key: cord-0695692-g2c38bf7
authors: Pradhan, Biswajita; Nayak, Rabindra; Patra, Srimanta; Bhuyan, Prajna Paramita; Behera, Pradyota Kumar; Mandal, Amiya Kumar; Behera, Chhandashree; Ki, Jang-Seu; Adhikary, Siba Prasad; MubarakAli, Davoodbasha; Jena, Mrutyunjay
title: A state-of-the-art review on fucoidan as an antiviral agent to combat viral infections
date: 2022-05-02
journal: Carbohydr Polym
DOI: 10.1016/j.carbpol.2022.119551
sha: 2226206a60aca4446669845393ec487b376538da
doc_id: 695692
cord_uid: g2c38bf7

As a significant public health hazard with several drug side effects during medical treatment, searching for novel therapeutic natural medicines is promising. Sulfated polysaccharides from algae, such as fucoidan, have been discovered to have a variety of medical applications, including antibacterial and immunomodulatory properties. The review emphasized on the utilization of fucoidan as an antiviral agent against viral infections by inhibiting their attachment and replication. Moreover, it can also trigger immune response against viral infection in humans. This review suggested to be use the fucoidan for the potential protective remedy against COVID-19 and addressing the antiviral activities of sulfated polysaccharide, fucoidan derived from marine algae that could be used as an anti-COVID19 drug in near future.

World Health Organization (WHO) has confirmed the occurrence of novel coronavirus (nCoV-2019) on January 12, 2020 in Wuhan, China. WHO has termed COVID-19, the first unknown acute respirational tract infection (Guo et al., 2020) . COVID-19 cases spread rapidly worldwide and were labeled a pandemic on March 11, 2020 (Elengoe, 2020) . The most communal indicators of COVID-19 comprise cough, fever, headache, sore throat, breathlessness, and fatigue, which gradually lead to the death of the patients. The death is due to severe infection in the respiratory tract, pneumonia and multiple organ failure. People with diabetes, cardiovascular problems, hypertension, cancer, HIV, and several auto-immune disorders have a great life threat due to COVID-19 (Singhal, 2020) .

The fresh and marine ecosystems are rich in biodiversity and hold a potential source of sulfated polysaccharides (Chhandashree Behera, Dash, Pradhan, Jena, & Adhikary, 2020; C Behera et al., virus) , hepatitis B virus, murine norovirus, and RSV (respiratory syncytial virus) (Shi et al., 2017; Wang, Wang, & Guan, 2012) . With this notation, the fucoidan can exert promising therapeutic value against coronavirus to halt the disease progression.

Immunity is considered the primary concern during the treatment of viral infections, such as COVID-19 (Dhar & Mohanty, 2020) . Studies on antiviral immunity have been demonstrated against several viral diseases and fucoidan has displayed promising effect (Wang et al., 2012) . To date, many sulfated polysaccharides from plant and animal sources, including marine organisms and microorganisms, have been tested against HIV and HSV (Alam et al., 2021) . Nutraceuticals from Spirulina have been well explored and commercially available as an innate and adaptive immunity booster against HIV and HSV (K. Hayashi, Hayashi, & Kojima, 1996; Ratha, Renuka, Rawat, & Bux, 2021) . Hence, the use of immune-boosting algal-derived fucoidans may contribute a leading role to combat against coronavirus infections via alleviating innate immune responses. Although vaccination against COVID-19 has developed and is in force, no clinically approved drugs have been approved for therapeutic purposes. Hence, the outbreak needs an imperative retort from the scientific community for the development of novel synthetic as well as natural drugs as immune boosters against COVID-19.

As limited research has been carried taking algal-derived sulfated polysaccharides concerning fucoidan, in this review, we have focussed on this aspect that might be castoff as an antiviral drug against SARS-CoV-2.

