title: Inhibition of Polyamine Biosynthesis Is a Broad-Spectrum Strategy against RNA Viruses.
abstract: RNA viruses present an extraordinary threat to human health, given their sudden and unpredictable appearance, the potential for rapid spread among the human population, and their ability to evolve resistance to antiviral therapies. The recent emergence of chikungunya virus, Zika virus, and Ebola virus highlights the struggles to contain outbreaks. A significant hurdle is the availability of antivirals to treat the infected or protect at-risk populations. While several compounds show promise in vitro and in vivo, these outbreaks underscore the need to accelerate drug discovery. The replication of several viruses has been described to rely on host polyamines, small and abundant positively charged molecules found in the cell. Here, we describe the antiviral effects of two molecules that alter polyamine levels: difluoromethylornithine (DFMO; also called eflornithine), which is a suicide inhibitor of ornithine decarboxylase 1 (ODC1), and diethylnorspermine (DENSpm), an activator of spermidine/spermine N1-acetyltransferase (SAT1). We show that reducing polyamine levels has a negative effect on diverse RNA viruses, including several viruses involved in recent outbreaks, in vitro and in vivo These findings highlight the importance of the polyamine biosynthetic pathway to viral replication, as well as its potential as a target in the development of further antivirals or currently available molecules, such as DFMO.
  
  
  OBJECTIVE
  RNA viruses present a significant hazard to human health, and combatting these viruses requires the exploration of new avenues for targeting viral replication. Polyamines, small positively charged molecules within the cell, have been demonstrated to facilitate infection for a few different viruses. Our study demonstrates that diverse RNA viruses rely on the polyamine pathway for replication and highlights polyamine biosynthesis as a promising drug target.
authors.affiliation: Viral Populations and Pathogenesis Unit, Institut Pasteur, Paris, France.
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Mounce
authors.affiliation: Viral Populations and Pathogenesis Unit, Institut Pasteur, Paris, France.
authors.forename: Teresa
authors.initials: T
authors.lastname: Cesaro
authors.affiliation: Viral Populations and Pathogenesis Unit, Institut Pasteur, Paris, France.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Moratorio
authors.affiliation: Viral Populations and Pathogenesis Unit, Institut Pasteur, Paris, France.
authors.forename: Peter Jan
authors.initials: PJ
authors.lastname: Hooikaas
authors.affiliation: Viral Populations and Pathogenesis Unit, Institut Pasteur, Paris, France.
authors.forename: Anna
authors.initials: A
authors.lastname: Yakovleva
authors.affiliation: Laboratory of Dendritic Cell Biology, Institut Pasteur, Paris, France Institut National de la Santé et de la Recherche Médicale, U818, Paris, France.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Werneke
authors.affiliation: Department of Pediatrics, the Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Everett Clinton
authors.initials: EC
authors.lastname: Smith
authors.affiliation: Viral Populations and Pathogenesis Unit, Institut Pasteur, Paris, France University Paris Diderot, Sorbonne Paris Cite, Cellule Pasteur, Paris, France.
authors.forename: Enzo Z
authors.initials: EZ
authors.lastname: Poirier
authors.affiliation: Unité de Génétique Fonctionnelle des Maladies Infectieuses, Institut Pasteur, Paris, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Simon-Loriere
authors.affiliation: Unité de Génétique Fonctionnelle des Maladies Infectieuses, Institut Pasteur, Paris, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Prot
authors.affiliation: Unité de Virologie Structurale, Institut Pasteur, Paris, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Tamietti
authors.affiliation: Unité de NeuroImmunologie Virale, Institut Pasteur, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Vitry
authors.affiliation: Unité de Biologie des Virus Entériques, Institut Pasteur, Paris, France INSERM, Unité 994, Paris, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Volle
authors.affiliation: Unité de Recherche et d'Expertise Environnement et Risques Infectieux, Institut Pasteur, Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Khou
authors.affiliation: Unité de Recherche et d'Expertise Environnement et Risques Infectieux, Institut Pasteur, Paris, France.
authors.forename: Marie-Pascale
authors.initials: MP
authors.lastname: Frenkiel
authors.affiliation: Unité de Génétique Fonctionnelle des Maladies Infectieuses, Institut Pasteur, Paris, France.
authors.forename: Anavaj
authors.initials: A
authors.lastname: Sakuntabhai
authors.affiliation: Unité de Biologie des Virus Entériques, Institut Pasteur, Paris, France INSERM, Unité 994, Paris, France.
authors.forename: Francis
authors.initials: F
authors.lastname: Delpeyroux
authors.affiliation: Unité de Recherche et d'Expertise Environnement et Risques Infectieux, Institut Pasteur, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pardigon
authors.affiliation: Unité de Virologie Structurale, Institut Pasteur, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Flamand
authors.affiliation: Unité de Virologie Structurale, Institut Pasteur, Paris, France.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Barba-Spaeth
authors.affiliation: Unité de NeuroImmunologie Virale, Institut Pasteur, Paris, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Lafon
authors.affiliation: Department of Pediatrics, the Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, Tennessee, USA Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Denison
authors.affiliation: Laboratory of Dendritic Cell Biology, Institut Pasteur, Paris, France Institut National de la Santé et de la Recherche Médicale, U818, Paris, France.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Albert
authors.affiliation: Viral Populations and Pathogenesis Unit, Institut Pasteur, Paris, France marco.vignuzzi@pasteur.fr.
authors.forename: Marco
authors.identifier: http://orcid.org/0000-0002-4400-771X
authors.initials: M
authors.lastname: Vignuzzi
mesh_terms: D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D065632:Chikungunya Fever / Q000188:drug therapy / Q000821:virology; D002646:Chikungunya virus / Q000187:drug effects / Q000378:metabolism; D004196:Disease Outbreaks; D029043:Ebolavirus / Q000187:drug effects / Q000378:metabolism; D000518:Eflornithine / Q000494:pharmacology; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy / Q000821:virology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011073:Polyamines / Q000378:metabolism*; D012328:RNA Viruses / Q000187:drug effects*; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects; D000071244:Zika Virus / Q000187:drug effects; D000071243:Zika Virus Infection / Q000188:drug therapy / Q000821:virology; D000099228:Diamine N-Acetyltransferase
chemical_list: D000123:Acetyltransferases; D000998:Antiviral Agents; D000518:Eflornithine; D011073:Polyamines; D013096:Spermine; D000099228:Diamine N-Acetyltransferase; C059685:N(1),N(11)-diethylnorspermine