Sulfated Polysaccharides from Seaweeds: History
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Qiang Wei
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Shuliang Song
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Jiarui Zhao
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Kai Ji

来自海藻的硫酸化多糖被认为是药物开发生物活性化合物的潜在来源，已显示出对广谱病毒的抗病毒活性，主要包括常见的DNA病毒和RNA病毒。此外，硫酸化多糖还可以提高人体的免疫力。来自海藻的硫酸化多糖，包括角叉菜胶，半乳聚糖，岩藻依聚糖，海藻酸盐，ulvan，p-KG03，纳维库仑和螺旋藻酸钙，可能为开发COVID-19疗法和疫苗提供新的思路。

  • sulfated polysaccharides
  • seaweed
  • algae
  • antiviral
  • COVID-19
  • SARS-CoV-2

1. Red Seaweed

1.1. Carrageenan

Carrageenan is a soluble sulfated galactan isolated from red seaweed where it is a component of the outer cell wall and intracellular matrix, and it accounts for 30–70% of the dry weight of red algae. The galactan backbone is produced in the Golgi apparatus and is subsequently sulfated by sulfotransferases in the cell wall [1]. Commercially, red seaweed is considered more valuable than brown and green algae. Furthermore, the kappa-(κ-), iota-(ι-), and lambda-(λ-) isoforms are most commonly used in industry. These differ in the position and numbers of sulfate groups attached to the hexose scaffold, with the κ, ι, and λ forms containing one, two, and three anionic sulfate ester moieties, respectively, on each disaccharide repeat [2]. The degree of sulfation of the κ-, ι, and λ isoforms is 25–30%, 28–30%, and 32–39%, respectively [3]. The sol-gel transition, chemical cross-linking, mechanical strength, and biological properties vary with the structural changes of carrageenan. Due to its unique properties, carrageenan is mainly used in industries, such as food, cosmetics, printing, textile formulations, and pharmaceuticals [4]. Significantly, a higher degree of sulfation in carrageenan does not necessarily correspond with higher antiviral activity [5], and it appears that both the position and density of the sulfate moieties on the backbone influence the molecule’s antiviral capability [6]. This suggests that carrageenan’s antiviral activity is not entirely dependent on the sulfate content. In addition, carrageenan is the most studied sulfated polysaccharide in human clinical trials for use against various viral diseases [7].

Kappa-(κ-)carrageenan

Kappa-(κ-)carrageenan inhibits viral replication both through blocking adsorption to the surface and inhibition of protein expression. Low-molecular-weight κ-carrageenan shows a better performance in these aspects [8][9]. Shao et al. investigated the molecular mechanism by which k-carrageenan protects cells from invasion by H1N2009 influenza (SW731) virus [8]. They treated MDCK cells with κ-carrageenan, observing significant inhibition of SW731 influenza virus replication resulting from interference with viral adsorption and protein expression [8]. Remarkably, low-molecular-weight κ-carrageenan has better antiviral activity because of its better tissue penetration. Wang and colleagues found that 2-kDa-κ-carrageenan (CO-1) prevented the replication of the influenza A (H1N1) virus in MDCK cells more effectively than the 3 and 5 kDa forms (CO-2 and CO-3, respectively), with IC50 values of 32.1, 239, and 519 µg/mL for the 3 isoforms, respectively [9]. Given these results, the authors recommend the use of low-molecular-weight carrageenan oligosaccharides for influenza treatment as an alternative strategy [9]. Schütz et al. showed that both nasal and oral sprays containing κ-carrageenan inhibited SARS-CoV-2 replication in human airway epithelial cells [10]. Furthermore, κ-carrageenan also showed significant inhibitory effects on HSV-2 and HPV16, with IC50 values of 1.6 and 0.044 µg/mL, respectively [4][11].