Sulfated polysaccharides are potent antiviral agents due to their diverse structure. They have a pivotal role in boosting the host antiviral retort by preventing virus attachment, adsorption, and viral reproduction. Systematic studies on the antiviral activity of marine algaederived polysaccharides have been achieved both in vitro and in precise animal models. Marine algae are rich in sulfated polysaccharides that prevent the replication of viruses clinically tested against HSV-1. Polysaccharides from Spirulina platensis has displayed antiviral activity against HSV-1, measles virus, influenza A virus, mumps virus, human cytomegalovirus, and HIV-1 (K. Hayashi et al., 1996) . Sulfated polysaccharides inhibit antiviral pathways and act as potential replication inhibitors of retroviruses such as HIV-V (Buck et al., 2006) . Carrageenan, a common polysaccharide isolated from red algae such as Gigartina, Chondrus, Eucheuma and Hypnea exhibits antiviral activity against virus infection. Carrageenan blocks the viral entry by inhibiting host cell binding capacity (Li, Shang, Li, Wang, & Yu, 2017) . It limits the dengue virus's reproduction in mosquitoes and mammalian cells (Buck et al., 2006) . Moreover, it plays an operative role against HPV (human papillomavirus), leading to genital warts and cervical cancer (Zeitlin, Whaley, Hegarty, Moench, & Cone, 1997) .

Carrageenans with low molecular weight (3-10 10 kDa) display a repressing effect against the influenza virus (Grassauer et al., 2008; Hilliou et al., 2006) . The nasal spray carrageenan administration (Iota-carrageenan), also recognized as "super-shedders," is operative against the communal cold by improving viral clearance and reducing the disease duration. Carrageenan extracted from red algae (Schizymenia pacifica) restricts infection of avian as well as mammalian retroviruses by activating reverse transcriptase function and subsequent inhibition of viral J o u r n a l P r e -p r o o f Journal Pre-proof replicate. In addition, carrageenan also prevents the binding between the host and viruses at the early stages of infection (Koenighofer et al., 2014) . Extracellular polysaccharides such as galactoses isolated from red algae Agardhiella tenera display antiviral properties against DENV, HIV-1, HIV-2, HSV-1, HSV-2, and Hep A virus (Hepatitis A virus) (Myriam Witvrouw et al., 1994) . With low cytotoxicity, galactans isolated from Callophyllis variegata show antiviral action against HSV-1, HSV-2, and DENV-2 (Rodríguez et al., 2005) . The antiviral efficacy of sulfated galactan isolated from Schizymenia binderi effectively counter HSV-1 and HSV-2 (Matsuhiro et al., 2005) . Extracellular sulfated polysaccharides such as A1 and A2 from Cochlodinium polykrikoides, reduce blood coagulation by inhibiting influenza A and B virus in MDCK cells. It is also effective against respirational virus types A and B in Hep-2 cells and immunodeficient virus type-1 in MT-4 cells (Hasui, Matsuda, Okutani, & Shigeta, 1995) . Sulfated exo-polysaccharide derived from Gyrodinium impudicum display antiviral properties against EMCV (Encephalomyocarditis virus) without toxicity in HeLa cells (Yim et al., 2004) . It also inhibits influenza A virus duplication via targeting adsorption and integration into the host cell (Yim et al., 2004) .

The main stages of the virus life cycle are classified as attachment of virus, viral penetration, uncoating, biogenesis, viral assembly, and release of a virus that play a key role during viral infection and disease progression (Fig. 3) . Algae-derived sulfated polysaccharides display exceptional molecular structures and exert potential antiviral properties by inhibiting several phases of the viral life cycle by directly deactivating virions before contamination starts J o u r n a l P r e -p r o o f or hindering its reproduction inside the host cell. Marine seaweeds are a promising source and rich in polysaccharides and give attention to the development and discovery of antiviral drugs. RNA (messenger RNA) (Queiroz et al., 2008) .

Fucoidan, the chief composition of the extracellular background of brown algae, is rich in fucose and sulfated polysaccharide. Fucoidan is a complicated structure with l-fucose molecule, sulfate groups, and one or more mannose, galactose, xylose, glucose, rhamnose, glucuronic acid, arabinose, and acetyl groups. Typically, there are two forms of homofucose in fucoidan (type (I) encompasses repeated (13)). -l-fucopyranose and type (II) include alternating and repetitive (13)and (14)-l-fucopyranose chains, as well as standard backbone chains. Fucoidan is the most frequent brown seaweed backbone chain. Type I (A) and type II (B) are represented in the figure and the molecular structure of isolated fucoidan used against SARS-CoV-2 such as F. vesiculosus (C) and Undaria pinnatifida (D) (Fig. 4) .

