title: Novel Arenavirus Entry Inhibitors Discovered by Using a Minigenome Rescue System for High-Throughput Drug Screening.
abstract: Certain members of the Arenaviridae family are category A agents capable of causing severe hemorrhagic fevers in humans. Specific antiviral treatments do not exist, and the only commonly used drug, ribavirin, has limited efficacy and can cause severe side effects. The discovery and development of new antivirals are inhibited by the biohazardous nature of the viruses, making them a relatively poorly understood group of human pathogens. We therefore adapted a reverse-genetics minigenome (MG) rescue system based on Junin virus, the causative agent of Argentine hemorrhagic fever, for high-throughput screening (HTS). The MG rescue system recapitulates all stages of the virus life cycle and enables screening of small-molecule libraries under biosafety containment level 2 (BSL2) conditions. The HTS resulted in the identification of four candidate compounds with potent activity against a broad panel of arenaviruses, three of which were completely novel. The target for all 4 compounds was the stage of viral entry, which positions the compounds as potentially important leads for future development.
  
  
  OBJECTIVE
  The arenavirus family includes several members that are highly pathogenic, causing acute viral hemorrhagic fevers with high mortality rates. No specific effective treatments exist, and although a vaccine is available for Junin virus, the causative agent of Argentine hemorrhagic fever, it is licensed for use only in areas where Argentine hemorrhagic fever is endemic. For these reasons, it is important to identify specific compounds that could be developed as antivirals against these deadly viruses.
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Jessica Y
authors.initials: JY
authors.lastname: Rathbun
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Magali E
authors.initials: ME
authors.lastname: Droniou
authors.affiliation: California NanoSystems Institute, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Damoiseaux
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Haworth
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Jill E
authors.initials: JE
authors.lastname: Henley
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Colin M
authors.initials: CM
authors.lastname: Exline
authors.affiliation: Department of Infectious Diseases, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Hyeryun
authors.initials: H
authors.lastname: Choe
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA pcannon@usc.edu.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Cannon
mesh_terms: D000998:Antiviral Agents / Q000302:isolation & purification / Q000494:pharmacology*; D001117:Arenaviridae Infections / Q000517:prevention & control*; D018050:Arenavirus / Q000502:physiology*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D018051:Junin virus / Q000235:genetics; D059386:Reverse Genetics / Q000379:methods; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents