Broad spectrum antiviral activity for paramyxoviruses is modulated by biophysical properties of fusion inhibitory peptides.
Human paramyxoviruses include global causes of lower respiratory disease like the parainfluenza viruses, as well as agents of lethal encephalitis like Nipah virus. Infection is initiated by viral glycoprotein-mediated fusion between viral and host cell membranes. Paramyxovirus viral fusion proteins (F) insert into the target cell membrane, and form a transient intermediate that pulls the viral and cell membranes together as two heptad-repeat regions refold to form a six-helix bundle structure that can be specifically targeted by fusion-inhibitory peptides. Antiviral potency can be improved by sequence modification and lipid conjugation, and by adding linkers between the protein and lipid components. We exploit the uniquely broad spectrum antiviral activity of a parainfluenza F-derived peptide sequence that inhibits both parainfluenza and Nipah viruses, to investigate the influence of peptide orientation and intervening linker length on the peptides' interaction with transitional states of F, solubility, membrane insertion kinetics, and protease sensitivity. We assessed the impact of these features on biodistribution and antiviral efficacy in vitro and in vivo. The engineering approach based on biophysical parameters resulted in a peptide that is a highly effective inhibitor of both paramyxoviruses and a set of criteria to be used for engineering broad spectrum antivirals for emerging paramyxoviruses.
CIRI, International Center for Infectiology Research, 21 Avenue Tony Garnier, 69365 Lyon Cedex 07, France.|INSERM U1111, Lyon, France.|CNRS, UMR5308, Lyon, France.|Université Lyon 1, Lyon, France.|Ecole Normale Supérieure de Lyon, Lyon, France.
Cyrille
C
Mathieu
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisbon, Portugal.
Marcelo T
MT
Augusto
Department of Veterinary Biosciences, College of Veterinary Medicine, Ohio State University, Columbus, USA.
Stefan
S
Niewiesk
CIRI, International Center for Infectiology Research, 21 Avenue Tony Garnier, 69365 Lyon Cedex 07, France.|INSERM U1111, Lyon, France.|CNRS, UMR5308, Lyon, France.|Université Lyon 1, Lyon, France.|Ecole Normale Supérieure de Lyon, Lyon, France.
Branka
B
Horvat
Department of Pediatrics, Columbia University Medical Center, 701 W. 168th St., New York, NY, USA.|Center for Host-Pathogen Interaction, Columbia University Medical Center, 701 W. 168th St., New York, NY, USA.
Laura M
LM
Palermo
Department of Pediatrics, Columbia University Medical Center, 701 W. 168th St., New York, NY, USA.|Center for Host-Pathogen Interaction, Columbia University Medical Center, 701 W. 168th St., New York, NY, USA.|Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, Monserrato, Cagliari, Italy.
Giuseppina
G
Sanna
Department of Pediatrics, Columbia University Medical Center, 701 W. 168th St., New York, NY, USA.|Center for Host-Pathogen Interaction, Columbia University Medical Center, 701 W. 168th St., New York, NY, USA.|Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, Monserrato, Cagliari, Italy.
Silvia
S
Madeddu
Department of Veterinary Biosciences, College of Veterinary Medicine, Ohio State University, Columbus, USA.
Devra
D
Huey
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisbon, Portugal.
Miguel A R B
MA
Castanho
Department of Pediatrics, Columbia University Medical Center, 701 W. 168th St., New York, NY, USA.|Center for Host-Pathogen Interaction, Columbia University Medical Center, 701 W. 168th St., New York, NY, USA.
Matteo
M
Porotto
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisbon, Portugal.
Nuno C
NC
Santos
Department of Pediatrics, Columbia University Medical Center, 701 W. 168th St., New York, NY, USA.|Center for Host-Pathogen Interaction, Columbia University Medical Center, 701 W. 168th St., New York, NY, USA.|Department of Microbiology &Immunology, Columbia University Medical Center, 701 W. 168th St., New York, NY, USA.|Department of Physiology &Biophysics, Columbia University Medical Center, 701 W. 168th St., New York, NY, USA.
Anne
A
Moscona
D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D015394:Molecular Structure; D010252:Paramyxoviridae / Q000187:drug effects*; D010455:Peptides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D012995:Solubility; D014760:Viral Fusion Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D010948:Viral Plaque Assay
D000998:Antiviral Agents; D010455:Peptides; D014760:Viral Fusion Proteins