Viral infections cause enormous health problems leading to death. Initially, nucleoside drugs were used as antiviral drugs and has several side effects such as acute renal failure, cardiac arrest, hepatological dysfunction and gastrointestinal problems (Marchetti et al., 1995) . Therefore, searching for new and effective drugs without toxicity has gained more importance in the present times (S. Srimanta Patra et al., 2021; structure conformation, and stereochemistry are key factors in sulfated polysaccharides' antiviral action fucoidan. Sulfated polysaccharides with low molecular weight and high sulfate concentration have greater antiviral activity (Duarte et al., 2001) . 

Fucoidan is a type of sulfated polysaccharide that provides a wide spectrum of antiviral activity with minimal toxicity (Queiroz et al., 2008) . Inclusively, fucoidan prevents HIV, human cytomegalovirus, HSV, bovine viral diarrhea virus, and influenza virus by inhibiting viral adsorption onto cells, thus hindering viral entry (Dinesh et al., 2016; Mandal et al., 2007; M. Witvrouw & De Clercq, 1997 crassifolia fucoidan prevented the influenza virus in subsequent infection (W. . LMWF fractions such as LF1 and LF2 derived from L. japonica, which include 42.0%and 30.5% fucose; 19.8% and 23.9% galactose; 5.3% and 3.7% uronic acid; and 30.7% and 32.5% sulfate, respectively, showed excellent antiviral activity in in vitro models at doses of 1.2 and 2.4 mg/mL (Sun et al., 2018) . After intravenous treatment of LMWFs (2.5, 5, 10, and 15 mg/kg; 14 days), in vivo results showed that LF1 and LF2 were able to lengthen the survival duration of mice infected with the virus, as well as dramatically increase the value of immune organs, immune cells, phagocytosis, and humoral immunity. LMW fucoidans extracted from L. japonica displayed antiviral activity in both in vitro (2.5, 5, 10, 15 mg, adenovirus, I-type influenza virus, and Parainfluenza virus I were used to infect Hep-2, Hela and MDCK cells) as well as in vivo (virus-infected mice;2.5, 5, 10, 15 mg kg−1) (Sun et al., 2018) . Fucoidan extracted from K. crassifolia could be used to combat extremely pathogenic strains like H5N1 and H7N9. Fucoidan has the immense potency to be used as a novel nasal drop or sprig for influenza therapy (Moscona, 2009) . In mice, fucoidan extracted from Fucus evanescens (130-400 kDa) worked as an adjuvant by encouraging the development of definite antibodies against HBV's surface antigens, like HBs-AG (Liang, 2009) . Fucoidan from Fucus vesiculosus repressed HBV reproduction in in vivo and in vitro models by activating the EKR signalling pathway. It also increased the type I interferon production by activating the host immune system (Kuznetsova et al., 2017) . In addition to this, fucoidan can be used as an individual drug or in combination with other drugs to treat HBV. HBV replication was considerably suppressed in a rat model of fucoidan (100 mg (Thuy et al., 2015) . S. polycystum (FSP), S. mcclurei (FSM), and Turbinaria ornata (FTO) fucoidans demonstrated anti-HIV activities with IC50s ranging from 0.33 to 0.7 g/mL (Thuy et al., 2015) . These fucoidans suppressed the HIV-1 infection when pre-incubated with the virus but not with the cells after infection, indicating that they can limit HIV entrance into aimed cells at an early stage (Thuy et al., 2015) .

With no cytotoxicity, Fucoidan (galactofucan) from Adenocystis utricularis inhibited HSV-1 and HSV-2 (Ponce, Pujol, Damonte, Flores, & Stortz, 2003) . Moreover, Dictyota dichotoma fucoidan (galactofucan) inhibited HSV-1 by decreased plaque formation (Rabanal, Ponce, Navarro, Gómez, & Stortz, 2014) . Fucoidan (glucuronic acid, sulfated fucose) isolated from Cladosiphon okamuranus inhibited DENV-2 directly binding to the spike protein (Hidari et al., 2008) . Sulfated fucans isolated from Cystoseira indica inhibited adsorption of HSV-1, HSV-2 (Mandal et al., 2007) . Xylan-fucoidan extracted from Caulerpa brachypus displayed inhibitory activity against HSV-1 via inhibiting attachment, penetration, and later stages of replication (J. HIV-1 Inhibition of virus with low IC 50 value ranging from 0.33 to 0.7 g/mL and limit HIV entry into target cells at an early stage (Thuy et al., 2015) 22 S. polycystum HIV-1 Inhibition of virus with low IC 50 value ranging from 0.33 to 0.7 g/mL and limit HIV entry into target cells at an early stage (Thuy et al., 2015) 23 Turbinaria ornata HIV-1 Inhibition of virus with low IC 50 value ranging from 0.33 to 0.7 g/mL and limit HIV entry into target cells at an early stage (Thuy et al., 2015) J o u r n a l P r e - Penaeus monodon has been found to be effective against with reported mortality of 61.65% (Sivagnanavel murugan et al., 2012) J o u r n a l P r e -p r o o f Journal Pre-proof

