title: Novel heparan sulfate-binding peptides for blocking herpesvirus entry.
abstract: Human cytomegalovirus (HCMV) infection can lead to congenital hearing loss and mental retardation. Upon immune suppression, reactivation of latent HCMV or primary infection increases morbidity in cancer, transplantation, and late stage AIDS patients. Current treatments include nucleoside analogues, which have significant toxicities limiting their usefulness. In this study we screened a panel of synthetic heparin-binding peptides for their ability to prevent CMV infection in vitro. A peptide designated, p5+14 exhibited ~ 90% reduction in murine CMV (MCMV) infection. Because negatively charged, cell-surface heparan sulfate proteoglycans (HSPGs), serve as the attachment receptor during the adsorption phase of the CMV infection cycle, we hypothesized that p5+14 effectively competes for CMV adsorption to the cell surface resulting in the reduction in infection. Positively charged Lys residues were required for peptide binding to cell-surface HSPGs and reducing viral infection. We show that this inhibition was not due to a direct neutralizing effect on the virus itself and that the peptide blocked adsorption of the virus. The peptide also inhibited infection of other herpesviruses: HCMV and herpes simplex virus 1 and 2 in vitro, demonstrating it has broad-spectrum antiviral activity. Therefore, this peptide may offer an adjunct therapy for the treatment of herpes viral infections and other viruses that use HSPGs for entry.
authors.affiliation: Department of Microbiology, The University of Tennessee, Knoxville, Tennessee, United States of America.
authors.forename: Pranay
authors.initials: P
authors.lastname: Dogra
authors.affiliation: Department of Medicine, The University of Tennessee Graduate School of Medicine, Knoxville, Tennessee, United States of America.
authors.forename: Emily B
authors.initials: EB
authors.lastname: Martin
authors.affiliation: Department of Medicine, The University of Tennessee Graduate School of Medicine, Knoxville, Tennessee, United States of America.
authors.forename: Angela
authors.initials: A
authors.lastname: Williams
authors.affiliation: Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, Tennessee, United States of America.
authors.forename: Raphael L
authors.initials: RL
authors.lastname: Richardson
authors.affiliation: Department of Medicine, The University of Tennessee Graduate School of Medicine, Knoxville, Tennessee, United States of America.
authors.forename: James S
authors.initials: JS
authors.lastname: Foster
authors.affiliation: Department of Medicine, The University of Tennessee Graduate School of Medicine, Knoxville, Tennessee, United States of America.
authors.forename: Nicole
authors.initials: N
authors.lastname: Hackenback
authors.affiliation: Department of Medicine, The University of Tennessee Graduate School of Medicine, Knoxville, Tennessee, United States of America; Department of Radiology, The University of Tennessee Graduate School of Medicine, Knoxville, Tennessee, United States of America.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kennel
authors.affiliation: Department of Microbiology, The University of Tennessee, Knoxville, Tennessee, United States of America.
authors.forename: Tim E
authors.initials: TE
authors.lastname: Sparer
authors.affiliation: Department of Medicine, The University of Tennessee Graduate School of Medicine, Knoxville, Tennessee, United States of America; Department of Radiology, The University of Tennessee Graduate School of Medicine, Knoxville, Tennessee, United States of America.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Wall
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000187:drug effects / Q000472:pathogenicity / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D006564:Herpesviridae / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology*; D006566:Herpesviridae Infections / Q000188:drug therapy / Q000517:prevention & control / Q000821:virology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018146:Muromegalovirus / Q000187:drug effects / Q000472:pathogenicity / Q000502:physiology; D017433:Protein Structure, Secondary; D053585:Virus Attachment / Q000187:drug effects; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D019812:Heparan Sulfate Proteoglycans