Journal Article

Novel Heparan Sulfate-Binding Peptides for Blocking Herpesvirus Entry

Williams, Angela, Hackenback, Nicole, Sparer, Tim E., Richardson, Raphael L., Wall, Jonathan S., Dogra, Pranay, Foster, James S., Kennel, Stephen J., Martin, Emily B.

2015

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acquired immune deficiency syndrome / Activation / Adsorption / AIDS / Amino Acid Sequence / Animals / Anticoagulants / Antiviral activity / Antiviral Agents - chemistry / Antiviral Agents - pharmacology / Auditory defects / Binding / Binding sites / Cancer / Cell surface / Cells, Cultured / Cytomegalovirus / Cytomegalovirus - drug effects / Cytomegalovirus - pathogenicity / Cytomegalovirus - physiology / Drug Evaluation, Preclinical / Genetic aspects / Glycoproteins / Growth factors / Health aspects / Hearing loss / Heparan sulfate / Heparan sulfate proteoglycans / Heparan Sulfate Proteoglycans - chemistry / Heparan Sulfate Proteoglycans - metabolism / Heparan Sulfate Proteoglycans - pharmacology / Heparin / Herpes simplex / Herpes viruses / Herpesviridae - drug effects / Herpesviridae - pathogenicity / Herpesviridae - physiology / Herpesviridae Infections - drug therapy / Herpesviridae Infections - prevention & control / Herpesviridae Infections - virology / Herpesvirus infections / Humans / In Vitro Techniques / Infections / Medicine / Methods / Mice / Models, Molecular / Molecular Sequence Data / Molecular targeted therapy / Morbidity / Muromegalovirus - drug effects / Muromegalovirus - pathogenicity / Muromegalovirus - physiology / Nucleoside analogs / Peptides / Prevention / Protein binding / Protein Structure, Secondary / Proteins / Proteoglycans / Reduction / Sulfates / Surface chemistry / Toxicity / Transplantation / Viral infections / Virology / Virus Attachment - drug effects / Virus Internalization - drug effects / Viruses