A wide range of fucoidans was used to examine the current pandemic produced by the SARS-CoV-2 in vitro and in vivo models. In in vitro models, fucoidan demonstrated direct inhibitory efficacy against SARS-CoV-2, indicating that it could be useful as a therapeutic drug.

The fucoidan fractions have an inhibitory effect on viral spike protein binding. In an in vitro infection model, unfractionated of fucoidan from F. vesiculosus and U. pinnatifida showed minimal efficacy against SARS-CoV-2 (Fitton, Park, Karpiniec, & Stringer, 2021) . Fucoidan (15.6 µg/mL) inhibitd SARS-CoV-2 in vitro via binding to the S glycoprotein of the virus. Sulfated polysaccharides (9.10 µg/mL) inhibited SARS-CoV-2 in vitro model via S glycoprotein binding (S. . LMW and HMW extracted from S. japonica are expected to display in vitro antiviral properties against SARS-CoV-2 via binding to S-proteins of SARS-CoV-2. HMW fucoidan (8.3 µg/mL) from Saccharina japonica are more potent than LMW (16 µg/mL) (Kwon et al., 2020) . Sulfated fucan extracted from Lytechnius variegatus and sulfated galactan isolated from Botryocladia occidentalis demonstrated an SGP binding efficacy and transduction efficacy of a third progeny lentiviral (pLV) vector. It modulated pLV-S particles even with an IC 50 of lower ng to higher µg/L (Tandon et al., 2021) . Sulfated galactofucan (1, 3linked-L-Fucp residues sulfated at C4 and C2/C4 and 1, 3-linked-L-Fucp residues sulfated at C4 and branched with 1, 6-linked-D-galacto-biose) reduced interaction between SARS-CoV-2 SGPs and heparin, but not ACE2 (W. Jin et al., 2020) . Sulfated fucoidan and crude polysaccharides, isolated from six seaweed species such as Laminaria japonica, Undaria pinnatifida sporophyll, Sargassum horneri, Hizikia fusiforme, Porphyra tenera, Codium fragile inhibited viral infection with an IC 50 value (12~289 µg/mL) against SARS-CoV-2 pseudo virus in HEK293/ACE2 (S. K. Yim et al., 2021) .

The crude polysaccharide extracted from S. horneri exhibited robust antiviral activity, with an IC 50 value of 12 µg/mL, to prevent the entry of the COVID-19 virus (S. K. Yim et al., 2021) . The crude polysaccharide from H. fusiforme can also hinder SARS-CoV-2 infection with an IC 50 value of 47 µg/mL (S. K. Yim et al., 2021) . The higher molecular weight (>800 kDa), higher total carbohydrate (62.7~99.1%), higher fucose content (37.3~66.2%), and highly branched structures contribute towards their antiviral activity. Fucoidan (3.90-500 μg/mL) can prevent the SARS-CoV-2 entry into the cell via binding to the S glycoprotein (S. . Fucoidan at a 0.01-10% concentration prevented the respirational tract infections triggered by the SARS-CoV-2 virus (Flaviviridae et al.) . Fucoidan, at an approximate concentration of 83 nM binds to the spike protein of the SARS-CoV-2 in in vitro model, averting its host cell binding (Kwon et al., 2020) . Moreover marine sulfated polysaccharides displayed a potent inhibitory activities against SARS-CoV-2 at concentrations of 3.90-500 μg mL −1 (Shuang . Fucoidan significantly restores the ΔΨm of HPBMC, suggesting that fucoidan can be useful to improve mitochondrial homeostasis after SARS-CoV-2 infection (Díaz-Resendiz et al., 2022) . Crude polysaccharides from seaweeds nhibits SARS-CoV-2 Virus entry (S.-K. Yim et al., 2021) . Rhamnan sulfate from Monostroma nitidum displayed strong antiviral activities against wild type SARS-CoV-2 and the delta variant in vitro (Song et al., 2021) .

