Glycobiology Advance Access originally published online on September 24, 2008
Glycobiology 2009 19(1):2-15; doi:10.1093/glycob/cwn092
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Review |
Focus on antivirally active sulfated polysaccharides: From structure–activity analysis to clinical evaluation
3 Department of Chemistry, Natural Products Laboratory, University of Burdwan, WB 713 104, India
4 Institute for Clinical and Molecular Virology, University of Erlangen-Nuremberg, Erlangen, Germany
1 To whom correspondence should be addressed: Tel: +91-342-25-56-56-6; Fax: +91-342-2634200; e-mail: bimalendu_ray{at}yahoo.co.uk
Received on July 29, 2008; revised on September 19, 2008; accepted on September 19, 2008
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Abstract |
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In recent years, many compounds having potent antiviral activity in cell culture have been detected and some of these compounds are currently undergoing either preclinical or clinical evaluation. Among these antiviral substances, naturally occurring sulfated polysaccharides and those from synthetic origin are noteworthy. Recently, several controversies over the molecular structures of sulfated polysaccharides, viral glycoproteins, and cell-surface receptors have been resolved, and many aspects of their antiviral activity have been elucidated. It has become clear that the antiviral properties of sulfated polysaccharides are not only a simple function of their charge density and chain length but also their detailed structural features. The in vivo efficacy of these compounds mostly corresponds to their ability to inhibit the attachment of the virion to the host cell surface although in some cases virucidal activity plays an additional role. This review summarizes experimental evidence indicating that sulfated polysaccharides might become increasingly important in drug development for the prevention of sexually transmitted diseases in the near future.
Key words: antiviral activity / mechanisms / sulfated polysaccharides / structural diversity / structure–function relationship
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Introduction |
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During the last decade, the number of antivirals approved for clinical use has been increased from 5 to more than 30 drugs (De Clercq 2004
). However, as these drugs are not always efficacious or well-tolerated and drug-resistant virus strains are rapidly emerging, there is still a great demand for further drug development including novel modes of action. A very promising approach is the antiviral screening of products derived from natural sources, such as marine flora and fauna, bacteria, fungi, and higher plants. Among them, marine algae represent one of the richest sources of bioactive compounds, and algae-derived products are increasingly used in medical and biochemical research (Mayer and Lehmann 2000). Research on natural products possessing antiviral activity is mainly focused on low-molecular-weight compounds isolated from plants since they can be selected on the basis of their ethno-medicinal use (Kinghorn 2001). However, some of the aqueous plant extracts used in traditional medicine against viral infection are highly viscous indicating the additional presence of high-molecular-weight compounds. In fact, the first report of the antiviral activity of high-molecular-weight polysaccharides appeared almost 60 years ago (Ginsberg et al. 1947). Seventeen years later, it was demonstrated that heparin can act as inhibitors of herpes simplex virus (HSV) (Nahmias and Kibrick 1964). In recent years, a number of sulfated carbohydrate compounds from marine algae, cyanobacteria, and animal sources were described showing potent inhibitory effects against several human and animal viruses (Luescher-Mattli 2003; Damonte et al. 2004; Arad et al. 2006; Pujol et al. 2007). Sulfated polysaccharides of synthetic origin also have antiviral potency (Witvrouw and De Clercq 1997). Some of these macromolecules are currently undergoing clinical evaluation (Kleymann 2005; McReynolds and Garvey-Hague 2007). They have a promising perspective to be developed into a novel type of antiviral drugs. This review presents an overview of recent preclinical and clinical developments of antivirally active sulfated polysaccharides, with a particular focus on their structures, structure–activity relationships, and mechanisms of action. |
Structural diversity |
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Structural analysis of carbohydrates is recognized as one of the most challenging tasks of glycosciences, given the structural complexity related to the monosaccharide composition, the various isomeric forms, the types of glycosidic linkages, the position and distribution of substituents, and the three-dimensional structures of the molecules (Venkataraman et al. 1999
; Nishimura et al. 2004; Ashline et al. 2005; Laroy et al. 2006). Extensive investigation on polysaccharides from various natural sources showed the presence of several classes of highly interesting macromolecules (Painter 1983; Berteau and Mulloy 2003). Structural features of representative polysaccharide classes possessing antiviral activities are discussed below.
Sulfated polysaccharides from marine algae
Fucan sulfates from marine brown algae usually have complex and heterogeneous structures. Recent studies have also shown that these polysaccharides consistently contain a backbone of either 
-(1
3)-linked or alternating -(13)- and -(14)-linked L-fucopyranosyl residues with sulfate groups at position 4 (Daniel et al. 1999; Chevelot et al. 1999; Patankar et al. 1993; Cumashi et al. 2007) (supplementary Figure 1). This regular backbone is frequently masked by different substituents, such as monosaccharides (galactose, glucose, mannose, xylose, or glucuronic acid), acetyl groups, and/or sulfate esters. The matrix-phase polysaccharides of red seaweeds are linear sulfated galactans, which contain alternating β-(13)-D- and -(14)-galactopyranosyl residues (Percival and Mcdowell 1967; Rees 1969; Painter 1983). These galactans differ in the configuration of the -linked units (supplementary Figure 2). If the configuration is L-type, the polymer is agaran; in the case of D-type, it is carrageenan. Different O-linked groups, such as sulfate esters, methyl ethers, pyruvate acetal, or monosaccharides, usually mask this regular backbone. Some of the -galactopyranosyl units may also occur in the 3,6-anhydro form. The third member of this class is DL-hybrid galactan sulfate, a polymer in which -linked units can have D- and L-configuration in the same molecule (Stortz and Cerezo 2000). Other polysaccharides having potent in vitro antiviral activities include rhamnan sulfates, spirulans, ulvans (supplementary Figure 3), and xylomannan sulfates (supplementary Figure 4).