Lambda-(λ-)carrageenan

Lambda-(λ-)carrageenan inhibits viral activity by inhibiting viral internalization through targeting attachment cell surface receptors and binding to viral envelope proteins [12][13][14]. Luo et al. found that λ-carrageenan P32 screened from different molecular weights (4–350 kDa) carrageenans had the highest inhibitory effect on RABV infection, which was consistent with the low molecular weight (4 kDa), high solubility, and high stability of closely related P32 [12]. These results suggested that λ-carrageenan P32 was a promising drug to inhibit RABV infection by preventing virus internalization and glycoprotein-mediated cell fusion [12]. In mice, the use of λ-carrageenan nasal drops not only reduced weight loss resulting from influenza viral infection but also prevented infection-related death in a majority of the mice [13]. In addition, λ-carrageenan was also effective against SARS-CoV-2. The EC50 of λ-carrageenan was 0.9 ± 1.1 μg/mL and the principal mechanism involved λ-carrageenan targeting viral attachment to cell surface receptors and subsequent prevention of viral entry [13]. λ-carrageenan extracted from the red alga Gigantina skotsbergii was found to be effective in preventing infection by equid herpesvirus 3(EHV3), bovine herpesvirus 1 (BoHV-1), and suid herpesvirus-1 (SuHV-1), most likely because the compound binds to the envelope glycoprotein of the virus, preventing viral attachment to the cell surface receptor [14]. In addition, λ-carrageenan also had a significant inhibitory effect on DENV-3, with an EC50 of 0.14 µg/mL [15]. λ-carrageenan polysaccharide induces the synthesis of interferon and has biological effects on the immune response. Studies have shown that microwave degradation of λ-carrageenan from Chondrus ocellatus can inhibit tumor growth, enhance interferon activity, and enhance lymphocyte multiplication [16]. However, it has been reported that λ-carrageenan can induce enteritis in rats after long-term oral administration [17]. Furthermore, these sulfated polysaccharides can be used in the manufacture of carbohydrate-based conjugate vaccines to achieve the desired immunogenicity and potency. Luo et al. proved that λ-carrageenan has increased the efficacy of ovalbumin-based prophylactic and therapeutic cancer vaccines [18].