Sulfated galactofucan from Saccharina japonica showed strong binding ability to SARS-CoV-2 SGPs, suggesting that might be a good candidates for preventing and/or treating SARS-CoV-2 (Weihua Jin et al., 2020).

Preclinical progress, also known as preclinical studies or nonclinical studies, is a stage of drug development that occurs before clinical trials (human testing) and collects essential J o u r n a l P r e -p r o o f Journal Pre-proof feasibility, iterative testing, and drug safety data, usually in laboratory animals. Preclinical studies' major goals are to select a starting, safe dose for first-in-human studies and to analyse the product's potential toxicity, which usually includes new medical devices, prescription medications, and diagnostics. Companies utilise exaggerated numbers to show the dangers of preclinical research, such as the fact that only one out of every 5,000 molecules that go from drug discovery to preclinical development becomes an approved medicine. In this regards, fucoidan gaining the attraction of preclinical test. Fucoidan from Kjellmaniella crassifolia significantly increased the survival and reduced the viral titers IAV-infected mice (Wei Wang et al., 2017) . Low molecular weight of fucoidan from brown algae Laminaria japonica tested in an infected mouse model displayed a prolonged survival time of mice infected with HPIV 1 (Sun et al., 2018) . Sulfated polysaccharide Laminaria japonica was tested in an infected mouse model. IV injection of low molecular weight fucoidan showed a prolonged survival time of virus-infected mice (Leibbrandt et al., 2010) . Furthermore, fucoidan from Undaria pinnatifida has been demonstrated to inhibit influenza A virus in vivo replication in mice infected models by lowering viral replication and enhancing humoral immunity (neutralizing antibodies) (Kyoko Hayashi, Lee, Nakano, & Hayashi, 2013; Synytsya et al., 2014) . Orally administration of fucoidan (7.04 mg/day) from Undaria pinnatifida significantly reduced gross lung pathology (consolidation) in a BALB/c mouse model of severe H1N1 (PR8) influenza, when administered at the same time as the viral infection (Richards et al., 2020) . Sun et al. isolated two LMWF fractions from L. japonica. In vivo data showed that LF1 and LF2 were able to extend the survival duration of virus-infected mice (Sun et al., 2018) . From the above preclinical status fucoidan as well as LMWF (low molecular weight fucoidan) may be further developed to be used for clinical purposes. Alhough the aforementioned findings suggest that J o u r n a l P r e -p r o o f fucoidan could be a promising anti-viral medication, more in vivo research is still needed before clinical trials can begin.

J o u r n a l P r e -p r o o f 

Immunity is the primary concern in COVID-19 suffering individuals (Sen et al., 2021) .

After treating with drugs, the patients gradually become immune-compromised (De Mello et On the other hand, a healthy gut microbiome is essential for modulating antiviral immunity via improving gut flora (Zuo et al., 2020) . In such circumstances, algae-based sulfated polysaccharides can be used as food supplements to enhance gut microbiota and reduce the infection of novel SARS-CoV-2. Gut microbiota symbiosis associated with ACE2 plays a pivotal role in improving antiviral immunity by stimulating interferon production, decreasing immunopathology, increasing natural killer (NK) and cytotoxicity in COVID-19 suffering patients (He, Wang, Li, & Shi, 2020) . Marine sulfated polysaccharides such as fucoidans trigger human gut microbiota and maintain the host health via controlling proper metabolism, the epithelial barrier integrity and immune system as prebiotics and nutritional food supplements (Tamama, 2021 and 4 (TLR2 and TLR4) (Neyrinck et al., 2017) . Fucoidan isolated from Sargassum polycystum modulates the gut microbiota and triggers immunity. Sulfated polysaccharides isolated from

Ascophyllum nodosum activate the abundance of beneficial firmicutes and bacteroidetes . Moreover, Other Algae-based polysaccharides also exhibit beneficial effects to human gut microbiota (Pereira & Critchley, 2020) . Sargassum muticum and Osmunde apinnatifida extracts have been used as novel functional foods and positively influence human gut microbiota (Rodrigues et al., 2016) . The immunomodulatory properties of fucoidan isolated from Brown algae is promising (Wu et al., 2016) . LMW fucoidans such as LF1 and LF2 could enhance the spleen index, thymus index, phagocytic index, half hemolysin and phagocytosis coefficient value even at doses of 2.5, 5, 10, 15 mg kg −1 . The aforementioned results indicated that LMW fucoidans can recover the eminence of immune organs, enlightening immune cell phagocytosis and humoral immunity of virus-infected cells (Sun et al., 2018) . Nanoparticular CpG-adjuvanted SARS-CoV-2 S1 protein triggers broadly neutralizing and Th1-biased immunoreactivity in mice (Lin et al., 2021) . The viral immune responses against COVID-19 and dermatologic immunomodulator targets are shown in 

