title: A highly lipophilic sulfated tetrasaccharide glycoside related to muparfostat (PI-88) exhibits virucidal activity against herpes simplex virus.
abstract: Although sulfated polysaccharides potently inhibit the infectivity of herpes simplex virus (HSV) and human immunodeficiency virus in cultured cells, these compounds fail to show protective effects in humans, most likely due to their poor virucidal activity. Herein we report on sulfated oligosaccharide glycosides related to muparfostat (formerly known as PI-88) and their assessment for anti-HSV activity. Chemical modifications based on the introduction of specific hydrophobic groups at the reducing end of a sulfated oligosaccharide chain enhanced the compound's capability to inhibit the infection of cells by HSV-1 and HSV-2 and abrogated the cell-to-cell transmission of HSV-2. Furthermore, modification with a highly lipophilic cholestanyl group provided a compound with virucidal activity against HSV. This glycoside targeted the viral particle and, to a lesser degree, the cell, and exhibited an antiviral mode of action typical for sulfated polysaccharides and virucides, i.e., interference with the virus attachment to cells and irreversible inactivation of virus infectivity, respectively. The virucidal activity was decreased in the presence of human cervical secretions suggesting that higher doses of this glycoside might be needed for in vivo application. Altogether, the sulfated oligosaccharide-cholestanyl glycoside exhibits potent anti-HSV activity and is, therefore, a good candidate for development as a virucide.
authors.affiliation: Department of Clinical Virology, University of Gothenburg, Guldhedsgatan 10B, Göteborg, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Ekblad
authors.forename: Beata
authors.initials: B
authors.lastname: Adamiak
authors.forename: Tomas
authors.initials: T
authors.lastname: Bergstrom
authors.forename: Ken D
authors.initials: KD
authors.lastname: Johnstone
authors.forename: Tomislav
authors.initials: T
authors.lastname: Karoli
authors.forename: Ligong
authors.initials: L
authors.lastname: Liu
authors.forename: Vito
authors.initials: V
authors.lastname: Ferro
authors.forename: Edward
authors.initials: E
authors.lastname: Trybala
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D012634:Bodily Secretions; D002460:Cell Line; D002522:Chlorocebus aethiops; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000502:physiology; D018258:Herpesvirus 2, Human / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D050296:Microbial Viability / Q000187:drug effects*; D046529:Microscopy, Electron, Transmission; D015394:Molecular Structure; D009844:Oligosaccharides / Q000737:chemistry / Q000494:pharmacology*; D010948:Viral Plaque Assay
chemical_list: D000998:Antiviral Agents; D009844:Oligosaccharides; C120158:phosphomannopentaose sulfate