Using a 3-<i>O</i>-Sulfated Heparin Octasaccharide To Inhibit the Entry of Herpes Simplex Virus Type 1

Copeland, Ronald J.; Balasubramaniam, Arun; Tiwari, Vaibhav; Zhang, Fuming; Bridges, Arlene S.; Linhardt, Robert J.; Shukla, Deepak; Liu, Jian

doi:10.1021/bi800205t

Cited by 120 publications

(106 citation statements)

References 41 publications

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“…This conclusion is supported by our finding that CYVIP concentrations, that blocked virus attachment were also effective in inhibiting infection. Interference with virus attachment is therefore a promising target for antiviral intervention (44)(45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

“…Sulfated polysaccharides have been discussed as antimicrobial drugs (46,(57)(58)(59), and the potential of compounds that interfere with virus attachment to HS proteoglycans as novel antiviral agents has been investigated (44,45,47,56,60,61). Most importantly, such compounds would be effective against viruses that have acquired resistance to currently available antiviral medications.…”

Section: Discussionmentioning

confidence: 99%

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A Peptide Inhibitor of Cytomegalovirus Infection from Human Hemofiltrate

Borst

Ständker

Wagner

et al. 2013

Antimicrob Agents Chemother

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Naturally occurring substances with antimicrobial activity can serve as a starting point for the rational design of new drugs to treat infectious diseases. Here, we screened a library of peptides derived from human hemofiltrate for inhibitory effects on human cytomegalovirus (CMV) infection. We isolated a previously unknown derivative of the neutrophil-activating peptide 2, which we termed CYVIP, for CMV-inhibiting peptide. The peptide blocked infection with human and mouse CMV as well as with herpes simplex virus type 1 in different cell types. We found that CYVIP interferes with virus attachment to the cell surface, and structure-activity relationship studies revealed that positively charged lysine and arginine residues of CYVIP are essential for its inhibitory activity. The N-terminal 29 amino acids of the peptide were sufficient for inhibition, and substitution with an acidic residue further improved its activity. The target structure of CYVIP on the cell surface seems to be the sulfate residues of heparan sulfate proteoglycans, which are known to serve as herpesvirus attachment receptors. Our data suggest that O-sulfation of heparan sulfate is required for binding of CYVIP, and furthermore, that the initial interaction of CMV particles with cells takes place preferentially via 6-O-linked sulfate groups. These findings about CYVIP's mode of action lay the basis for further development of antivirals interfering with attachment of CMV to cells, a crucial step of the infection cycle.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Peptide Inhibitor of Cytomegalovirus Infection from Human Hemofiltrate

Borst

Ständker

Wagner

et al. 2013

Antimicrob Agents Chemother

View full text Add to dashboard Cite

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“…After 48 h, cells were infected with the b-galactosidase expressing recombinant HSV-1(KOS) gL86 in a twofold serial dilution for 6 h at 37 uC. b-Galactosidase expression can be induced by early viral protein synthesis upon HSV infection (Copeland et al, 2008). At 6 h post-infection, cells were washed twice with PBS and the soluble substrate O-nitrophenyl-b-D-galactopyranoside (ONPG; Pierce) was added.…”

Section: Methodsmentioning

confidence: 99%

Syndecan-1 and syndecan-2 play key roles in herpes simplex virus type-1 infection

Bacsa

Karasneh

Dósa

et al. 2010

Journal of General Virology

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Herpes simplex virus type 1 (HSV-1) is an important human pathogen and a leading cause of infectious blindness in the developed world. HSV-1 exploits heparan sulfate proteoglycans (HSPG) for attachment to cells. While the significance of heparan sulphate (HS) moieties in HSV-1 infection is well established, the role of specific proteoglycan core proteins in the infection process remains poorly understood. The objective of this study was to assess the roles of syndecan-1 and syndecan-2 core proteins in HSV-1 infection, both of which are expressed by many HSV-1 target cell types. Our results demonstrate that syndecan-1 and syndecan-2 gene silencing by RNA interference reduces HSV-1 entry, plaque formation and facilitates cell survival. Furthermore, HSV-1 infection increases syndecan-1 and syndecan-2 protein synthesis and a resultant increase in cell surface expression of HS. Our observations suggest that changes in syndecan-1 and syndecan-2 expression levels may be related to active viral infection. Taken together, our findings provide new insights into HSPG functions during HSV-1 entry and spread. INTRODUCTIONHerpes simplex virus type 1 (HSV-1) is a clinically important pathogen and a leading cause of infectious blindness in the developed world. HSV-1 productively infects epithelial cells and establishes latent infection in sensory ganglia for the life of the host (Kumaraguru & Rouse, 2002;Terasaka et al., 2010). Currently, no cure exists against HSV-1, which can be transmitted via asymptomatic shedding by latently infected individuals (Hill & Clement, 2009). Prevention of virus transmission to uninfected people is a real challenge compounded by our limited understanding of HSV-1-host cell interactions including virus entry, which is the first essential step for the establishment of an acute and/or latent infection.Enveloped viruses including HSV-1 penetrate host cells by inducing fusion between the virus envelope and the host cell membrane. HSV-1 entry is a stepwise process, which starts when HSV-1 envelope glycoproteins gB and gC attach to cell surface heparan sulfate proteoglycans (HSPGs) (Herold et al., 1991;Nicola et al., 2003;Trybala et al., 2000). This initial interaction enables HSV-1 glycoprotein D (gD) to bind to one of the known gD entry co-receptors. There are three classes of gD co-receptors that have been characterized: nectin-1 (HveC) and nectin-2 (HveB), which are both members of the immunoglobulin superfamily (Geraghty et al., 1998), herpesvirus entry mediator (HVEM) that belongs to the tumour necrosis factor receptor family (Montgomery et al., 1996), and 3-O-sulfated heparan sulfate (3-OS HS) which is a specifically modified form of heparan sulfate (HS) (Shukla et al., 1999b; O'Donnell et al., 2010). The binding of gD to one of its receptors leads to conformational changes in gD that allows it to activate a multiglycoprotein complex involving gB, gD, gH and gL that triggers the viral fusion with the host cell membrane (Atanasiu et al., 2007;Spear et al., 2000). This fusion mechanism is utilized...