Sulfated polysaccharides from animal sources
Chondroitin sulfate (CS) and heparin are the two principal antivirally active macromolecules from animal sources. The precursor polysaccharide for heparin contains repeating β-D-glucuronic acid (14) linked to -D-glucosamine (Sugahara et al. 2003; Mulloy 2005). Postpolymerization, enzymes remove N-acetyl and replace with N-sulfate, epimerize glucuronate residues at its C-5 position, and introduce sulfates at 2 and 6 positions (Kusche-Gullberg and Kjellen 2003). The final result of all these transformations is shown in supplementary Figure 5. On the other hand, CS chains are composed of glucuronic acid and N-acetylgalactosamine at alternating positions. Several types of CS chains can be distinguished based on the disaccharide units characterized by sulfate groups at specific positions and the presence of gluco-/iduronic acid residues (Figure 1). Recently, a β-D-(13) linked galactan sulfate from Meretrix petechialis (a marine clam) with antiviral activity has been reported (Amornrut et al. 1999).
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Chemically modified compounds
Chemical structures of selected naturally occurring polysaccharides, such as cellulose, curdlan, dextran, xylan, and others that have been chemically modified by sulfation, have been reviewed (Kennedy and White 1988
; Witvrouw and De Clercq 1997). Low-molecular-weight compounds such as highly sulfated mannose-containing oligosaccharides and sulfated polymannuronates with a defined structure (supplementary Figure 6) also have potential antiviral activity. Recently a novel strategy that uses heparan sulfate (HS) biosynthetic enzymes to generate biologically active polysaccharides and oligosaccharides has gained momentum (Munoz et al. 2006; Chen et al. 2007; Linhardt and Kim 2007; Xu et al. 2008). |
Structure–activity relationships |
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 TopAbstractIntroductionStructural diversity Structure-activity relationships Mechanism of action against...Mechanism of action against...Clinical applicationsConclusionsSupplementary DataFundingReferences |
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Research over the last 20 years has shown that sulfated polysaccharides possess a broad spectrum of antiviral activities in vitro (supplementary Tables 1–5). The huge structural diversity of these macromolecules, however, has given a major hindrance in the establishment of their structure–activity relationship. Nevertheless, on the basis of the accumulated data, several common structural motifs emerge that are highly suggestive to possess general importance for antiviral activity.
Degree of sulfation has a major impact on the antiviral activity of polysaccharides
The bulky acidic sulfate substituents that dominate the physical characteristics of polyanions can equally dominate the effects of such macromolecules in biological systems. Indeed, the important parameter for the antiviral activity is the degree of sulfation (DS) of the polymer (i.e., the number of sulfate groups per monosaccharide residue). For a particular class of semisynthetic polysaccharides (e.g., sulfated cyclodextrins), it is well documented that the higher the DS, the better its antiviral potency (Witvrouw and De Clercq 1997). The general validity of this finding can be proven with naturally occurring sulfated polysaccharides of particular classes, such as carrageenans, fucans, or others, provided they show distinct structural similarities (Figure 2A). Interestingly, antiviral potencies amongst sulfated polysaccharides of a given class with similar degree of sulfation, but of different origin, may vary significantly. For example, the antiviral activity of carrageenan fractions derived from Callophyllis variegate (Rodriguez et al. 2005), Gigartina skottsbergi (Carlucci et al. 1997), Gymnogongrus griffithsiae (Talarico et al. 2004), and Meristiella gelidium (Tischer et al. 2006), which all possessed a similar sulfate content (approximately 50 mol%), was individually different (Figure 2B). On the other hand, the antiviral IC50 values (herpes simplex virus type 1, HSV-1), fractions obtained from the same algal species (Carlucci et al. 1997), correlated well with their charge density (Figure 2A). Although there are clear links between algal species and polysaccharide classes, the finer structural details differ between certain classes of polysaccharides isolated from different species (Lahaye 2001). Against this background, it seems not surprising that IC50 values for various animal viruses can differ to markable extents regarding agaroids and carrageenans with equal charge density (supplementary Table 1). Again, amongst carrageenans, the 
-type is more effective than 
/
- and µ/
-type (Carlucci et al. 1997). The increased activity for the -type (IC50 lower than 1 µg mL–1 for HSV-1 and HSV-2) compared to the -carrageenan (IC50 = 1.6–4.1 µg mL–1) can be correlated with DS values. For sulfated fucan-containing fractions (Ec and Ea) of Leathessia difformis, the activity against HSV-1 is proportional to the sulfate content. Recently, it was shown that the antiherpetic activity of several other families of polysaccharides such as spirulan, agaran, fucan, xylomannan, and their desulfated and furthersulfated derivatives, is largely dependent on the presence of sulfate groups (Adhikari et al. 2006; Chattopadhyay et al. 2007, 2008; Lee et al. 2007; Mandal et al. 2007, 2008) (Figure 3). As seen from a structural point of view, a highly charged molecule is more likely to interfere efficiently with electrostatic interactions between the positively charged region of a viral glycoprotein and the negatively charged HS chains of the cell-surface glycoprotein receptor. In general, sulfated polysaccharides with a sulfate content higher than 20 (mol%) have a clear tendency to show an antiviral activity (supplementary Tables 1 and 2). The distribution of sulfate groups seems also important since a low degree of sulfation does not necessarily eliminate the possibility of highly charged zones in the polysaccharide backbone.
