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Mar. Drugs 2012, 10(12), 2795-2816; doi:10.3390/md10122795
Abstract: Recently, the studies on the antiviral activities of marine natural products, especially marine polysaccharides, are attracting more and more attention all over the world. Marine-derived polysaccharides and their lower molecular weight oligosaccharide derivatives have been shown to possess a variety of antiviral activities. This paper will review the recent progress in research on the antiviral activities and the mechanisms of these polysaccharides obtained from marine organisms. In particular, it will provide an update on the antiviral actions of the sulfated polysaccharides derived from marine algae including carrageenans, alginates, and fucans, relating to their structure features and the structure–activity relationships. In addition, the recent findings on the different mechanisms of antiviral actions of marine polysaccharides and their potential for therapeutic application will also be summarized in detail.
In recent years, the constant outbreak of some emerging or reemerging viral diseases has caused serious harm to human health. During the last decade, the number of antivirals approved for clinical use has been increased from five to more than 30 drugs . Despite these successes, drug efficacy, toxicity, and cost remained unresolved issues, which is particularly large in developing countries due to the relative unavailability of drugs and the continuous emergence of drug resistance. Hence, the development of novel antiviral agents that can be used alone or in combination with existing antivirals is of high importance.
Marine polysaccharides are very important biological macromolecules which widely exist in marine organisms. Marine polysaccharides present an enormous variety of structures and are still under-exploited, thus they should be considered as a novel source of natural compounds for drug discovery . Marine polysaccharides can be divided into different types such as marine animal polysaccharides, plant polysaccharides and microbial polysaccharides according to their different sources. Marine derived polysaccharides have been shown to have a variety of bioactivities such as antitumor, antiviral, anticoagulant, antioxidant, immuno-inflammatory effects and other medicinal properties. In particular, the studies on the antiviral actions of marine polysaccharides and their oligosaccharide derivatives are attracting increasing interests, and marine polysaccharides are paving the way for a new trend in antiviral drugs.
This review presents an overview of recent progress in research on the antiviral activities of marine polysaccharides, relating to their structure features and structure–activity relationships. Moreover, this review will mainly focus on the heparinoid polysaccharides and the sulfated polysaccharides present in seaweed. Recent developments in the mechanisms of antiviral actions of marine polysaccharides and their oligosaccharide derivatives will also be discussed in detail.
2. The Classification and Main Structure Features of Marine Polysaccharides
Marine polysaccharides usually exhibit structural features such as sulfate and uronic acid groups, which distinguish them from polysaccharides of terrestrial plants, but are similar to mammalian glycosaminoglycans, such as heparin and chondroitin sulfate . Marine polysaccharides can be classified into three main types: marine animal polysaccharides, marine plant polysaccharides, and marine microbial polysaccharides according to their different sources, and each have different structure features.
2.1. The Main Structure Features of Marine Animal Polysaccharides
Marine animals are rich in polysaccharides, and the polysaccharides derived from marine fishes, shellfishes, and mollusks often possess a wide range of pharmacological activities . The marine animal polysaccharides usually include chitosans derived from crustaceans, chondroitin sulfates from cartilaginous fishes, sulfated polysaccharides from sponge, and glycosaminoglycans from scallops and abalone [5,6].
Chitin, a long-chain polymer of N-acetylglucosamine, is one of the most abundant polysaccharides and usually prepared from the shells of crabs and shrimps [7,8]. Chitosan, a partially deacetylated polymer of N-acetylglucosamine, is produced commercially by deacetylation of chitin . The molecular weight of commercially produced chitosan is usually between 3800 and 20,000 Daltons. Chitosan is a linear randomly distributed, hetero polysaccharide consisting of β-(1→4)-linked 2-acetamido-2-deoxy-D-glucopyranose and 2-amino-2-deoxy-D-glucopyranose units . Chemical modification of chitin and chitosan can generate new biofunctional products which possess good biological activities and physicochemical properties [10,11,12,13,14]. Moreover, it was reported that the marine polysaccharides isolated from cartilaginous fishes also contain trace neutral mannose, xylose and rhamnose besides the galactosamine and glucuronic acid, which have certain structure-specific properties .
Furthermore, Cimino et al.  reported that rosacelose, a new anti-HIV polysaccharide composed of glucose and fucose sulfate, could be isolated from the aqueous extract of the marine sponge Mixylla rosacea. They also found that this marine polysaccharide has a linear polysaccharide structure mainly composed of 4,6-disulfated 3-O-glycosylated α-D-glucopyranosyl and 2,4-disulfated 3-O-glycosylated α-L-fucopyranosyl residues (in a 3:1 molar ratio) . Moreover, it was reported that one kind of sugar polymer which contains hexosamine, hexuronic acid, and fucose sulfate could be separated from Apostichopus japonicus selenka . In a word, marine animal polysaccharides have extremely broad distribution, and exist in almost all marine animal tissues and organs.
