title: Addition of a C-terminal cysteine improves the anti-herpes simplex virus activity of a peptide containing the human immunodeficiency virus type 1 TAT protein transduction domain.
abstract: Previous studies have shown that peptides containing the protein transduction domain (PTD) of the human immunodeficiency virus tat protein (GRKKRRQRRR) were effective inhibitors of herpes simplex virus type 1 (HSV-1) entry (H. Bultmann and C. R. Brandt, J. Biol. Chem. 277:36018-36023, 2002). We now show that the addition of a single cysteine residue to the C terminus of the TAT PTD (TAT-C peptide) improves the antiviral activity against HSV-1 and HSV-2. The principle effect of adding the cysteine was to enable the peptide to inactivate virions and to induce a state of resistance to infection in cells pretreated with peptide. The TAT-C peptide acted extracellularly, immediately blocked entry of adsorbed virus, prevented VP16 translocation to the nucleus, and blocked syncytium formation and cell-cell spread. Thus, TAT-C peptides are fusion inhibitors. The induction of the resistance of cells to infection was rapid, recovered with a half-life of 5 to 6 h, and could be reinduced by peptide treatment. TAT-C bound to heparan sulfate but was a poor competitor for viral attachment. The antiviral activity depended on the net positive charge of the peptide but not on chirality, and a free sulfhydryl group was not essential for antiviral activity because TAT-C dimers were at least as effective as monomers. The unique combination of antiviral activities and low toxicity combine to make TAT-C a strong candidate for further development as a drug to block HSV infection.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, 6630 Medical Sciences Center, Madison, WI 53706, USA.
authors.forename: Hermann
authors.initials: H
authors.lastname: Bultmann
authors.forename: Jeremy
authors.initials: J
authors.lastname: Teuton
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Brandt
mesh_terms: D000327:Adsorption; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D003545:Cysteine; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D015696:Gene Products, tat / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000737:chemistry*; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000502:physiology; D018258:Herpesvirus 2, Human / Q000187:drug effects; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D014709:Vero Cells; D014771:Virion / Q000187:drug effects; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D000998:Antiviral Agents; D015696:Gene Products, tat; D054322:tat Gene Products, Human Immunodeficiency Virus; D003545:Cysteine