Iota-(ι-)carrageenan

Iota-(ι-)carrageenan’s antiviral activity against a variety of viruses, especially respiratory viruses, has been well documented [19][20][21][22]. Some scholars have proposed to improve the therapeutic effect by combining carrageenan with other clinically common antiviral drugs. A study using a combination of ι-carrageenan and oseltamivir showed that this combination significantly improved the survival rate of infection with the H1N1 virus compared with a single therapy [21]. Ludwig et al. found that patients treated with ι-carrageenan recovered more quickly than those in the placebo group, with a duration of 11.6 days compared with 13.7 days in the placebo group. In addition, the ι-carrageenan group showed significantly faster remission of symptoms than the placebo group, with lower viral loads in the nasal cavity [23]. ι-carrageenan from Euchema spinosum was able to neutralize the SARS-CoV-2 Spike pseudotyped lentivirus (SSPL) in a concentration-dependent manner at an MOI of 0.1 and an IC50 of 2.6 µg/mL [24]. In addition, different forms of administration of ι-carrageenan can play a significant role in its antiviral activity. Morokutti et al. found that ι-carrageenan in lozenge form significantly reduced the amount of SARS-CoV-2 virus in saliva, thus limiting interpersonal viral transmission and the transfer of the virus to the lower respiratory tract [25]. In addition, ι-carrageenan can be given directly to infected patients to treat COVID-19 with ivermectin via nasal spray and oral antivirals. The number of people diagnosed with COVID-19 in the treatment group was 3.4%, which was significantly lower than 21.4% in the control group (p = 0.0001) [26]. The Xylitol nasal spray containing ι-carrageenan has been found to prevent SARS-CoV-2 infection in vitro, with an IC50 < 6.0 µg/mL [27]. Graf et al. developed a nasal spray formulation containing 0.05% xylimeta-zoline hydrochloride and 0.12% ι-carrageenan. The formulation was reported to be effective in relieving nasal congestion symptoms while also providing antiviral protection to the respiratory mucosa [28]. Hassanzadeh et al. found that ι-carrageenan can significantly inhibit SARS-CoV-2 in vitro, an effect caused by the effect of positively charged regions on the glycoprotein envelope and protein aggregation in host cells on the surface [29].®
Although the three types of carrageenan, namely, κ-, ι-, and λ-carrageenan, showed antiviral action against SARS-CoV-2, including the alpha, beta, gamma, and delta variants of concern [10][13][24], ι-carrageenan showed the strongest antiviral activity with an IC50 value approximately ~1 log-stage lower than either λ-or κ-carrageenan [30]. Therefore, ι-carrageenan is a potential respiratory virus inhibitor that can be used to prevent and treat SARS-CoV-2 infection, irrespective of the viral variant.
In addition, the combined use of antiviral drugs often has a multiplier effect. Morokutti-Kurz et al. showed that carrageenan and Zanamivir act synergistically against several influenza A virus strains (H1N1(09)pdm, H3N2, H5N1, H7N7) in vitro; therefore, by acting synergistically, they can provide a broader spectrum of anti-influenza activity [22]. When using ι- and k-carrageenan at the same time, the physical interaction of carrageenan with the virus did not interfere with the inhibitory effect of zanamivir, and the spray effect was increased [22]. Xylimidazolines have been used for over 50 years to relieve vasoconstriction and acute nasal edema. Graf et al combine this vasoconstrictor and ι-carrageenan in a scientific formulation. The experimental results show that ι-carrageenan does not reduce the efficacy and safety of the drug, and the antiviral effect of iota-carrageenan is also not affected [28]. Therefore, the most successful antiviral formulation of carrageenan may be the recently developed nasal spray formulation for use against rhinoviruses and SARS-CoV-2 [27][28].

1.2. Galactan

Sulfated galactans are the principal extracellular polysaccharides found in red seaweed. With few exceptions, they consist mainly of linear chains of galactose. These polysaccharides show good antiviral activity against HSV, DENV, HIV, and HAV [31][32][33][34]. Galactan from the red alga Agardhiella tenera has been shown to inhibit HIV-1 and HIV-2 infection by preventing the interaction between HIV gp120 and the CD4 + T cell receptor [33][35]. Similarly, 12.5 μg/mL galactan isolated from Schizymenia binderi was found to inhibit HIV replication in vitro, and block the replication of HSV-1 in Vero cells [36]. Matsuhiro et al. found that Schizymenia binderi galactan showed strongly selective antiviral activity against HSV-1 and HSV-2, with EC50 values of 0.76 and 0.63 μg/mL, respectively [37]. Similarly, 3 galactan (F1, F2, and F3) isolated from Callophyllis variegate are effective inhibitors of HSV-1 and HSV-2, with IC50 values ranging from 0.16 to 2.19 μg/mL, and are effective against DENV-2 with IC50s in the range of 0.10–0.41 μg/mL [38]. The galactan (C2S-3) extracted from Cryptonemia crenulata can inhibit the proliferation of DENV-2 in Vero cell lines [39]. The result of the experiment showed that C2S-3 blocked the initial binding of the virus to cells and its subsequent penetration, preventing DENV-2 from RNA replication and other biomacromolecule synthesis functions in host cells. Moreover, compared with heparin, C2S-3 was more effective as an antiviral against various DENV-2 strains [39]. Therefore, galactan is a very promising antiviral drug.