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Polysaccharides containing high amounts of uronic acid residues, such as alginic acid and pectin, show very little antiviral activity, which stands in contrast to other polyanionic compounds. For example, while the uronofucan fractions from Adenocystis utricularis (5–12% of sulfate and 22–42% of uronic acid) contain very little antiviral activity (IC50 values >100 µg mL–1 for HSV-1 and HSV-2), the galactofucan fractions (21–24% of sulfate and 4–7% of uronic acid) from the same seaweed showed a strong activity (Ponce et al. 2003
) (IC50 values of 0.28–0.87 and 0.52–1.36 µg mL–1 for HSV-1 and HSV-2, respectively). Similarly, a high uronic acid/low sulfate fraction (F1M) obtained by anion-exchange chromatography from galactofucan sulfate of Undaria pinnatifida is less active (IC50 values of 4.6, 1.0, and 4.0 µg mL–1 for HSV-1, HSV-2, and human cytomegalovirus [HCMV], respectively), than that of the low uronic acid/high sulfate fraction (F2M) having higher efficacy (IC50 values of 1.1, 0.1, and 0.5 µg mL–1, respectively) (Hemmingson et al. 2006). Therefore, with regard to antiviral potency, the polyanionic nature of a polysaccharide is an absolutely critical factor. In addition, the type of the anionic group is also important. Sulfates are in many cases required for activity, whereas carboxyl groups generally do not promote antiviral activity. Thus, the antiviral activity is not merely a function of high charge density, but has distinct structural specificities.
Specific positioning of sulfates might be important for antiviral activity
In addition to the well-documented DS dependence, the specific position of the sulfate ester group appears to be additionally important for the antiviral activity of sulfated polysaccharides. This can be demonstrated by using selectively sulfated type E chondroitin sulfates (CS-E). Research data showed that CS types A, B, C, and D exhibited either little or no antiherpetic activity (Banfield et al. 1995; Marchetti et al. 2004) while CS-E isolated from squid cartilage exhibited potent antiviral activity (Bergefall et al. 2005). The specific positioning of sulfates (at positions 4 and 6) in the predominant CS-E disaccharide unit (Figure 1) can explain this surprising inhibitory effect on HSV-1 infection. The squid cartilage CS-E chains also contain an extra sulfate group at position 3 of glucuronic acid (GlcA) residue. As up to 10% of GlcA residues can be 3-O-sulfated, the CS-E chains may possess a domain-like structure with specific positioning of trisulfated disaccharide units relative to disulfated units (Kinoshita et al. 1997, 2001). However, one cannot exclude that in addition to the specific position, the extensive sulfation of CS-E might contribute to its antiherpetic activity. Another study (Carlucci et al. 1997) showed that the antiherpetic activity of natural carrageenans is directly correlated to the amount of -D-galactose 2,6-disulfate residues, supporting the possibility that the specific sulfation of galactose residues might be important. The results from a more recent study revealed that a 3-O-sulfated octasaccharide generated from heparin using an enzymatic approach has stronger activity in blocking HSV-1 infection than that of the 3-OH octasaccharide (Copeland et al. 2008). Therefore, the inhibition of HSV-1 infection requires a specific sulfation pattern.
Thus, modifications of the sulfation pattern may generate activities which normally require higher DS. However, it should be mentioned that there is no general pattern as in which position sulfate groups exert the most pronounced antiviral activity, although it appears that the positioning of the O-sulfates on specific sugars is important. Hereby, the density of sulfate groups on sugars in a particular class of polysaccharide appears to be mostly critical. Sulfated polysaccharides containing 35–60 sulfate groups (in the case of sulfated polysaccharides from seaweed) per hundred sugar residues provide the best antiviral activity (supplementary Tables 1 and 2). In the case of semisynthetic sulfated compounds, polymers containing one and two sulfate groups per monosaccharide residue appear to be optimal (supplementary Table 4).
Molecular weight contributes to antiviral activity
Usually an antiviral activity of sulfated polysaccharides correlates with the molecular mass of the chain. The higher the average molecular weight (MW), the higher is the antiviral activity in many cases. When various fractions of semisynthetic glucan sulfates with MWs ranging from 1 to 500 kDa were examined for their antiviral activity, it was found that the higher MW fractions were more effective than the lower ones (Witvrouw and De Clercq 1997). Above 
100 kDa, no further increase in activity was observed. This correlation that is valid for semisynthetic sulfated polysaccharide can also be extended to naturally occurring sulfated polysaccharides (Figure 4). In some cases, the effect of the chain length might overcome that of charge density. For example, CS-E blocked HSV-1 entry into cells at substantially lower concentrations (IC50 = 0.06 to 0.2 µg mL–1) than standard heparin (IC50 = 1.0–0.8 µg mL–1) (Bergefall et al. 2005). Although the DS of CS-E chains (1.7 sulfates/disaccharide) is smaller than that of heparin (2.7 sulfates/disaccharide), the chain length of CS-E (70 kDa) is much larger than that of heparin (12.5 kDa). This illustrates that the chain length is an important parameter for antiviral potency. The variation of MW amongst sulfated polysaccharides and their antiviral potency is given in supplementary Tables 1–4.