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“…A mixture of polysaccharides can sometimes confound structure and activity relationship studies. Methods for the synthesis of structurally defined oligosaccharides have been reported (11,12). These methods describe synthetic strategies that targeted a single product from a specialized oligosaccharide starting material.…”

mentioning

confidence: 99%

Chemoenzymatic Design of Heparan Sulfate Oligosaccharides*

Liu

Chen

et al. 2010

Journal of Biological Chemistry

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Heparan sulfate is a sulfated glycan that exhibits essential physiological functions. Interrogation of the specificity of heparan sulfate-mediated activities demands a library of structurally defined oligosaccharides. Chemical synthesis of large heparan sulfate oligosaccharides remains challenging. We report the synthesis of oligosaccharides with different sulfation patterns and sizes from a disaccharide building block using glycosyltransferases, heparan sulfate C 5 -epimerase, and sulfotransferases. This method offers a generic approach to prepare heparan sulfate oligosaccharides possessing predictable structures. Heparan sulfate (HS)3 is a unique class of macromolecular natural product that is present in large quantities on the mammalian cell surface and in the extracellular matrix. HS participates in regulating blood coagulation, embryonic development, and the inflammatory response and assists viral/bacterial infections. It consists of a repeating disaccharide unit of glucuronic acid (GlcUA) or iduronic acid (IdoUA) and glucosamine, both capable of carrying sulfo groups (1). The sulfation pattern of HS dictates its biological activity (2, 3). Heparin, a widely used anticoagulant drug, is a specialized form of highly sulfated HS. The diverse biological functions present considerable opportunities for exploiting HS or HS-protein conjugates for developing new classes of anticancer (4), antiviral (5), and improved anticoagulant drugs (6). Furthermore, a recent worldwide outbreak of contaminated heparin underscores the needs for synthetic heparins to replace those isolated from animal tissues (7). Chemical synthesis is a powerful tool to obtain structurally defined heparin/HS oligosaccharides. The most successful example is the total synthesis of an antithrombin-binding pentasaccharide (8). This pentasaccharide is marketed under the trade name Arixtra for the treatment of venous thromboembolic disorders. However, the chemical synthesis of oligosaccharides larger than an octasaccharide is extremely difficult, especially when multiple target structures are required for biological evaluation (8). An enzyme-based method offers a promising alternative approach to synthesize HS.The HS biosynthetic pathway involves multiple enzymes, including HS polymerase, epimerase, and sulfotransferases ( Fig. 1). HS polymerase is responsible for building the polysaccharide backbone, containing the repeating unit of -GlcUA-GlcNAc-. The backbone is then modified by N-deacetylase/N-sulfotransferase (having two separate domains exhibiting the activity of N-deacetylase and N-sulfotransferase, respectively), C 5 -epimerase (C 5 -epi, converting GlcUA to IdoUA), 2-O-sulfotransferase (2-OST), 6-O-sulfotransferase (6-OST) and 3-O-sulfotransferase (3-OST) to produce the fully elaborated HS. With the exception of HS polymerase, all of these biosynthetic enzymes have been expressed at high levels in Escherichia coli (1), permitting easy access to an abundance of enzymes. Using HS sulfotransferases and C 5 -epi, we previously developed a method ...

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Using a 3-O-Sulfated Heparin Octasaccharide To Inhibit the Entry of Herpes Simplex Virus Type 1

Cited by 120 publications

References 41 publications

A Peptide Inhibitor of Cytomegalovirus Infection from Human Hemofiltrate

A Peptide Inhibitor of Cytomegalovirus Infection from Human Hemofiltrate

Syndecan-1 and syndecan-2 play key roles in herpes simplex virus type-1 infection

Chemoenzymatic Design of Heparan Sulfate Oligosaccharides*

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