title: Premature activation of the paramyxovirus fusion protein before target cell attachment with corruption of the viral fusion machinery.
abstract: Paramyxoviruses, including the childhood pathogen human parainfluenza virus type 3, enter host cells by fusion of the viral and target cell membranes. This fusion results from the concerted action of its two envelope glycoproteins, the hemagglutinin-neuraminidase (HN) and the fusion protein (F). The receptor-bound HN triggers F to undergo conformational changes that render it competent to mediate fusion of the viral and cellular membranes. We proposed that, if the fusion process could be activated prematurely before the virion reaches the target host cell, infection could be prevented. We identified a small molecule that inhibits paramyxovirus entry into target cells and prevents infection. We show here that this compound works by an interaction with HN that results in F-activation prior to receptor binding. The fusion process is thereby prematurely activated, preventing fusion of the viral membrane with target cells and precluding viral entry. This first evidence that activation of a paramyxovirus F can be specifically induced before the virus contacts its target cell suggests a new strategy with broad implications for the design of antiviral agents.
authors.affiliation: Departments of Pediatrics and of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021.
authors.forename: Shohreh F
authors.initials: SF
authors.lastname: Farzan
authors.affiliation: Departments of Pediatrics and of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Palermo
authors.affiliation: Departments of Pediatrics and of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021.
authors.forename: Christine C
authors.initials: CC
authors.lastname: Yokoyama
authors.affiliation: Departments of Pediatrics and of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021.
authors.forename: Gianmarco
authors.initials: G
authors.lastname: Orefice
authors.affiliation: Department of Medicinal Chemistry and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia, 23298-0540.
authors.forename: Micaela
authors.initials: M
authors.lastname: Fornabaio
authors.affiliation: Department of Medicinal Chemistry and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia, 23298-0540.
authors.forename: Aurijit
authors.initials: A
authors.lastname: Sarkar
authors.affiliation: Department of Medicinal Chemistry and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia, 23298-0540.
authors.forename: Glen E
authors.initials: GE
authors.lastname: Kellogg
authors.affiliation: Departments of Pediatrics and of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021; Department of Pediatrics, Mount Sinai School of Medicine, New York, New York 10029.
authors.forename: Olga
authors.initials: O
authors.lastname: Greengard
authors.affiliation: Departments of Pediatrics and of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021.
authors.forename: Matteo
authors.initials: M
authors.lastname: Porotto
authors.affiliation: Departments of Pediatrics and of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021. Electronic address: anm2047@med.cornell.edu.
authors.forename: Anne
authors.initials: A
authors.lastname: Moscona
mesh_terms: D000327:Adsorption; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology; D015707:HN Protein / Q000737:chemistry*; D006801:Humans; D008561:Membrane Fusion; D008956:Models, Chemical; D009439:Neuraminidase / Q000378:metabolism; D011487:Protein Conformation; D014760:Viral Fusion Proteins / Q000737:chemistry* / Q000378:metabolism*; D014764:Viral Proteins / Q000737:chemistry
chemical_list: D000998:Antiviral Agents; D015707:HN Protein; D014760:Viral Fusion Proteins; D014764:Viral Proteins; D009439:Neuraminidase