title: In Vivo Efficacy of Measles Virus Fusion Protein-Derived Peptides Is Modulated by the Properties of Self-Assembly and Membrane Residence.
abstract: Measles virus (MV) infection is undergoing resurgence and remains one of the leading causes of death among young children worldwide despite the availability of an effective measles vaccine. MV infects its target cells by coordinated action of the MV hemagglutinin (H) and fusion (F) envelope glycoproteins; upon receptor engagement by H, the prefusion F undergoes a structural transition, extending and inserting into the target cell membrane and then refolding into a postfusion structure that fuses the viral and cell membranes. By interfering with this structural transition of F, peptides derived from the heptad repeat (HR) regions of F can inhibit MV infection at the entry stage. In previous work, we have generated potent MV fusion inhibitors by dimerizing the F-derived peptides and conjugating them to cholesterol. We have shown that prophylactic intranasal administration of our lead fusion inhibitor efficiently protects from MV infection in vivo We show here that peptides tagged with lipophilic moieties self-assemble into nanoparticles until they reach the target cells, where they are integrated into cell membranes. The self-assembly feature enhances biodistribution and the half-life of the peptides, while integration into the target cell membrane increases fusion inhibitor potency. These factors together modulate in vivo efficacy. The results suggest a new framework for developing effective fusion inhibitory peptides.
  
  
  OBJECTIVE
  Measles virus (MV) infection causes an acute illness that may be associated with infection of the central nervous system (CNS) and severe neurological disease. No specific treatment is available. We have shown that fusion-inhibitory peptides delivered intranasally provide effective prophylaxis against MV infection. We show here that specific biophysical properties regulate the in vivo efficacy of MV F-derived peptides.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: T N
authors.initials: TN
authors.lastname: Figueira
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Palermo
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: A S
authors.initials: AS
authors.lastname: Veiga
authors.affiliation: Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA.
authors.forename: D
authors.initials: D
authors.lastname: Huey
authors.affiliation: Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Alabi
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: N C
authors.initials: NC
authors.lastname: Santos
authors.affiliation: CIRI, International Center for Infectiology Research, Immunobiology of Viral Infections Team, INSERM U1111, University Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Lyon, France.
authors.forename: J C
authors.initials: JC
authors.lastname: Welsch
authors.affiliation: CIRI, International Center for Infectiology Research, Immunobiology of Viral Infections Team, INSERM U1111, University Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Lyon, France.
authors.forename: C
authors.initials: C
authors.lastname: Mathieu
authors.affiliation: CIRI, International Center for Infectiology Research, Immunobiology of Viral Infections Team, INSERM U1111, University Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Lyon, France.
authors.forename: B
authors.identifier: http://orcid.org/0000-0003-0578-7765
authors.initials: B
authors.lastname: Horvat
authors.affiliation: Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA.
authors.forename: S
authors.initials: S
authors.lastname: Niewiesk
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.|Departments of Pediatrics, Microbiology and Immunology, and Physiology and Cellular Biophysics, Columbia University Medical Center, New York, New York, USA.
authors.forename: A
authors.initials: A
authors.lastname: Moscona
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal macastanho@medicina.ulisboa.pt mp3509@columbia.edu.
authors.forename: M A R B
authors.initials: MARB
authors.lastname: Castanho
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, New York, USA macastanho@medicina.ulisboa.pt mp3509@columbia.edu.
authors.forename: M
authors.initials: M
authors.lastname: Porotto
mesh_terms: D000281:Administration, Intranasal; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000276:immunology; D002784:Cholesterol / Q000737:chemistry; D005260:Female; D006207:Half-Life; D006389:Hemagglutinins, Viral / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000276:immunology; D008297:Male; D008457:Measles / Q000276:immunology / Q000401:mortality / Q000517:prevention & control* / Q000821:virology; D008458:Measles Vaccine / Q000008:administration & dosage* / Q000138:chemical synthesis; D008459:Measles virus / Q000737:chemistry / Q000187:drug effects* / Q000276:immunology; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010455:Peptides / Q000138:chemical synthesis / Q000276:immunology*; D016205:Sigmodontinae; D016019:Survival Analysis; D014760:Viral Fusion Proteins / Q000737:chemistry / Q000276:immunology*; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D006389:Hemagglutinins, Viral; D008458:Measles Vaccine; D010455:Peptides; D014760:Viral Fusion Proteins; C032397:hemagglutinin protein G, measles virus; D002784:Cholesterol
keywords: Viral fusion inhibitor; lipid tagging; membrane insertion; self-assembling nanoparticles