2.2. The Main Structure Features of Marine Plant Polysaccharides
The marine plant polysaccharides especially the seaweed polysaccharides are widely distributed in the ocean, occurring from the tide level to considerable depths, free-floating or anchored, which are the most abundant polysaccharides in marine organisms. Moreover, the polysaccharide content of seaweed is very high, accounting for more than 50% of the dry weight, thus the seaweed polysaccharides are very important resources for the development of marine polysaccharide drugs. The principal cell wall polysaccharides in green seaweeds are ulvans, those in red seaweeds are agarans and carrageenans, and those in brown seaweeds are alginates and fucans, as well as the storage polysaccharide laminarin [18,19].
Alginates are the major constituent of brown seaweeds’ cell walls and are linear acidic polysaccharides composed with a central backbone of poly-D-glucuronic acid (G blocks), poly-D-mannuronic acid (M blocks) and alternate residues of D-guluronic acid and D-mannuronic acid (GM blocks) . Fucans are also one of the major constituents of brown seaweed cell walls, and are ramified sulfated polysaccharides constituted by a central backbone of fucose sulfated in positions C2 and/or C4 and ramifications at each two or three fucose residues .
Red seaweed polysaccharides are primarily classified as agarans and carrageenans based on their stereochemistry, specifically galactans with 4-linked α-galactose residues of the L-series are termed agarans, and those of the D-series are termed carrageenans . Carrageenans are sulfated D-galactans composed of repeating disaccharide units with alternating 3-linked β-D-galactopyranose (G-units) and 4-linked α-galactopyranose (D-units) or 3,6-anhydro-α-galactopyranose (AnGal-units), which possess broad-spectrum antiviral activities . In conclusion, the seaweed polysaccharides are the most abundant polysaccharides in marine plants, and usually possess the special characteristics of high sulfation and carboxylation.
2.3. The Main Structure Features of Marine Microbial Polysaccharides
Marine microorganisms, including bacteria, fungi, and microalgae, are of considerable importance as promising new sources of a huge number of biologically active products [23,24,25,26]. Some of these marine species live in high-pressure, high-salt, low-temperature, and oligotrophic environments, which provide the opportunity for them to produce unique active substances that differ from the terrestrial ones .
Marine microbial polysaccharides, especially the extracellular polysaccharides, have structural diversity, complexity, and particularity. Most of these polysaccharides are heteropolysaccharides which composed by different monosaccharides in a certain percentage, wherein the glucose, galactose and mannose are the most common components in microbial polysaccharides. It was reported that spirulan, a sulfated polysaccharide isolated from Arthrospira platensis (formely Spirulina platensis) is composed of two types of disaccharide repeating units, [→3)-α-L-Rha(1→2)-α-L-Aco-(1→] where Aco (acofriose) is 3-O-methyl-Rha with sulfate groups and O-hexuronosyl-rhamnose .
In addition, the marine microbial polysaccharides also contain glucuronic acid, galacturonic acid, amino sugars, and pyruvate. Roger et al.  reported that the exopolysaccharide (EPS) derived from marine bacterium Alteromonas infernus is a highly branched acidic heteropolysaccharide with a high molecular weight and low sulfate content (less than 10%). Its nonasaccharide repeating unit is composed of uronic acid (galacturonic and glucuronic acid) and neutral sugars (galactose and glucose), and substituted with one sulfate group . In conclusion, the marine microbial polysaccharides with novel chemical compositions and structure features have been found to possess potential applications in fields such as pharmaceuticals, food additives, and industrial waste treatments.
During the last decade, numerous bioactive polysaccharides with interesting functional properties have been discovered from marine organisms . Marine polysaccharides, especially the sulfated polysaccharides derived from marine algae, often possess good inhibitory effects on a variety of viruses [18,112]. This review mainly focuses on the antiviral activities and mechanisms of marine polysaccharides, which is expected to attract more interest for future explorations. The antiviral activities of most marine polysaccharides are usually related to the specific sugar structure, molecular weights and their degree of sulfation. Marine polysaccharides can inhibit the replication of viruses through interfering with a few steps in virus life cycle or improving the host antiviral immune responses to accelerate the process of viral clearance. Despite having good antiviral effects, marine polysaccharides are structurally diverse and heterogeneous, which makes studies of their structures challenging, and may also have hindered their development as therapeutic agents to date .
In conclusion, marine polysaccharides, especially the polysaccharides derived from seaweed, have many advantages, such as relatively low production costs, broad spectrum of antiviral properties, low cytotoxicity, and wide acceptability, which suggest marine polysaccharides merit further investigation as promising antivirals that can be used alone or in combination with existing drugs . Until now, most of the studies on antiviral effects of marine polysaccharides have been observed in vitro or in mouse model systems. Therefore, further studies are needed in order to investigate their antiviral activities in human subjects . Moreover, the structure–activity relationships and the underlying molecular mechanisms of antiviral actions of marine polysaccharides need to be understood precisely and elucidated clearly by intensive studies in the future .
We thank Lijuan Zhang (Ocean University of China, China) for her helpful advice and critical readings of the manuscript. This work was supported in part by the Program for Changjiang Scholars and Innovative Research Team in University (IRT0944), the National Natural Science Foundation of China (31271923), Shandong Provincial Natural Science Foundation (ZR2011HQ012), the Fundamental Research Funds for the Central Universities (201113013), the Special Fund for Marine Scientific Research in the Public Interest (201005024), and Qingdao science and technology development project (12-1-4-1-(20)-jch).
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