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.
The main three types of carrageenans are λ-, κ-, and ι-carrageenan, and each show different inhibitory effects on different viruses [32,33,34,35,36,37]. Buck et al. demonstrated that carrageenans could inhibit the initial infection process of human papillomavirus (HPV), and the antiviral effect of ι-carrageenan is better than that of λ- and κ-carrageenans . Talarico and co-workers reported that ι-carrageenan could inhibit dengue virus (DENV) replication in mammalian and mosquito cells, and the mode of action of ι-carrageenan in both cell types is strikingly different. [33,37]. Yamada and co-workers reported that O-acylated carrageenan polysaccharides with different molecular weights had increased anti-HIV activity by depolymerization and sulfation [39,40]. Thus, the antiviral activities of carrageenan polysaccharides are associated with their molecular weights and the content of sulfates. Despite having good inhibitory effects on virus infection, the high molecular weight (MW) and poor tissue-penetrating ability of carrageenan polysaccharides have limited potential antiviral application in humans.
The marine heparinoid polysaccharides are similar to heparin in structure, and possess GAG-like biological properties, which contain alginates, ulvans, and their sulfated derivatives, as well as the dextran sulfate and chitosan sulfate (Figure 1). Recent studies showed that the cell surface heparinoid sulfate proteoglycans are the initial receptors of human herpes virus HSV-1, HSV-2, and bovine herpes virus in their infection processes [54,55,56]. Heparinoid polysaccharides can interact with the positive charge regions of cell surface glycoproteins, leading to the shielding effect on these regions, thus preventing the binding of viruses to the cell surface .
Xin et al. reported that a marine polysaccharide drug 911 derived from alginate could significantly inhibit the acute infection of MT4 cells and the chronic infection of H9 cells with HIV-1 . 911 can significantly inhibit the replication of HIV in vitro and in vivo, and its inhibitory action is attributed to the inhibition of viral reverse transcriptase, the interference with viral adsorption, and the enhancement of immune function [61,62]. Geng et al. found that the sulfated polymannuroguluronate (SPMG) could inhibit HIV adsorption mainly through interfering with the interaction of virus gp120 protein with the CD4 molecule on the surface of T cells [63,64,65]. In addition, their studies also indicated that the octasaccharide unit is established to be the minimal active fragment of SPMG inhibiting syncytium formation and lowering the P24 antigen level in HIV-IIIB-infected CEM cells . Moreover, 911 can improve the immune function of host cells, and inhibit the activity of hepatitis B virus (HBV) DNA polymerase, thus 911 can also be used to inhibit the replication of HBV .
Yu et al.  studied the inhibition actions of scallop skirt glycosaminoglycan (SS-GAG) on the type I-herpes simplex virus (HSV-I) at different concentrations, and they found that SS-GAG has a significant anti-HSV-1 effect in vitro. The antiviral activity of SS-GAG gradually increases with the prolonged duration of action . Zhang et al. found that marine polysaccharides isolated from Perna viridis could significantly inhibit the replication of influenza virus in MDCK cells, and has an additive effect on the anti-IAV actions of ribavirin, which suggest that Perna viridis polysaccharides merit further investigation as novel anti-influenza virus agents that can be used alone or in combination with existing antivirals .
Moreover, Wu et al. reported that the oyster polysaccharides could inhibit the DNA replication of duck hepatitis B virus (DHBV), and reduce the content of DHBV-DNA in duck serum, thus having obvious anti-HBV effects in vivo . In addition, Woo et al. investigated the inhibition effects of marine shellfish polysaccharides derived from seven kinds of shellfish (Ruditapes philippinarum, Mytilus coruscus, Scapharca broughtonii, Scapharca subcrenata, meretrix lusoria, Meretrix petechialis and Sinonovacula constricta Lamark) on the infection of HIV-1 in vitro, and the results showed that the seven species of marine shellfish polysaccharides all could inhibit the fusion of virus gp120/gp41 with CD4 protein on the surface of T lymphocytes, of which the Meretrix petechialis polysaccharide possesses the most significant anti-HIV activity .