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In some cases, low-molecular-weight-sulfated carbohydrates can also possess a strong antiviral activity, particularly when the sulfate content is high. The linear β-(1
4)-polymannuronate-derived sulfated oligosaccharides (SPMG) with approximately three sulfates per disaccharide showed size-dependent binding to human immunodeficiency virus type 1 (HIV-1) glycoprotein gp120 (Liu, Geng, et al. 2005). However, a certain minimum chain length is required for any of these compounds to show antiviral activity: fragments containing two to five monomeric residues exhibited low binding capacity to recombinant gp120, whereas a 3-fold to 4-fold increase in capacity was observed from hexa- to octasaccharides. This supports the hypothesis that antiviral activity correlates positively with MW even for low-molecular-weight compounds. Importantly, the octasaccharide seems to be the optimum size requirement for inhibiting HIV-1 infection, whereas a 19–20 saccharide fragment displays similar inhibitory potency as native SPMG. These authors used a competitive inhibition assay together with stoichiometric analysis and concluded that sugar chains longer than 15–16 saccharide residues display multivalent interactions with gp120 molecules while shorter sugar chains only bind two to three gp120 molecules. The second example is the HS-mimetic, PI-88, which is a mixture of highly sulfated (3 sulfates/disaccharides) mannose-containing oligosaccharides (supplementary Figure 6) (Ferro et al. 2002). Although the DS of PI-88 is very high, because of its low MW, the inhibitory activity is weak (IC50 = 6 µg mL–1) in comparison to large polysaccharides (IC50 = 1 µg mL–1). This confirms that a certain minimum chain length is necessary for the antiviral activity of specific compounds (Nyberg et al. 2004). This concept also implies that a larger chain is more likely to recognize and interact with numerous copies of the viral attachment protein(s) and possibly has the ability to cross-link virions. Exceptions from this rule are some low-molecular-weight compounds, such as heparin-derived oligosaccharides (DP 10–12), pentosan polysulfates (3 kDa), dextran sulfates (5 kDa), and PI-88 analogs, still possessing an antiviral activity which is obviously based on other determinants than MW (Feyzi et al. 1997; Ekblad 2007). An alternative way of small-molecular-weight compounds to express antiviral activity may be the formation of a higher order structure, such as helixes, that may recognize complementary regions on target proteins. Albeit, for a great number of antiviral macromolecules, a certain minimum charge density as well as a certain minimum chain length seems to be essential. Hereby, their threshold values are variable and may relate to basic structural features.
Low-molecular-weight compounds inhibit cell-to-cell spread of viruses more efficiently
A rapid cell-to-cell spread of viruses is of pivotal importance for the efficiency of viral dissemination in the host organism and thus to establish productive infections in humans. The inhibition of viral spread may require the penetration of a compound into a narrow intercellular space, and hence the size of the compound is frequently a limiting factor. As an example, the low-molecular-weight compounds, PI-88 (2.4 kDa) and its analogs, substantially reduce intercellular transmission of HSV-1 (Nyberg et al. 2004; Ekblad 2007). Also in support of this hypothesis, the high-molecular-weight polysaccharide compounds heparin (15 kDa) and chondroitin sulfate E (70 kDa) are known to affect cell-to-cell spread of HSV-1 only inefficiently, albeit these compounds are potent inhibitors of infectivity through other mechanisms.
Effect of counter cations
A recent study has demonstrated that the nature of the counter cations of anionic sites such as sulfate groups of polyanions play an important role in controlling antiviral activity (Lee et al. 2001). For example, Na-spirulan exhibited potent antiherpetic activity but with the replacement of Na+ by another cation, such as Ag+or Cd2+, the antiviral potency of this polymer remarkably decreased (Figure 5).
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Hydrophobic and hydrogen bonding interactions
Sulfated acylated polysaccharides have been shown to have potent antiviral activity. For example, Yamada and co-workers (2000
) reported that the low-molecular-weight O-acylated derivatives of - and -carrageenans prepared from native polysaccharides increase the anti-HIV-1 activity of the polysaccharides, while minimizing the native anticoagulant properties. It was also observed that the butanoylated derivatives with 0.55–0.70 mol of butanoyl and 1.5 mol of sulfate per monosaccharide residue of -carrageenan showed a higher antiviral activity (IC50 = 3.9 µg mL–1) than dextran sulfate (IC50 = 7.8 µg mL–1).
Sulfated oligosaccharides, having a linear or branched alkylated group as aglycon, also possess potent antiviral activity (Katsuraya et al. 1994, 1999; Ekblad 2007). These compounds were prepared by glycosylation of oligosaccharides with a variety of linear, branched, or cyclic aliphatics followed by sulfation of the generated glycosides. The lipid chain was attached to create surface-active agents whereby the alkyl chains coalesced. All of the sulfated alkyl oligosaccharides evaluated had good anti-HIV-1 activity. Interestingly, the length of the alkyl chain correlated with unwarranted cytotoxicity, with longer chains giving higher cytotoxicity than shorter ones. Moreover, more hydrophilic chains typically were associated with a lower anti-HIV-1 activity (18–110 µg mL–1) compared to long, branched or cyclic chains with a higher anti-HIV-1 activity (0.24–0.97 µg mL–1). The most active compound in this series was a laminarapentaoside with a cholesterol aglycone. Terada and co-workers (2005) studied the HIV-1-inhibiting potency of alkylated polysulfated sialic acid derivatives. While the correlation of the methyl group or linear chains with antiviral activity was low (no activity with the methyl group, and IC50 = 139 µM with the linear chain), branched chains possessed a high activity (IC50 1–10 µM). However, a decrease in antiviral activity was observed for chains containing 26 or more methylene units. The study by Katsuraya and co-workers (1999) showed that sulfated butylated lamina-oligosaccharides containing four glucose residues had only one thirtieth of the anti-HIV activity of the sulfated pentasaccharide (IC50 values of 43 and 3.4 µg mL–1, respectively). Thus, here again, it is suggestive that a certain minimum chain length is required for these compounds to exhibit antiviral activity.
In conclusion, the studies on structure–activity relationships of sulfated polysaccharides with high antiviral activity demonstrated that the antiviral activity of the sulfated polysaccharides varies both quantitatively and qualitatively in dependence on their structure.
