Antiviral effects of synthetic membrane-active peptides on Herpes Simplex Virus, Type 1

Egal, Mariam; Conrad, Monta; MacDonald, Dorothy; Maloy, W L; Motley, Milwood; Genco, Caroline Attardo

doi:10.1016/s0924-8579(99)00094-1

Cited by 44 publications

(42 citation statements)

References 15 publications

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“…Thus, it is possible that the inactivation of virions involves peptide binding to sialic acids on the viral glycoproteins. In this respect, TAT-C may be acting in a manner similar to positively charged defensins, some of which have been shown to bind to negatively charged carbohydrates (5,15,33,49,63). The binding of TAT-C to sialic acids on viral glycoproteins could inhibit infection in several ways.…”

Section: Discussionmentioning

confidence: 99%

“…Several cationic peptides or proteins including lactoferrin analogues and peptides derived from it, rabbit ␣-defensin NP-1, dermaseptins, magainin derivatives, and a synthetic -defensin (retrocyclin 2 [RC2]), inhibit HSV infection (2,5,15,25,29,30,31,35,36,49,58,63) by blocking attachment and/or entry. RC2 binds to N-and O-linked carbohydrates on viruses and may be acting as a "mini-lectin" (33,57,63).…”

mentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

mentioning

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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“…The measurements were performed at 298 K using 2,2-dimethyl-2-silapentane-5-sulfonate sodium salt as an internal standard (0.0 ppm). Two-dimensional TOCSY and two-dimensional NOESY spectra for free TL were also obtained at 290 K to avoid resonance overlap between residues Val 2 and Leu 13 . A series of one-dimensional 1 H NMR spectra were recorded for TL, TB, and a mixture of TLϩTB with various concentrations, ranging from 9 to 18 M, of LPS.…”

Section: Methodsmentioning

confidence: 99%

“…AMPs, being a fundamental component of the innate immunity, are bestowed with a broad-spectrum of antimicrobial activities, killing bacteria, both Gram-negative and Gram-positive, viruses, and fungi (2, 3, 8 -10). Many AMPs are also active against multidrug-resistant pathogens (11)(12)(13). Thus, AMPs are thought to be an important source of new antibiotics (4, 14 -16).…”

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confidence: 99%

NMR Structures and Interactions of Temporin-1Tl and Temporin-1Tb with Lipopolysaccharide Micelles

Bhunia

Saravanan

Mohanram

et al. 2011

Journal of Biological Chemistry

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Temporins are a group of closely related short antimicrobial peptides from frog skin. Lipopolysaccharide (LPS), the major constituent of the outer membrane of Gram-negative bacteria, plays important roles in the activity of temporins. Earlier studies have found that LPS induces oligomerization of temporin-1Tb (TB) thus preventing its translocation across the outer membrane and, as a result, reduces its activity on Gram-negative bacteria. On the other hand, temporin-1Tl (TL) exhibits higher activity, presumably because of lack of such oligomerization. A synergistic mechanism was proposed, involving TL and TB in overcoming the LPS-mediated barrier. Here, to gain insights into interactions of TL and TB within LPS, we investigated the structures and interactions of TL, TB, and TL؉TB in LPS micelles, using NMR and fluorescence spectroscopy. In the context of LPS, TL assumes a novel antiparallel dimeric helical structure sustained by intimate packing between aromatic-aromatic and aromatic-aliphatic residues. By contrast, independent TB has populations of helical and aggregated conformations in LPS. The LPS-induced aggregated states of TB are largely destabilized in the presence of TL. Saturation transfer difference NMR studies have delineated residues of TL and TB in close contact with LPS and enhanced interactions of these two peptides with LPS, when combined together. Fluorescence resonance energy transfer and 31 P NMR have pointed out the proximity of TL and TB in LPS and conformational changes of LPS, respectively. Importantly, these results provide the first structural insights into the mode of action and synergism of antimicrobial peptides at the level of the LPS-outer membrane.

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“…Examples of these peptides include rabbit ␣-defensin NP-1, a synthetic -defensin (retrocyclin 2), magainins, lactoferricin, and dermaseptins. These peptides have been shown to block HSV infection at the attachment and/or entry step (2,4,18,33,55,67). Lactoferricin binds to heparan sulfate, thereby blocking viral attachment (38).…”

mentioning

confidence: 99%

Inhibition of Herpes Simplex Virus Type 1 Infection by Cationic β-Peptides

Akkarawongsa

Potocky²,

English³

et al. 2008

Antimicrob Agents Chemother

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Previously, it was shown that cationic ␣-peptides derived from the human immunodeficiency virus TAT protein transduction domain blocked herpes simplex virus type 1 (HSV-1) entry. We now show that cationic oligomers of ␤-amino acids ("␤-peptides") inhibit HSV-1 infection. Among three cationic ␤-peptides tested, the most effective inhibition was observed for the one with a strong propensity to adopt a helical conformation in which cationic and hydrophobic residues are segregated from one another ("globally amphiphilic helix"). The antiviral effect was not cell type specific. Inhibition of virus infection by the ␤-peptides occurred at the postattachment penetration step, with a 50% effective concentration of 3 M for the most-effective ␤-peptide. The ␤-peptides did not inactivate virions in solution, nor did they induce resistance to infection when cells were pretreated with the ␤-peptides. The ␤-peptides showed little if any toxicity toward Vero cells. These results raise the possibility that cationic ␤-peptides may be useful antiviral agents for HSV-1 and demonstrate the potential of ␤-peptides as novel antiviral drugs.Herpes simplex virus type 1 (HSV-1) is a significant human pathogen causing mucocutaneous lesions primarily in the oral mucosa (cold sores), as well as other sites. More-severe diseases caused by HSV-1 infection include encephalitis, meningitis, and blinding keratitis (65), and HSV-1 is the leading cause of blindness due to infection in developed countries (5). Following an initial infection, HSV-1 establishes latent infection of neurons in sensory ganglia of the host (29), from where it periodically reactivates and causes recurrent lesions at the site of primary infection. To date, none of the currently approved antivirals can eliminate an established latent infection. Because of the difficulties dealing with latency, preventing HSV-1 from entering the cell is an attractive antiviral strategy.HSV-1 entry is a complex process, involving multiple components on both the cell plasma membrane and the viral envelope. The initial interaction involves the binding of viral glycoprotein C (gC) or gB to cell surface heparan sulfate proteoglycan (58). Four viral glycoproteins, gB, gD, and the gH-gL heterodimer, are essential for the subsequent membrane fusion and entry steps (56,57). Following attachment, gD interacts with any of three cellular receptors: herpes virus entry mediator, nectin-1, and 3-O-sulfated heparan sulfate, leading to a conformational change in gD (12,13,21,22,34,39,54,62). This conformational change in gD is believed to trigger the formation of the fusion complex, which is thought to involve the sequential binding of gB to gD, followed by the binding of gH-gL to the gB-gD complex (10,20,23,24,36,41,50,62).

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Antiviral effects of synthetic membrane-active peptides on Herpes Simplex Virus, Type 1

Cited by 44 publications

References 15 publications

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

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

NMR Structures and Interactions of Temporin-1Tl and Temporin-1Tb with Lipopolysaccharide Micelles

Inhibition of Herpes Simplex Virus Type 1 Infection by Cationic β-Peptides

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