyridines