title: A sialic acid binding site in a human picornavirus.
abstract: The picornaviruses coxsackievirus A24 variant (CVA24v) and enterovirus 70 (EV70) cause continued outbreaks and pandemics of acute hemorrhagic conjunctivitis (AHC), a highly contagious eye disease against which neither vaccines nor antiviral drugs are currently available. Moreover, these viruses can cause symptoms in the cornea, upper respiratory tract, and neurological impairments such as acute flaccid paralysis. EV70 and CVA24v are both known to use 5-N-acetylneuraminic acid (Neu5Ac) for cell attachment, thus providing a putative link between the glycan receptor specificity and cell tropism and disease. We report the structures of an intact human picornavirus in complex with a range of glycans terminating in Neu5Ac. We determined the structure of the CVA24v to 1.40 Å resolution, screened different glycans bearing Neu5Ac for CVA24v binding, and structurally characterized interactions with candidate glycan receptors. Biochemical studies verified the relevance of the binding site and demonstrated a preference of CVA24v for α2,6-linked glycans. This preference can be rationalized by molecular dynamics simulations that show that α2,6-linked glycans can establish more contacts with the viral capsid. Our results form an excellent platform for the design of antiviral compounds to prevent AHC.
authors.affiliation: Interfaculty Institute of Biochemistry, University Tübingen, Tübingen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Zocher
authors.affiliation: Division of Virology, Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
authors.forename: Nitesh
authors.initials: N
authors.lastname: Mistry
authors.affiliation: Biognos AB, Göteborg, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Frank
authors.affiliation: Interfaculty Institute of Biochemistry, University Tübingen, Tübingen, Germany.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Hähnlein-Schick
authors.affiliation: Department of Molecular Biology, Umeå University, Umeå, Sweden.
authors.forename: Jens-Ola
authors.initials: JO
authors.lastname: Ekström
authors.affiliation: Division of Virology, Department of Clinical Microbiology, Umeå University, Umeå, Sweden; Laboratory for Molecular Infection Medicine (MIMS), Umeå University, Umeå, Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Arnberg
authors.affiliation: Interfaculty Institute of Biochemistry, University Tübingen, Tübingen, Germany; Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Thilo
authors.initials: T
authors.lastname: Stehle
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D030015:Enterovirus C, Human / Q000737:chemistry*; D006801:Humans; D010849:Picornaviridae / Q000737:chemistry*; D011991:Receptors, Virus / Q000276:immunology* / Q000378:metabolism; D012794:Sialic Acids / Q000737:chemistry*
chemical_list: D011991:Receptors, Virus; D012794:Sialic Acids