title: The Suramin Derivative NF449 Interacts with the 5-fold Vertex of the Enterovirus A71 Capsid to Prevent Virus Attachment to PSGL-1 and Heparan Sulfate.
abstract: NF449, a sulfated compound derived from the antiparasitic drug suramin, was previously reported to inhibit infection by enterovirus A71 (EV-A71). In the current work, we found that NF449 inhibits virus attachment to target cells, and specifically blocks virus interaction with two identified receptors--the P-selectin ligand, PSGL-1, and heparan sulfate glycosaminoglycan--with no effect on virus binding to a third receptor, the scavenger receptor SCARB2. We also examined a number of commercially available suramin analogues, and newly synthesized derivatives of NF449; among these, NF110 and NM16, like NF449, inhibited virus attachment at submicromolar concentrations. PSGL-1 and heparan sulfate, but not SCARB2, are both sulfated molecules, and their interaction with EV-A71 is thought to involve positively charged capsid residues, including a conserved lysine at VP1-244, near the icosahedral 5-fold vertex. We found that mutation of VP1-244 resulted in resistance to NF449, suggesting that this residue is involved in NF449 interaction with the virus capsid. Consistent with this idea, NF449 and NF110 prevented virus interaction with monoclonal antibody MA28-7, which specifically recognizes an epitope overlapping VP1-244 at the 5-fold vertex. Based on these observations we propose that NF449 and related compounds compete with sulfated receptor molecules for a binding site at the 5-fold vertex of the EV-A71 capsid.
authors.affiliation: Division of Infectious Diseases, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America; Department of Virology II, National Institute of Infectious Diseases, Musashimurayama-shi, Tokyo, Japan.
authors.forename: Yorihiro
authors.initials: Y
authors.lastname: Nishimura
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Noel P
authors.initials: NP
authors.lastname: McLaughlin
authors.affiliation: Division of Infectious Diseases, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Jieyan
authors.initials: J
authors.lastname: Pan
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Sara
authors.initials: S
authors.lastname: Goldstein
authors.affiliation: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Susan
authors.initials: S
authors.lastname: Hafenstein
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Musashimurayama-shi, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Winkler
authors.affiliation: Division of Infectious Diseases, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Bergelson
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000494:pharmacology*; D001665:Binding Sites; D002213:Capsid / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D029821:Enterovirus A, Human / Q000187:drug effects / Q000378:metabolism; D004769:Enterovirus Infections / Q000378:metabolism / Q000821:virology*; D006367:HeLa Cells; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D013498:Suramin / Q000031:analogs & derivatives; D053585:Virus Attachment / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D001557:Benzenesulfonates; D006497:Heparan Sulfate; D008562:Membrane Glycoproteins; D013498:Suramin; C110258:4,4,',4'',4'''-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis(benzene-1,3-disulfonate); C084882:P-selectin ligand protein