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Mechanism of action against herpes simplex virus |
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The entry of HSV into host cells is a complex process initiated by the specific interaction between host-cell-surface receptors and viral envelope glycoproteins (Schneider-Schaulies 2000
; Spear 2004; Kleymann 2005; Olofsson and Bergstrom 2005). All hitherto investigated human herpesviruses, i.e., HSV-1, HSV-2, varicella–zoster virus (VZV), human cytomegalovirus (HCMV), human herpesvirus (HHV)-7 and HHV-8, except Epstein–Barr virus (EBV), may utilize cell-surface HS chains for primary attachment (WuDunn and Spear 1989; Neyts et al. 1992; Secchiero et al. 1997; Trybala et al. 2002; Akula et al. 2001). Bergefall et al. (2005) analyzed cell lines deficient in the expression of glycosaminoglycans (GAGs) and postulated that HSV-1 glycoprotein C (gC) binds to chondroitin sulfate (CS, characterized by E disaccharide units) and that the CS-E unit is an essential component to function as a HSV-1 receptor. More recently, this group showed that chondroitin 4-O-sulfotransferase-1 regulates the E disaccharide expression of chondroitin sulfate required for HSV-1 infection (Uyama et al. 2006). In the case of HSV-1 and HSV-2, attachment to HS seems to be primarily mediated through glycoprotein C (gC) although glycoprotein B (gB) may contribute to this function (Herold et al. 1991, 1994; Cheshenko and Herold 2002). Following HS binding, secondary entry receptors are recognized in a cell-type specific manner, before virus entry requires the activity of another glycoprotein (gD). gD can interact with the herpesvirus entry mediator (HVEM, a member of the tumor necrosis factor receptor family), with nectin-1 and nectin-2 (two related members of the immunoglobulin superfamily) and, additionally, with specific sites in HS generated by certain 3-O-sulfotranferases (Montgomery et al. 1996; Geraghty et al. 1998; Spear and Longnecker 2003; O’Donnell et al. 2006; Xu et al. 2005). The gD interactions possibly trigger conformational changes in viral gB and gH/gL components thus initializing fusion between the viral lipid envelope and cell plasma membrane (Spear 2004; Perez-Romero et al. 2005). Subsequently, viral capsids and teguments proteins are released into the cytoplasm of the host cell. Alternative pathways of HSV-1 entry into the cell can occur in some cell-types through endocytosis. Endocytosed HSV-1 fuses with the endosomal membrane instead of the cytoplasmic membrane (Nicola et al. 2003). By using a second entry pathway, viral glycoproteins can mediate HSV-1 entry via the apical cellular surface in the form of a cell-to-cell spread, i.e., the movement of virions across the narrow space between infected and adjacent uninfected cells (Cocchi et al. 2000; Kusche-Gullberg and Kjellen 2003).
The receptor-binding site of viral glycoproteins
HSV gC (designated gC1 and gC2 for HSV-1 and HSV-2, respectively) is a type 1 membrane glycoprotein that contains 511 (gC1) or 480 (gC2) amino acids and exhibits 65% identity in the primary amino acid sequences between gC1 and gC2 (Swain et al. 1985). Although the receptor-binding motifs of gC have not been completely elucidated yet, it is well documented that gC1 has nine sites for N-linked oligosaccharides and numerous sites for O-linked glycans. The latter are clustered at the N-terminal part of the protein, which make this region structurally similar to mucins. The mucin-like region is not present in gC2. The eight cysteins in gC1 form four disulfide bonds (Rux et al. 1996). Clusters of basic and hydrophobic amino acids located between residues 129 and 160 of gC1 (Trybala et al. 1994; Mardberg et al. 2001, 2002) as well as the mucin-like region (amino acids 33–123) of this protein (Tal-Singer et al. 1995) were identified as important for HSV-1 attachment to cell-surface HS/CS.
HSV-1 gB1 consists of 904 amino acids, and approximately 85% of the sequence is homologous to its HSV-2 counterpart (Heldwein et al. 2006). Most of the variability between gB1 and gB2 is seen in a lysine-rich region (amino acids 68–76), which is also responsible for binding to HS (Laquerre et al. 1998). gB1 occurs as a trimer with each of the monomers divided in five distinctive domains: I base, II middle, III core, IV crown, and V arm (Heldwein et al. 2006; Figure 6). The results from a more recent study suggest that specific hydrophobic/aromatic amino acids from domain I are important for the fusogenic activity of gB (Hannah et al. 2007).
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Cell-surface glycosaminoglycan receptors
Heparan sulfate, an endogenous ligand for many viral proteins, is initially synthesized as a copolymer of alternating (1
4)-linked β-D-glucuronic acid and N-acetylated -D-glucosamine, and then undergoes various modifications in the Golgi apparatus (Esko and Lindahl 2001; Lindahl et al. 1998). These modifications include N-deacetylation and N-sulfation of glucosamine, C5 epimerization of glucuronic acid to form iduronic acid residues, 2-O-sulfation of iduronic and glucuronic acid residues, as well as 6-O-sulfation and 3-O-sulfation of glucosamine residue (Gorsi and Stringer 2007). HS chains can provide specific binding sites for various proteins, exemplified by binding of HSV-1 gB that depends on the presence of one or more 6-O-sulfate and 2-O-sulfate groups, and gD that requires a HS chain modified by 3-O-sulfotransferases isoforms II–VI (Shukla et al. 1999; Xia et al. 2002; Chen et al. 2003; Tiwari et al. 2005; Xu et al. 2005 O’Donnell et al. 2006). A gD binding octasaccharide motif (Liu et al. 2002) and a gC binding N-sulfated dodecasaccharide motif (Feyzi et al. 1997) were characterized confirming that HSV-1 utilizes a unique HS sequence for its entry. The structural motifs of the glycoepitopes on HS chains are given in Figure 7. Recent results from cell-based assays revealed that the inhibition of HSV-1 infection requires a unique sulfation moiety (Copeland et al. 2008).