2. Brown Seaweed

2.1. Fucoidan

Fucoidan is an intercellular or mucilage matrix component of brown seaweed, accounting for approximately 5–20% of the dry weight of the plant [40][41]. Fucoidan is documented to be effective against a wide variety of viruses, including HIV, HSV, and SARS-CoV-2, and numerous other RNA and DNA viruses [42][43][44][45][46][47][48]. Dinesh et al. extracted fucoidan (CFF, FF1, and FF2) from Sargassum swartzii, observing that the FF2 fraction was effective against HIV-1 at concentrations between 1.56 and 6.25 μg/mL, shown by significant reductions in the p24 antigen levels (95.6 ± 1.1%) and reverse transcriptase (78.9 ± 1.43%) at a concentration of 25 µg/mL [45]. Fucoidans isolated from Dictyota mertensii, Lobophora variegate, Fucusvesiculosus, and Spatoglossum schroederi were found to inhibit HIV reverse transcriptases, thus preventing infection; it was further observed that the antiviral action was positively associated with the numbers of sulfate moieties on the compound [49]. Lee et al. demonstrated that the fucoidan extracted from Mekabu and Sargassum trichophyllum significantly inhibited HSV-1, HSV-2, H5N3, and influenza A viral infection together with enhancing the immune function [50]. High-molecular-weight fucoidan (KW) from the brown alga Kelmanella crassifolia was shown to bind and block influenza A virus neuraminidase activity, inhibiting the release of viral particles. Fucoidan was also found to block EGFR and subsequent activation of downstream PI3K/Akt and NF-κB signaling [51]. In addition, fucoidan also inhibits NDV La Sota infection (IS50 > 2000), significantly reducing the number of syncytia (inhibition rate of 70%), suggesting specific binding of fucoidan to the F0 protein [52]. Fucoidan is considered a possible candidate for treating COVID-19 as it has significant antiviral activity [53]. Recovery of the mitochondrial membrane potential Δψm was observed in the PBMCs of patients after recovery from COVID-19, showing that fucoidan has strong antioxidant activity and can restore cellular homeostasis [54][55][56]. RPI-27 extracted from Saccharina japonica is a high-molecular-weight fucoidan similar in structure to glycosaminoglycans on the surfaces of host cells [57]. This could provide opportunities for binding the S protein of SARS-CoV-2, resulting in competitive inhibition with the virus, with an EC50 value of 8.3 ± 4.6 μg/mL [57].
Fucoidan has a variety of immunomodulatory effects, such as stimulating the production of NK (natural killer) cells, promoting cell development and other functions of dendritic cells. In addition, it enhances Th1-type immune responses by producing antibodies against specific antigenic determinants and generating memory T cells against specific viruses [58]. Sulfated polysaccharides could provide an important approach to designing therapeutic vaccines based on their desired physicochemical properties and easily modifiable structural features. Fucoidan is reported to have the best adjuvant quality for future vaccine production and can elicit strong cell-mediated and humoral immune responses [59].

2.2. Alginate

Alginate is a soluble acidic polysaccharide found in the cell walls of brown seaweed, especially Macrocystis pyrifera, Laminaria hyperborea, and Ascophyllum nodosum, amongst others [60]. Alginate is a linear polymer formed by 1,4-linked β-D-mannuronic acid and 1,4 α-L-guluronic acid moieties assembled in blocks [61]. The compound has both antiviral and immunomodulatory activities [62][63][64][65][66]. Serrano-Aroca et al. summarized and analyzed the effects of biomaterials constructed of alginate on 17 viruses, finding that these materials were essentially non-toxic and effective against a variety of viruses [67]. In vivo results showed that oral administration of marine polysaccharide drug 911 reduced viral infection and the plasma RNA copy number. In addition, the introduction of 911 has a protective effect on CD4 cells [68][69][70]. Furthermore, the inhibitory effect of 911 on HIV-1 is dose dependent with low toxicity. Moreover, it can also inhibit HBV viral replication by inhibiting DNA replication [71].