Chemical modification of chitin and chitosan can generate novel compounds that possess good pharmacological properties such as antiviral activities. Sosa et al. reported that the N-carboxymethylchitosan N,O-sulfate (NCMCS), a polysaccharide derived from N-carboxymethyl chitosan by sulfation modification, could prevent HIV-1 infection by inhibiting viral adsorption to the CD4 receptor and reverse transcription of the viral genome . Moreover, Nishimura et al. found that the chitin sulfate had good inhibitory effect on HIV-1 infection, and its inhibition action on HIV-1 depends significantly on the sites of sulfation . In addition, it was reported that the aminoethyl-chitosan, prepared from 50% deacetylated chitosan also shows good inhibitory activity against HIV-1 in vitro .
In addition, chitosan and chitosan oligosaccharides were reported to be able to effectively reduce the infectivity of two human enteric viral surrogates: feline calicivirus F-9 (FCV-F9), and bacteriophage MS2 (MS2) by incubating the two viruses with chitosan or chitosan oligosaccharides for 3 h at 37 °C before infection [75,95]. The inhibition actions might be due to the direct inactivation of these two enteric viral surrogates by chitosan. Furthermore, reduction of MS2 infectivity by chitosan increases as the molecular weight of chitosan increases, while the inhibitory effects of chitosan on FCV-F9 is not MW-dependent .
Several studies have shown that carrageenan can mask the positive charge of host cell surfaces by the negative charge of its sulfate groups, so as to interfere with the adsorption process of viruses. Mazumder et al. obtained a high molecular weight sulfated galactan from red algae, and showed its antiviral activities against herpes simplex virus 1 and 2 in bioassays, which is likely due to an inhibition of the initial viral attachment to the host cells . Carlucci et al. noted that λ-carrageenan and partially cyclized μ/ι-carrageenan from Gigartina skottsbergii have potent antiviral effects against different strains of HSV types 1 and 2 during the virus adsorption stage . They subsequently confirmed the firm binding of carrageenan to virus receptors on the host cell surface. Their studies demonstrate that λ-carrageenan interferes with the adsorption process of the virus to the host cell surfaces [97,98].
Fucoidan isolated from brown algae has good antiviral activities against viruses such as HIV , HSV and human cytomegalovirus [100,101,102,103]. The antiviral actions of fucoidan seem to stem from inhibiting the binding of the virus particles to the host cell . In addition, sulfated polymannuroguluronate (SPMG), a new form of marine polysaccharide extracted from brown algae, could inhibit HIV-1 adsorption and entry by sharing common binding sites on gp120 with sCD4 or masking the docking sites of gp120 for sCD4 on the surface of T lymphocytes .
Buck et al. found that carrageenan could directly bind to the HPV capsid, so as to inhibit not only the viral adsorption process but also the subsequent entry and uncoating process of the virus . They also found that the inhibition actions of carrageenan against HPV might be related to a mechanism that is independent of the heparan sulfate after viral adsorption . Moreover, Talarico and co-workers reported that λ- and ι-carrageenans could interfere with both DENV-2 adsorption and internalization into host cells and are only effective if added together with the virus or shortly after infection . The mechanism of this inhibition action may be due to that although DENV virus can enter into host cell in the presence of carrageenans, their subsequent uncoating and releasing from endosomes may be interfered by the carrageenans. The inhibition action of ι-carrageenan on the uncoating process of dengue virus may be attributed to the direct interaction of carrageenans with the virus membrane glycoprotein E (gE) [33,48,105].
Moreover, Grassauer et al. reported that ι-carrageenan could inhibit rhinovirus (HRV) multiplication by interfering with the very early stages of virus replication, and this inhibition is probably due to the interference of the allosteric process of virus particles during HRV internalization . Furthermore, Kim et al. reported that the sulfated polysaccharide, p-KG03, purified from the marine microalga, Gyrodinium impudium, exhibit good inhibitory effect on influenza A virus infection . The mechanism studies showed that the inhibition of virus replication is maximized when p-KG03 is added during or within 6 h after viral infection, suggesting that mainly the viral adsorption and internalization steps are targeted by this compound. Thus the marine polysaccharide p-KG03 cannot only inhibit the binding of influenza virus to host cells, but also prevents the cellular internalization of the virus and early viral replication . 2b1af7f3a8