An Amphipathic α -Helical Synthetic Peptide Analogue of Melittin Inhibits Herpes Simplex Virus-1 (HSV-1)-Induced Cell Fusion and Virus Spread

Baghian, Abolghasem; Jaynes, Jesse M.; Enright, Frederick M.; Kousoulas, Konstantin G.

doi:10.1016/s0196-9781(96)00290-2

Cited by 58 publications

(46 citation statements)

References 22 publications

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“…The membrane-targeted activity of peptide antibiotics was demonstrated in voltage-dependent channel formation in artificial membranes (1,18), lysis of liposomes, and direct lysis of enveloped virus (2,8,11,21,27,43). Despite general membrane disruption phenomena, the peptide antibiotics generally have strong selectivity against microbes but not normal host cells.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Activity of Synthetic Peptide Antibiotics on Feline Immunodeficiency Virus Infectivity In Vitro

Kennedy‐Stoskopf

Jaynes³

et al. 2002

J Virol

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for up to 7 days, The virions from the D4E1-treated culture had impaired infectivity, as measured by the 50% tissue culture infectious dose and nested PCR analysis of proviral DNA. However, these noninfectious virions were able to bind and internalize, suggesting a defect at some postentry step. After chronically infected CrFK cells were treated with D4E1 for 24 h, increased cell-associated mature p26 Gag and decreased extracellular virus-associated p26 Gag were observed by Western blot analysis, suggesting that virus assembly and/or release may be blocked by D4E1 treatment, whereas virus binding, penetration, RNA synthesis, and protein synthesis appear to be unaffected. Synthetic peptide antibiotics may be useful tools in the search for antiviral drugs having a wide therapeutic window for host cells.

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Section: Discussionmentioning

confidence: 99%

Inhibitory Activity of Synthetic Peptide Antibiotics on Feline Immunodeficiency Virus Infectivity In Vitro

Kennedy‐Stoskopf

Jaynes³

et al. 2002

J Virol

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“…The soluble ectodomains of the cellular receptors have also been reported to prevent entry (19,38). Although these soluble ectodomains inhibit fusion in cell culture, they have not been tested in vivo.A number of HSV entry inhibitors have been described, including a 23-amino-acid structural analog of melittin (hecate), a 33-amino-acid peptide homologous to a heptad-like repeat structure in bovine herpes virus type 1, n-docosanol, and cobalt chelates (3,4,22,40,41,43,48,53). Some of these agents may act by disrupting the membrane or envelope structure, but little is known about the actual mechanisms involved.…”

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confidence: 99%

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

Bultmann¹,

Teuton

Brandt

2007

Antimicrob Agents Chemother

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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.Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are widespread human pathogens. Between 70 and 90% of adults in the United States are infected with HSV-1, and 22% of individuals over the age of 12 are seropositive for HSV-2 (7, 61). Both viruses infect mucous membranes causing ulcerative lesions that are usually self-limited in immunocompetent individuals. However, serious infections can occur, including lethal neonatal HSV, encephalitis, and blinding keratitis (34,61). A number of antivirals are approved for HSV treatment, and the use of these drugs has had a significant impact on the disease. These antivirals reduce the frequency of recurrent viral shedding and disease and reduce transmission of genital herpes between discordant partners (12,42,46). Although these treatment regimens significantly reduce disease, they are not completely effective and cannot clear latent infections. One significant problem in dealing with HSV infections is the ability of the virus to persist in the host in the form of latent infection (45). Preventing the establishment of a persistent infection, which could be accomplished either by blocking the initial infection or preventing the establishment of latency, would be ideal for dealing with this virus.One strategy for preventing infection is to block the attachment of virus. Attachment of HSV can be inhibited by heparin, which competes directly with the binding of gC and gB to cell surface heparan sulfate (HS) on cells (23,24,(26)(27)(28). Other polymeric anions and polyoxotungstate compounds have been shown to inhibit attachm...

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“…A suggested model is as follows: (i) a direct, electrostatic interaction with the negatively charged bacterial cytoplasmic membrane, (ii) interaction of the peptide with the hydrocarbon core of the membrane and (iii) subsequent peptide conformational change into alpha-helical peptides that form membrane-spanning pores that disrupt the ionic homeostasis of the bacterium and lead to cell lysis (31). Several antimicrobial peptides have also been reported to act against fungi (8), parasites (42), viruses (2,3,34,39), and tumors (43). In addition to the cytolytic capacities, other mechanisms are probably involved.…”

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confidence: 99%

Activities of Synthetic Hybrid Peptides against Anaerobic Bacteria: Aspects of Methodology and Stability

Hedberg

Wade

et al. 2000

Antimicrob Agents Chemother

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The increasing problem of antibiotic resistance among pathogenic bacteria requires development of new antimicrobial agents. One line of investigation is the synthesis of antimicrobial hybrid peptides. The aim of the present investigation was to determine the in vitro activities of 16 cecropin-melittin hybrid peptides (CAMEL analogues) against 60 anaerobic bacterial strains, to compare their activities with those of seven clinically used antimicrobial agents, and to compare different methods for anaerobic susceptibility testing of these peptides. The stability of one of the peptides, temporin B, with different stereoisomeric configurations was investigated in a fecal milieu. The CAMEL analogues showed antimicrobial activity against the anaerobic bacteria, with MICs ranging from 0.125 to 32 g/ml. The overall activities (the MICs at which 90% of isolates are inhibited) of the CAMEL analogues against anaerobic bacteria were mainly inferior to those of imipenem, clindamycin, and piperacillin but were equal to or superior to those of metronidazole, cefoxitin, ciprofloxacin, and chloramphenicol. The agarose dilution method was found to be an accurate method for the testing of large numbers of bacterial strains. The D isomer of temporin B was inactivated more slowly in feces than the L isomer. This study shows that the CAMEL analogues are potential agents for the treatment of anaerobic infections.

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An Amphipathic α -Helical Synthetic Peptide Analogue of Melittin Inhibits Herpes Simplex Virus-1 (HSV-1)-Induced Cell Fusion and Virus Spread

Cited by 58 publications

References 22 publications

Inhibitory Activity of Synthetic Peptide Antibiotics on Feline Immunodeficiency Virus Infectivity In Vitro

Inhibitory Activity of Synthetic Peptide Antibiotics on Feline Immunodeficiency Virus Infectivity In Vitro

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

Activities of Synthetic Hybrid Peptides against Anaerobic Bacteria: Aspects of Methodology and Stability

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