title: Inhibition of Rift Valley fever virus replication and perturbation of nucleocapsid-RNA interactions by suramin.
abstract: Rift Valley fever virus (RVFV) is an emerging infectious pathogen that causes severe disease in humans and livestock and has the potential for global spread. There are currently no proven safe and effective treatment options for RVFV infection. Inhibition of RNA binding to RVFV nucleocapsid protein (N) represents an attractive antiviral therapeutic strategy because several essential steps in the RVFV replication cycle involve N binding to viral RNA. In this study, we demonstrate the therapeutic potential of the drug suramin by showing that it functions well as an inhibitor of RVFV replication at multiple stages in human cell culture. Suramin has been used previously to treat trypanosomiasis in Africa. We characterize the dynamic and cooperative nature of N-RNA binding interactions and the dissociation of high-molecular-mass ribonucleoprotein complexes using suramin, which we previously identified as an N-RNA binding inhibitor in a high-throughput screen. Finally, we elucidate the molecular mechanism used by suramin in vitro to disrupt both specific and nonspecific binding events important for ribonucleoprotein formation.
authors.affiliation: Division of Biological Sciences and Center for Biomolecular Structure and Dynamics, The University of Montana, Missoula, Montana, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Ellenbecker
authors.affiliation: Division of Biological Sciences and Center for Biomolecular Structure and Dynamics, The University of Montana, Missoula, Montana, USA.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Lanchy
authors.affiliation: Division of Biological Sciences and Center for Biomolecular Structure and Dynamics, The University of Montana, Missoula, Montana, USA stephen.lodmell@umontana.edu.
authors.forename: J Stephen
authors.initials: JS
authors.lastname: Lodmell
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D004305:Dose-Response Relationship, Drug; D058492:Drug Repositioning; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D019590:Nucleocapsid Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D012367:RNA, Viral / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012296:Rift Valley fever virus / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D013498:Suramin / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D019590:Nucleocapsid Proteins; D012367:RNA, Viral; D014344:Trypanocidal Agents; D013498:Suramin