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Sulfated polysaccharide acts through complex processes
An attractive concept is that sulfated polysaccharides act as antiviral agents in cell culture due to the fact that these charged polymers may mimic HS chains on cell-surface proteoglycans and thus block viral attachment by competitive inhibition. A novel approach to inhibiting HSV-1 infection by targeting the gD-mediated membrane fusion step has recently been described (Copeland et al. 2008
). This inhibition was achieved by using a unique 3-O-sulfated octasaccharide, which was generated from heparin using an enzymatic approach. The results of this study also demonstrate that the inhibition of HSV-1 can be blocked by saturating the viral envelope glycoprotein gD using a small molecule of defined structure. The antiherpetic properties of sulfated polysaccharides may depend not only on their charge density but also on the characteristics of their uncharged portions which may be involved in hydrophobic and hydrogen bonding interactions. Mardberg and co-workers (2001) reported that hydrophobic interactions, in addition to electrostatic forces, are decisive for the CS as well as HS binding to viral glycoprotein gC. It has been suggested that sulfated carbohydrates can elicit profound conformational changes in hydrophobic regions of proteins and cause disassembly of complex proteins consisting of subunits (Sedlak and Antalik 1998). Therefore, the interaction of the methyl groups of fucoidan with the hydrophobic pocket of HSV-1 gC seems to be important in the binding of the polysaccharide to the viral glycoprotein. While sulfated oligosaccharide chains can bind to and block the viral attachment/receptor-binding proteins, it was speculated that for this class of viral inhibitors the hydrophobic group might additionally insert into the viral lipid envelope (Uryu et al. 1992). This might lead to a destabilization and irreversible inactivation of the virion.
Finally, in addition to the polysaccharide-mediated antiviral effects directed to the cell surface (viral receptor binding, entry, fusion), a second type of effects may play a role, i.e., the induction of intracellular events contributing to the antiviral activity of sulfated polysaccharides. As the binding of a number of known polysaccharides to cell-surface receptors can induce intracellular signaling pathways, this second type of effects should be additionally taken into consideration. As an example, the anticytomegaloviral effect of spirulan-like polysaccharides was demonstrated to be composed of these two antiviral activities, i.e., an inhibition of HCMV entry on the one side in addition to the induction of intracellular anti-HCMV effects on the other side (Rechter et al. 2006). Due to the fact that the replication efficiency of most viruses is dependent on specific intracellular signaling pathways, the inhibition or the induction of particular signaling of surface-binding polysaccharides can provide a significant part of the overall antiviral activity. One explanation for such intracellularly produced activity is the stimulatory effect of sulfated polysaccharides onto interferon production with the consequence of a broad antiviral effect.
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Mechanism of action against human immunodeficiency virus type 1 |
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HIV-1 infection is a multistep process beginning with the attachment of the virion to cell surfaces and entry into lymphoid target cells. In several cell types, including CD4+ helper T cells, macrophages, and dendritic cells (Balzarini and Van Damme 2007
; McReynolds and Garvey-Hague 2007; Nikolic et al. 2007), the virus can establish productive or persistent infection. During virus spread, HSV-1 virons are attached via their envelope gp120 glycoprotein to the CD4 surface protein of T-lymphocytes in conjunction with a chemokine (CXCR4 or CCR5) coreceptor. The formation of a ternary complex between gp120 and the receptor/coreceptor triggers the fusion between the virion and cytoplasmic membrane, a step mediated by viral gp41. Fusion is followed by the internalization of the virus and particularly the viral genome into the nucleus of the target cell (Moore and Stevenson 2000). Besides CD4 and chemokine receptors, attachment determinants of the cell surface play a role in viral infection. For example, HIV-1 can bind to cell-surface heparan sulfate proteoglycans via the polybasic V3 loop of gp120 (Roderiquez et al. 1995). This is a sequential process in which HS first binds through a high-affinity, selective interaction with the V3 loop on gp120, followed by a second, lower affinity interaction with the conserved chemokine coreceptor region of gp120 (Moulard et al. 2000). Other studies have shown that HS can compensate for low levels of CD4 in macrophages, thus regulating HIV-1 infection in these cells (Saphire et al. 2001). A recent study by de Parseval and co-workers (2005) highlighted a single highly conserved amino acid in the V3 loop, Arg 298, and its importance in binding to both HS and CCR5. The interesting and perhaps most significant, aspect of the findings in this study was that a specific sulfation motif of HS was preferred, 6-O-sulfation, indicating that random sulfation or negative charges were not sufficient to yield a strong binding event between the virus and the host cell.
One of the important questions regarding viral envelope proteins is what are their finer structural details and recent X-ray crystallographic studies have provided a complete picture of the gp120 structure (Chen et al. 2005; Huang et al. 2007). Huang and co-workers (2005) reported the structure of HIV-1 gp120, complexed to CD4 and the X5 antibody, whereby the V3 loop structure was maintained (Figure 8). This was an important finding, as it confirmed the role of the V3 loop in HIV-1 entry, providing critical structural information about a region that is prone to mutation.
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Numerous investigations on the mechanism of action of sulfated polysaccharides have been conducted for HIV-1. Sulfated polysaccharides can block viral entry into host cells by interfering with the attachment of virus to the cell-surface receptors. These macromolecules may exert their anti-HIV-1 activity by shielding off the positively charged amino acids present in the viral envelope glycoprotein gp120 (Harrop and Rider et al. 1998
; Moulard et al. 2000). gp120 has several highly basic regions, most notably, the V3 loop, which can interact with polyanionic regions of host-cell-surface molecules (Vives et al. 2005). |
Clinical applications |
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Many researchers have conducted in vivo studies on the bioavailability of sulfated polysaccharides. It has been observed that the in vivo effectiveness of oral administration of dextran sulfate to HIV-1 was disappointing (Flexner et al. 1991
). But, in an open phase I/II dose-escalation study, in which six AIDS patients were treated with i.p. administration of dextrin 2-sulfate, there was a significant decrease in viral load (Shaunak et al. 1998). Data from a more recent clinical study suggest that dextran sulfate is absorbed rapidly in humans after oral administration. Curdlan sulfate (CRDS), another potent anti-HIV-1 polysaccharide was found to produce a marked dose-related increase in CD4+ lymphocytes (Gordon et al. 1994, 1997). This increase mainly returned to baseline after 24 h. In the later study, these authors found that after 21 days of intravenous administration at three dose levels of CRDS in HIV-1- and HCMV-infected individuals, 12 out of 21 patients tested were negative for HCMV.
