**3. Relationship among glycosaminoglycans, carrageenans and viruses**

The discovery that viruses are highly abundant in natural waters initiated renewed research on the impact of viral infection and lysis on aquatic microorganisms [49]. It is believed that viruses influence the composition of marine communities and are a major force behind biogeochemical cycles. Each infection has the potential to introduce new genetic information into an organism or progeny virus, thereby driving the evolution of both, host and virus [50].

The eukaryotic algae represent the oldest known eukaryote for which there exist clear geological data [51] and all classes of algae have their specific DNA virus. The HSV is an ancient DNA virus which is widespread in nature and has coevolved with its hosts. Many viruses interact with their host polysaccharides present on the cell wall; HSV uses HS.

The basic structural motifs and modifications of HS glycosaminoglycans seem to have been conserved for several hundred million years of evolution [52,53].

One suggested explanation is that endogenous heparan sulfate-binding proteins may have developed different binding specificities with evolutionary time. At first glance, this may seem an exception to the suggestion made here, in view that extensive glycan diversification has accompanied species evolution. However, HS can generate numerous intrinsic structural variations, and there are currently inadequate data about the extent of speciesspecific differences in the specificities of the binding proteins and/or the expression of structural motifs in different cell lineages.

540 The Complex World of Polysaccharides

**Hialuronates** 

**Heparan sulfate** 

**Heparin** 

[50].

HS.

**GAG Location Comments** 

**Chondroitin sulfate** cartilages, bone and cardiac

**Dermatan sulfate** Skin, cardiac valves and

**Table 2.** Normal distribution of GAGs in the body.

Synovial fluid, vitreous humor, extracellular matrix with loss of connective tissue (vasculogenesis).

Basal Membrane and components of the cellular surface.

Components of the intracellular granules of the mastocytes, coating of the lung arteries, liver and skin.

blood vessels.

**keratan sulfate** Cornea, bone and cartilage. More abundant GAGs.

**3. Relationship among glycosaminoglycans, carrageenans and viruses** 

The discovery that viruses are highly abundant in natural waters initiated renewed research on the impact of viral infection and lysis on aquatic microorganisms [49]. It is believed that viruses influence the composition of marine communities and are a major force behind biogeochemical cycles. Each infection has the potential to introduce new genetic information into an organism or progeny virus, thereby driving the evolution of both, host and virus

The eukaryotic algae represent the oldest known eukaryote for which there exist clear geological data [51] and all classes of algae have their specific DNA virus. The HSV is an ancient DNA virus which is widespread in nature and has coevolved with its hosts. Many viruses interact with their host polysaccharides present on the cell wall; HSV uses

The basic structural motifs and modifications of HS glycosaminoglycans seem to have been

One suggested explanation is that endogenous heparan sulfate-binding proteins may have developed different binding specificities with evolutionary time. At first glance, this may seem an exception to the suggestion made here, in view that extensive glycan diversification has accompanied species evolution. However, HS can generate numerous intrinsic structural variations, and there are currently inadequate data about the extent of species-

conserved for several hundred million years of evolution [52,53].

Long polymers (containing no sulfates), shockabsorbing.

More sulfated than the Heparan sulfate.

Long polymers (no sulfates), shock-absorbing.

valves. More abundant GAGs.

HS is highly sulfated and it is thought to be the most biologically active GAG. The sulfated monosaccharide sequences within HS determine the protein binding specificity and regulate fundamental biological functions including growth control, signal transduction, cell adhesion, homeostasis, morphogenesis, lipid metabolism and pathophysiology [14]. Numerous viruses including herpesviruses utilize cell surface HS as receptor to infect target cells.

It has been reported that in the course of an inflammation, an infection or tissue damage, the proteoglycan HS is cleaved causing fragments of soluble HS [54]. On the other hand, in healthy tissues, no significant fractions of soluble HS are found, though they can be found in the fluids of damaged tissues –at concentrations within the required ranges to stimulate dendritic cells [55] and in the infected individuals urine [56].

HSV attaches to cells by an interaction between the envelope glycoprotein C and cell surface HS. The virus-cell complex is formed by ionic interactions between the anionic (mainly sulfate) groups in the polysaccharide and basic amino acids of glycoproteins, and non-ionic ones depending on hydrophobic amino acids interspersed between the basic ones in the glycoprotein-binding zone [57]. This interaction is a decisive step in virus multiplication and may be differentiated but not dissociated from an evolutive point of view.

CGNs resemble to some extent the naturally occurring GAGs owing to their backbone composition of sulfated disaccharides are believed to be of potential therapeutic importance because they can mimic with GAGs present in cell membranes.

Natural CGNs, extracted from red seaweeds, are well known as potent and selective inhibitors of HSV-1 and HSV-2. CGNs chemical structures are similar to that of HS that serves as a primary receptor for adsorption of HSV onto cells. Mode of antiviral action is mediated by the interference with HSV attachment to cells, blocking the interaction virus-HS, a mandatory step during the multiplication cycle to achieve a productive infection that involves viral glycoproteins. In this work were used the and CGNs, their structures are present in the compound named 1C3 CGN, which is an "hybrid" /-and partially cyclized / CGN (Figure 2).

Since most pathogens and the toxins they produce bind to specific sugar sequences to initiate infection and disease, it is reasonable to assume that at least some glycan variation must have arisen from this selection pressure [12]. On this basis, pressure of selection *in vitro* with an antiviral drug like HS in the case of HSV may be employed to shorten the time necessary for attenuation. Moreover, in this last case we may speculate that if herpesviruses which are extensively spread in the environment are exposed to sulfated polysaccharide (its natural receptor), in the form of CGN, the appearance of virus variants would readily occur as a consequence of an intense virus-host interaction. Our results indicate that attenuation is a common trait of HSV obtained under selective pressure of CGN.

**Figure 2.** 1C3 CGN isolated from the red algae *Gigartina skottbergii* has a chemical structure similar to cellular HS. Attenuated HSV can be isolated from viral populations grown in the presence of increasing concentrations of CGN. This procedure may reflect an accelerated evolution process for HSV where biological modification of the viral particle can be demonstrated.
