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

Akkarawongsa, Radeekorn; Potocky, Terra; English, Emily P.; Gellman, Samuel H.; Brandt, Curtis R.

doi:10.1128/aac.01424-07

Cited by 31 publications

(21 citation statements)

References 68 publications

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“…11,12 These unnatural peptides can also act as scaffolds with sophisticated biological functions that include antibacterial magainin mimetics 13,14 as well as inhibitors of protein-protein interactions 15,16 and viral infections. 17,18 In a recent review, developments in structural characterization and in vitro and in vivo evaluation of foldamers document the extensive chemotherapeutic potential and diversity of cyclic and acyclic peptide backbones derived from natural and unnatural amino acids. 19 …”

Section: Introductionmentioning

confidence: 99%

Synthesis and Structural Characterization of Sialic Acid−Glutamic Acid Hybrid Foldamers as Conformational Surrogates of α-2,8-Linked Polysialic Acid

2009

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Surface expression of α-(2,8)-linked polymers of sialic acid in adult tissues has been correlated with metastasis of several human cancers. One approach to chemotherapeutic intervention against the spread of these cancers involves the development of immunogenic molecules that elicit an antibody response against α-(2,8)-linked polysialic acids. Naturally occurring polysialic acids are not viable candidates because they are present during embryonic development and are recognized as self by the immune system. These natural polymers also have poor pharmacokinetic properties because they are readily degraded by neuraminidase enzymes. We have been interested in developing structural surrogates of polysialic acids in an effort to overcome these limitations. Reported herein are microwave-assisted solid phase peptide syntheses and structural characterization studies of a series of α/δ hybrid peptides derived from Fmoc-Neu2en and Fmoc-Glu(OtBu)-OH. Conformational experiments including circular dichroism, NH/ND exchange and ROESY in aqueous solution were performed in order to study the secondary structures of these hybrid foldamers. ROESY data were analyzed with the assistance of XPLOR-NIH that was modified to include parameter and topology files to accommodate unnatural amino acids and the δ amide linkages. The results indicate that stable secondary structure is dependent upon both the amino acid sequence and the configuration of Glu. The most stable foldamer was composed of a total of 6 residues beginning with L-Glu at the carboxy terminus and alternating Neu2en and L-Glu residues. In water, this foldamer adopts a right-handed helical conformation with 3.7 residues per turn, 7.4 Å pitch, 5.8 Å diameter, and a length of 18.5 Å, which is stabilized by both classical C=O•••H-N backbone interactions and by pyranose ring O and L-Glu HN H-bonding. These structural features orient the L-Glu carboxylates along the helical backbone with a periodicity that matches the carboxylate positions along the reported G2+ left-handed helix of α-(2,8)-polysialic acid. However, the charge density of the foldamer is half that of the natural polymer. These findings provide a fundamental understanding of the factors that influence stable secondary structure in hybrid Neu2en/Glu systems, and the tools we have developed establish a viable platform for the rational design of α-(2,8)-polysialic acid surrogates.

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Section: Introductionmentioning

confidence: 99%

Synthesis and Structural Characterization of Sialic Acid−Glutamic Acid Hybrid Foldamers as Conformational Surrogates of α-2,8-Linked Polysialic Acid

2009

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“…Viral attachment to cell surface was assessed at 4°C, which allows for HSV-1 binding but excludes entry (41), using cellular enzyme-linked immunosorbent assay (ELISA), as well as flow cytometry. The ELISA binding assay was performed as previously described with some modifications (2,31). Briefly, 96-well plates were seeded with A549 cells (2 ϫ 10 4 cells per well) and allowed to grow overnight.…”

mentioning

confidence: 99%

Hydrolyzable Tannins (Chebulagic Acid and Punicalagin) Target Viral Glycoprotein-Glycosaminoglycan Interactions To Inhibit Herpes Simplex Virus 1 Entry and Cell-to-Cell Spread

Lin

Chen

Chung

et al. 2011

J Virol

163

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Herpes simplex virus 1 (HSV-1) is a common human pathogen that causes lifelong latent infection of sensory neurons. Non-nucleoside inhibitors that can limit HSV-1 recurrence are particularly useful in treating immunocompromised individuals or cases of emerging acyclovir-resistant strains of herpesvirus. We report that chebulagic acid (CHLA) and punicalagin (PUG), two hydrolyzable tannins isolated from the dried fruits of Terminalia chebula Retz. (Combretaceae), inhibit HSV-1 entry at noncytotoxic doses in A549 human lung cells. Experiments revealed that both tannins targeted and inactivated HSV-1 viral particles and could prevent binding, penetration, and cell-to-cell spread, as well as secondary infection. The antiviral effect from either of the tannins was not associated with induction of type I interferon-mediated responses, nor was pretreatment of the host cell protective against HSV-1. Their inhibitory activities targeted HSV-1 glycoproteins since both natural compounds were able to block polykaryocyte formation mediated by expression of recombinant viral glycoproteins involved in attachment and membrane fusion. Our results indicated that CHLA and PUG blocked interactions between cell surface glycosaminoglycans and HSV-1 glycoproteins. Furthermore, the antiviral activities from the two tannins were significantly diminished in mutant cell lines unable to produce heparan sulfate and chondroitin sulfate and could be rescued upon reconstitution of heparan sulfate biosynthesis. We suggest that the hydrolyzable tannins CHLA and PUG may be useful as competitors for glycosaminoglycans in the management of HSV-1 infections and that they may help reduce the risk for development of viral drug resistance during therapy with nucleoside analogues.Herpes simplex virus 1 (HSV-1) is an alphaherpesvirus that typically causes mucocutaneous lesions in oral, perioral, and other mucosal sites in the body (58). The virus commonly uses the oropharyngeal mucosa as a port of entry, and after primary infection, establishes a lifelong latent state in the host's trigeminal ganglia sensory neurons. Sporadic recurring infections occur when HSV-1 is reactivated by various stimuli, such as sunlight, immunosuppression, menstruation, fever, or stress (23). Although primary or reactivated HSV-1 infections can be subclinical or manifested by mild and self-limited diseases, severe cases of this viral infection may lead to complications such as keratoconjunctivitis, meningitis, and encephalitis (3, 5). Importantly, corneal HSV-1 infection can lead to stromal keratitis, which remains one of the leading causes of blindness in developing countries (37). More aggressive diseases due to HSV-1 are common in immunocompromised individuals (3,5,23). To date, no treatment has been identified that eradicates or resolves latent infections by this ubiquitous pathogen.HSV-1 viral entry into cells is initiated by interaction of viral envelope glycoproteins (gB and gC) with host cell surface proteoglycans (PGs) conjugated to glycosaminoglycans (GAGs) containing...