Low-molecular-weight anionic compounds generally seem to possess a better bioavailability than high-molecular-weight compounds. Indeed, the smaller size of the highly sulfated mannose-containing oligosaccharides (PI-88) may account for their in vivo biological activity (Lee et al. 2006). SPMG, the alginate-derived sulfated oligosaccharides that are in phase II clinical trial as virucides is another example (Liu, Geng, et al. 2005; Hui et al. 2006).
Side effects
The major undesirable side effect of sulfated polysaccharides is their well-known anticoagulant activity. This adverse effect can be avoided by selecting sulfated polymers, such as fucoidan, galactan, spirulan, xylomannan, and heteroglycan, that have no discernible anticoagulant activity at the therapeutically administrable doses (Hayashi et al. 1996; Ghosh et al. 2004; Adhikari et al. 2006; Chattopadhyay et al. 2007, 2008; Mandal et al. 2007, 2008). Among anionic polysaccharides, soluble cellulose acetate phthalate, a potential candidate as microbicide, had a minimal effect on plasma coagulation (Neurath, Strick, Li, et al. 2002).
Cytotoxicity at the site of administration is a common problem with the use of low-molecular-weight compounds with virucidal effects. This may be explained by the unwarranted detergent effect of these compounds toward both, viral and cellular membranes. The adverse interaction of polysaccharide compounds with other medications is rather unlikely due to the relatively large size of the polysaccharides and their inefficient resorption into the body. For this reason, topical administration of polysaccharide compounds seems generally much more promising than oral/parenteral administration. Indeed, the most active sulfated carbohydrates are able to block in vitro viral infection at a concentration as low as 0.01 µg mL–1, whereas no toxicity to host cells has been detected at concentrations up to 1–2.5 mg mL–1 (supplementary Tables 1, 2, and 4). Therefore, the selectivity index and hence the antiviral potency of these compounds are very high.
Drug resistance
Sulfated polysaccharides may inhibit the attachment of viruses with target molecules on the cell surface. The viral attachment peptides are highly conserved regions within rather variable scaffolds of viral surface glycoproteins. These peptides are only poorly subject to alterations by the natural antigenic drift of viruses. Likewise, they are not expected to represent frequent sites of drug-induced resistance mutation. Sulfated polysaccharides that are directed toward these target peptides are therefore preferred candidates for antiviral drug development. Moreover, sulfated carbohydrates showed in vitro antiviral activity against virus mutants resistant to nucleoside analogs (Adhikari et al. 2006; Chattopadhyay et al. 2007; Mandal et al. 2007, 2008). Further research is certainly needed to address other open questions of polysaccharide-induced resistance of viruses.
Virucidal activity
The virucidal activity of compounds is highly relevant for their antiviral activity in vivo. For example, -carrageenan showed an irreversible, virucidal mode of action against HSV-1 probably due to its high affinity binding to the virion and exhibited antiherpetic activity in laboratory mice (Carlucci et al. 1997). Other such polysaccharides include dextrin-x-sulfate (DxS, ML Laboratories, UK), cellulose acetate phthalate (CAP), galactan sulfates from Grateloupia longifolia and Grateloupia filicina (Wang et al. 2007) and a linear β-(13) and (14) linked sulfated glucan from Avena sativa bran (Wang et al. 2008). In comparison with other antivirally active sulfated polysaccharides, heparin does not inactivate HSV-1 virions and does not show an interaction with virion components in an irreversible, virucidal way.
Polysaccharides as microbicides
Microbicides are compounds that applied vaginally or rectally and protect the user from sexually transmitted infections. Polyanions are one of the most studied microbicides. This group of potential microbicides includes cellulose sulfate, dextran/dextrin sulfates, carrageenan, and cellulose acetate phthalate.
Carraguard®, the Population Council's lead candidate microbicide, is a sulfated polysaccharide containing a mixture of - and -carrageenan (Coggins et al. 2000; Kilmarx et al. 2006). In contrast to detergents and pH-buffering agents (two other classes of microbicides), Carraguard has not demonstrated contraceptive properties, a possible advantage in situations where protection against pathogens, but not contraception, is desired.
DxS is a synthetic sulfated polysaccharide ( 20 kDa), whose antiviral activity is distinct from related dextran sulfate (Javan et al. 1997; Shaunak et al. 1994, 2003). These macromolecules have shown varying levels of protection against a simian human immunodeficiency virus 89.6 (SHIV-89.6) vaginal challenge in the rhesus macaque model (Veazey et al. 2005). A recent study showed that DxS are active against R5 virus in cellular and tissue models (Fletcher et al. 2006). AusAm Biotechnologies is considering phase I clinical trials in the herpes indication with DES-6, a sulfated dextran derivative (Kleymann 2005).
A number of studies have demonstrated the efficiency of CAP as a topical microbicide (Orozco-Topete et al. 1997; Gyotoku et al. 1999; Kawamura et al. 2000; Neurath et al. 2001; Neurath, Strick, Jiang, et al. 2002; Neurath, Strick, Li, et al. 2002). CAP is not soluble at pH <5.5, normal for microbicide target sites. Micronized CAP is the only candidate topical microbicide with the capacity to remove rapidly by adsorption from physiological fluids HIV-1 of both the X4 and R5 biotypes and is likely to prevent virus contact with target cells. The interaction between micronized CAP and HIV-1 leads to rapid virus inactivation. In contrast to sulfated polysaccharides, CAP had a minimal effect on plasma coagulation.
Finally, cellulose sulfate (Ushercell, Polydex Pharmaceuticals, Ontario, Canada) was tolerated in phase I and II studies (Balzarini and Van Damme 2007; Nikolic et al. 2007). This sulfated polysaccharide exhibits a broad spectrum of activity against Chlamydia trachomatis, Gardnerella vaginalis, Gradnerella vaginalis, Neisseria gonnorhoeae, and human papilomavirus (McReynolds and Garvey-Hague 2007).