Polymannuroguluronate

Polymannuroguluronate (PMG) is a common low-molecular-weight alginate. Polymannuroguluronate sulfate (PMGS) is capable of inactivating HPV particles and of blocking virus capsid L1 protein binding, and downregulating the levels of the E6 and E7 viral oncogenic proteins [72]. In addition, sulfated polymannuronate (SPMG) inhibits the interaction between the HIV-1 gp120 protein and the CD4 + T lymphocyte receptor, thus preventing entry of the virus into the lymphocyte [73]. In addition, Miao et al. suggested that the interaction between SPMG and the CD4 + T lymphocyte may provide a mechanistic explanation for the immunoenhancement and anti-AIDS activity of SPMG in HIV-infected individuals [74]. Therefore, PMGS deserves further study as a novel candidate for the prevention of HPV infection, treatment of genital warts or cervical cancer, and HIV infection.

Polyguluronate

Polyguluronate (PG) is another low-molecular-weight alginate. Polyguluronate sulfate (PGS) significantly reduces the levels of HBsAg (51.8%) and HBeAg (36.2%), showing dose- and time-dependent inhibitory effects [75]. PGS likely binds to HepG2.2.15 cells, upregulating the NF-κB and RAF/MEK/ERK pathways to promote interferon-β production and thus interfering with HBV transcription and exerting an anti-HBV effect [75]. In addition, PGS can significantly reduce oxidative stress induced by H2O2 and improve the survival rate of HepG2 hepatocytes due to its strong antioxidant activity [76].因此，PGS作为一种旨在调节宿主自然免疫系统的新型抗HBV药物，值得进一步研究。

3. 绿色海藻

乌尔文

Ulvan是绿海藻细胞壁中最常见的多糖，占藻类干重的8-29%[77].体外和体内研究表明，ulvan具有抗凝，抗菌，抗病毒和免疫调节活性[78][79][80][81][82].从百日菀中纯化了几种低分子量ulvan亚型（ULVAN-F1，ULVAN-F2和ULVAN-F3），发现它们可有效预防水疱性口炎病毒的感染和复制[83].然而，ulvan的抗病毒活性与其分子量并不一致相关。SU1F1的抗病毒作用主要是通过抑制DNA复制和转录，同时下调HSV蛋白合成[84].含有ulvan的多糖提取物阻断JEV（日本脑炎病毒）的吸附并抑制病毒进入宿主细胞。此外，它们还有效减少了促炎细胞因子的产生。[85].除抗病毒活性外，ulvan还具有一定的免疫调节活性。来自石莼的石莼提取物可以通过在体外激活鸟类异性恋和单核细胞来诱导促炎细胞因子的释放，最终增强鸡的先天免疫系统[86].来自绿色海藻的Ulvan仍然需要进一步的研究，尽管对其亚型的研究表明，它并不比来自红色和棕色海藻的多糖更有效。

4. 微藻

4.1. p-KG03

p-KG03是一种均相多糖，衍生自绞股蓝，由半乳糖与糖醛酸和磺酸基团复合而成[31].从甲藻中提取的p-KG03是最早的海洋化合物（EC50 = 26.9μg/ mL），据报道在体外显着抑制脑心肌炎RNA病毒（EMCV）感染[87].
Naviculan来源于硅藻Navicula directa。Lee及其同事报告说，纳维库仑通过抑制HSV-1，HSV-2，HIV和INF A的结合和内化来减少病毒感染，IC50值在7.4-170μg/ mL范围内[88].

4.2. 钙螺旋藻

螺旋藻钙是从海藻关节螺旋体中获得的。由于钙离子与多糖上的硫酸盐基团螯合，因此对包被病毒具有很高的抗病毒活性[89][90][91][92].Hayashi及其同事发现，螺旋藻的螺旋藻钙（Ca-SP）是几种病毒的抑制剂。它可以抑制HSV-1，HCMV，MeV，MUV，INF A和HIV-1的复制和浸润，EC50值在0.92-23μg/ mL范围内[93].

This entry is adapted from the peer-reviewed paper 10.3390/ph15050581

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