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“…2). Tat and other highly cationic peptides have been shown to prevent cell attachment by HSV-1 (45). In cell enzyme-linked immunosorbent assay experiments, we found that Tat-only and Tat-Ebo have similar modest effects on viral attachment to cells (data not shown).…”

Section: Enhanced Activity Of Endosome-targeted Ebov C-peptides-mentioning

confidence: 54%

Inhibition of Ebola Virus Entry by a C-peptide Targeted to Endosomes

Miller¹,

Harrison

Radoshitzky

et al. 2011

Journal of Biological Chemistry

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Ebola virus (EboV) and Marburg virus (MarV) (filoviruses)are the causative agents of severe hemorrhagic fever. Infection begins with uptake of particles into cellular endosomes, where the viral envelope glycoprotein (GP) catalyzes fusion between the viral and host cell membranes. This fusion event is thought to involve conformational rearrangements of the transmembrane subunit (GP2) of the envelope spike that ultimately result in formation of a six-helix bundle by the N-and C-terminal heptad repeat (NHR and CHR, respectively) regions of GP2. Infection by other viruses employing similar viral entry mechanisms (such as HIV-1 and severe acute respiratory syndrome coronavirus) can be inhibited with synthetic peptides corresponding to the native CHR sequence ("C-peptides"). However, previously reported EboV C-peptides have shown weak or insignificant antiviral activity. To determine whether the activity of a C-peptide could be improved by increasing its intracellular concentration, we prepared an EboV C-peptide conjugated to the arginine-rich sequence from HIV-1 Tat, which is known to accumulate in endosomes. We found that this peptide specifically inhibited viral entry mediated by filovirus GP proteins and infection by authentic filoviruses. We determined that antiviral activity was dependent on both the Tat sequence and the native EboV CHR sequence. Mechanistic studies suggested that the peptide acts by blocking a membrane fusion intermediate. Ebola virus (EboV)6 and Marburg virus (MarV) are members of the Filoviridae family of non-segmented negative-strand RNA viruses that produce filamentous enveloped particles (1, 2). Several filoviruses cause rapidly progressing hemorrhagic fevers, with human case-fatality rates exceeding 90% in larger outbreaks (1, 3). There are currently no vaccines or antivirals approved in the United States to treat filovirus infections. The infectious filovirus particle possesses a single membrane glycoprotein (GP), which is necessary and sufficient to mediate entry into host cells (4, 5). During viral assembly, GP is cleaved into two subunits (GP1 and GP2) by furin to produce the mature envelope spike that consists of a trimer of disulfide-linked GP1-GP2 heterodimers (6 -9). The surface subunit, GP1, mediates viral attachment and regulates the conformation of the membrane fusion subunit, GP2 (7, 10 -16). Filovirus GP proteins are categorized into the structurally defined "class I" viral membrane fusion glycoproteins that have a high ␣-helical content (17-19). Similar to the prototypic class I fusion proteins of HIV-1 and influenza A virus, GP2 contains a hydrophobic fusion peptide near its N terminus, followed by N-and C-terminal heptad repeat (NHR and CHR, respectively) sequences and the transmembrane domain (7, 17, 20 -24).A current model for filovirus entry into cells based on experimental evidence and analogy to the HIV-1 and influenza A virus entry mechanisms is schematically depicted in Fig. 1 (17,20,25). Following cell attachment, virus particles are internalized into endosomes. He...

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

Cited by 31 publications

References 68 publications

Synthesis and Structural Characterization of Sialic Acid−Glutamic Acid Hybrid Foldamers as Conformational Surrogates of α-2,8-Linked Polysialic Acid

Synthesis and Structural Characterization of Sialic Acid−Glutamic Acid Hybrid Foldamers as Conformational Surrogates of α-2,8-Linked Polysialic Acid

Hydrolyzable Tannins (Chebulagic Acid and Punicalagin) Target Viral Glycoprotein-Glycosaminoglycan Interactions To Inhibit Herpes Simplex Virus 1 Entry and Cell-to-Cell Spread

Inhibition of Ebola Virus Entry by a C-peptide Targeted to Endosomes

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