The phase III clinical trial of candidate microbicides, Carraguard, and cellulose sulfate did not show that these compounds are effective in preventing HIV transmission (Cohen 2008; Population Council 2008). Therefore, for the next generation of microbicide candidates, more emphasis must be placed on the selection of only the most potent compounds prior to commencing a clinical trial process that moves inexorably toward phase III efficacy trials. In this respect, the R5 SHIV vaginal challenge model in nonhuman primates (Lederman et al. 2004; Veazey et al. 2005) provides the most relevant and stringent available test of how a product might perform in humans. This model is a vitally important tool when rational choices between candidates and formulations must be made. Had the current generation of microbicide products undergone challenge studies in the primate model, fewer might have failed in efficacy trials in humans (Shattock and Doms 2002). Next generation concept now in or approaching clinical trials offer improved prospects for efficacy. The most plausible approach involves a combination of several drugs, preferentially targeting different steps in the viral infection process. Because sulfated polysaccharides are safe and acceptable (Bollen et al. 2008; Kilmarx et al. 2008; van der Straten et al. 2008), development of several second-generation combination formulation based on first generation lead candidates may be more effective (Liu, Lu, et al. 2005; Brache et al. 2007; Gantlett et al. 2007; Klasse et al. 2008). PC-815, a novel combination microbicide containing carrageenan and the nucleoside reverse transcriptase inhibitor MIV-150, is one such second-generation microbicide. Pharmacological testing conducted in vitro indicated that PC-815's activity against HIV-1 is significantly higher than the activity of Carraguard alone (Fernandez-Romero et al. 2007). Because Carraguard and MIV-150 have different mechanisms of action against HIV-1 when formulated into PC-815, there is an additive effect in activity. Similarly, the combination of CADA with CAP resulted in a synergistic inhibition of HIV-1 and SIV infection (Vermeire et al. 2008). How these inhibitors are applied may also be critical, with sustained release formulations and vaginal ring delivery systems (Woolfson et al. 2000, 2006; Malcom et al. 2005) now becoming a high priority.
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Conclusions |
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Recent structural studies showed that sulfated polysaccharides represent a group of macromolecules possessing more properties in common than previously thought. These macromolecules have a variety of antiviral properties, particularly due to their ability to imitate patterns of sulfate substitution on GAGs present in cell membranes. Because the structures of sulfated polysaccharides are complex and heterogeneous and as many studies of antiviral activity were carried out using relatively crude polysaccharide preparations, it is presently not easy to determine the overall relationship between activity and structure. However, the results of many studies demonstrate that the antiviral activity of sulfated polysaccharides is not merely a function of high charge density and chain length but also distinct structural characteristics. Generally, high-molecular-weight polysaccharides appear to possess the most pronounced inhibitory activity toward viral receptor binding and entry. With respect to the bioavailability and the cell-to-cell spread of virions, however, low-molecular-weight compounds appear to be superior to their high-molecular-weight counterparts. Investigations of the mechanism of action revealed that viral adhesion, transport, and entry into host cells are complex processes mediated by proteins, glycans, and lipids, which all may be subject to inhibitory effects mediated by sulfated polysaccharides. In addition, there are a number of further mechanisms of the antiviral activity of sulfated polysaccharides. Combined modes of antiviral action displayed by polysaccharide compounds are mainly determined by molecular weight, structure, and sulfation.
Recent studies demonstrated that sulfated polysaccharides could be used as a vaginal antiviral formulation without disturbing essential functions of the vaginal epithelial cells and normal bacterial flora. Although the first generation of candidates was considered to be only poorly effective in preventing HIV-1 transmission, the second generation of combinations of compounds, possibly combining two or more polysaccharides with mechanistically different antiviral activities, may be potentially more effective for controlling viral infection and pathogenesis. It will be a continuous challenge to select the most promising drug candidates among the wide array of available polysaccharide compounds. The numerous advantages over other classes of antiviral drugs, such as relatively low production costs, broad spectrum of antiviral properties, low cytotoxicity, low induction of viral drug resistance, high lyophilicity, safety, wide acceptability, and novel modes of action, suggest sulfated polysaccharides as promising drug candidates in the near future.
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Supplementary Data |
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Supplementary data for this article is available online at http://glycob.oxfordjournals.org/.
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Funding |
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Department of Science and Technology, New Delhi, India to B.R.
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Acknowledgements |
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We acknowledge the advice and encouragement from Prof. Dr. Mark A. Lehrman during the preparation of this manuscript. T.G. thanks CSIR for a fellowship.
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Footnotes |
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2 These authors equally contributed to this work.
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Abbreviations |
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AIDS, acquired immunodeficiency syndrome; CAP, cellulose acetate phthalate; CC50, cytotoxic concentration 50%; CS, chondroitin sulfate; DP, degree of polymerization; DS, degree of sulfation; GAG, glycosaminoglycan; gB, glycoprotein B; gC, glycoprotein C; gD, glycoprotein D; GlcA, glucuronic acid; gp, glycoprotein; HCMV, human cytomegalovirus; HHV, human herpesvirus; HIV, human immunodeficiency virus; HS, heparan sulfate; HSV, herpes simplex virus; HVEM, herpesvirus entry mediator; IC50, inhibitory concentration 50%; MW, molecular weight; PH, pleckstrin homology; RS, rhamnan sulfate; SHIV, simian human immunodeficiency virus; SIV, simian immunodeficiency virus; SP, polysaccharides containing fractions derived from Spirulina platensis; SPMG, sulfated polymannuronate; Tat, transactivator of transcription; TNF, tumor necrosis factor; VZV, varicella–zoster virus
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