title: Release of dengue virus genome induced by a peptide inhibitor.
abstract: Dengue virus infects approximately 100 million people annually, but there is no available therapeutic treatment. The mimetic peptide, DN59, consists of residues corresponding to the membrane interacting, amphipathic stem region of the dengue virus envelope (E) glycoprotein. This peptide is inhibitory to all four serotypes of dengue virus, as well as other flaviviruses. Cryo-electron microscopy image reconstruction of dengue virus particles incubated with DN59 showed that the virus particles were largely empty, concurrent with the formation of holes at the five-fold vertices. The release of RNA from the viral particle following incubation with DN59 was confirmed by increased sensitivity of the RNA genome to exogenous RNase and separation of the genome from the E protein in a tartrate density gradient. DN59 interacted strongly with synthetic lipid vesicles and caused membrane disruptions, but was found to be non-toxic to mammalian and insect cells. Thus DN59 inhibits flavivirus infectivity by interacting directly with virus particles resulting in release of the genomic RNA.
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.
authors.forename: Shee-Mei
authors.initials: SM
authors.lastname: Lok
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Costin
authors.forename: Yancey M
authors.initials: YM
authors.lastname: Hrobowski
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Hoffmann
authors.forename: Dawne K
authors.initials: DK
authors.lastname: Rowe
authors.forename: Petra
authors.initials: P
authors.lastname: Kukkaro
authors.forename: Heather
authors.initials: H
authors.lastname: Holdaway
authors.forename: Paul
authors.initials: P
authors.lastname: Chipman
authors.forename: Krystal A
authors.initials: KA
authors.lastname: Fontaine
authors.forename: Michael R
authors.initials: MR
authors.lastname: Holbrook
authors.forename: Robert F
authors.initials: RF
authors.lastname: Garry
authors.forename: Victor
authors.initials: V
authors.lastname: Kostyuchenko
authors.forename: William C
authors.initials: WC
authors.lastname: Wimley
authors.forename: Sharon
authors.initials: S
authors.lastname: Isern
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rossmann
authors.forename: Scott F
authors.initials: SF
authors.lastname: Michael
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002499:Centrifugation, Density Gradient; D003716:Dengue Virus / Q000187:drug effects* / Q000235:genetics* / Q000472:pathogenicity / Q000648:ultrastructure; D016679:Genome, Viral / Q000235:genetics*; D006801:Humans; D008051:Lipid Bilayers / Q000378:metabolism; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D014759:Viral Envelope Proteins / Q000378:metabolism; D014771:Virion / Q000187:drug effects / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D008051:Lipid Bilayers; D010455:Peptides; D014759:Viral Envelope Proteins