Immunocompromised people have a diminished the ability to fight aganist infections and other disorders. The immune system has been weakened in primary immunocompromised people. Many types of primary immunodeficiency illnesses can benefit from treatments that enhance the immune system (Sobh & Bonilla, 2016) . The signs and symptoms of primary immunodeficiency disorders fluctuate based on the type, and also vary from person to person.

Inflammation and infection of internal organs, blood disorders (low platelet count or anaemia), igestive problems (cramping, loss of appetite, nausea and diarrhea), and symptoms of immunocompromised disorders such as frequent and recurrent pneumonia, bronchitis, sinus infections, ear infections, meningitis, or skin infections, inflammation and infection of internal organs (Sobh & Bonilla, 2016) . People with the illness will benefit from new therapies and a higher quality of life as a result of ongoing research (Oguntibeju, 2012) . Immunomodulatory properties of fucoidan have interesting applications, such as vaccine adjuvants (Kyoko Hayashi et al., 2013) . Fucoidan from Undaria pinnatifida (9kDa) tested in H1N1 (A/NWS/33) virus yield in the mucosa of immunocompetent and compromised mice was reduced and stimulated mucosal immunoresponse with IC 50 value 15 µg/mL 5 mg/day post infection (Kyoko Hayashi et al., 2013) . Furthermore, fucoidan from Undaria pinnatifida has been shown to inhibit influenza A virus in vivo replication in infected mice and improve innate immunity (natural killer and macrophage activity) via immunity pathways (Kyoko Hayashi et al., 2013; Synytsya et al., 2014) . Hayashi et al. discovered that a fucoidan isolated from Undaria pinnatifida had anti-IAV activity enhancing immune system in mice In mice with normal and reduced immunity (Kyoko Hayashi et al., 2013) . Fucoidans could also be employed as vaccine adjuvants in mice, activating J o u r n a l P r e -p r o o f Journal Pre-proof spleen cells and increasing antigen-specific antibody production (Kim & Joo, 2015) . Intranasal administration of fucoidan from Kjellmaniella crassifolia (10 and 20 μg/day) treatment significantly increases the survival of IAV-infected mice and improved the immunity (Fukushi et al., 2011) . Fucoidan could be a promising candidate in immunocompromised patients.

Algal sulfated polysaccharides could be used as antiviral drugs as individual entities or in combination with clinically approved antiviral drugs, which can combat COVID-19. Although the vaccination program has started, sulfated polysaccharides like fucoidan can still exert potential immunomodulatory efficacy against COVID-19 infection. Moreover, it can also modulate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and lesser the risk of viral contaminations in the post-COVID era. Furthermore, fucoidan can act as food supplements that can limit the injury of the respiratory system post-viral infections via restoring innate immune function and preventing inflammation. Study of the chemical composition, antiviral potency, and mechanisms associated with SARS-CoV-2 of sulfated polysaccharides with the special notation to fucoidan is urgently needed to be established as an antiviral agent as well as an immunomodulator in pharmaceutical sectors.

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Inhibitory activities of marine sulfated polysaccharides against SARS-CoV-2

Inhibitory activities of marine sulfated polysaccharides against SARS-CoV-2

Anti-SARS-CoV-2 Activity of Rhamnan Sulfate from Monostroma nitidum

Respiratory Virus Infections: Understanding COVID-19

Studies on antiviral and immuno-regulation activity of low molecular weight fucoidan from Laminaria japonica

Mekabu fucoidan: Structural complexity and defensive effects against avian influenza A viruses

Potential benefits of dietary seaweeds as protection against COVID-19

Effective Inhibition of SARS-CoV-2 Entry by Heparin and Enoxaparin Derivatives

The trinity of COVID-19: immunity, inflammation and intervention

Anti-HIV activity of fucoidans from three brown seaweed species

Antiretroviral activity of fucoidans extracted from the brown seaweed Adenocystis utricularis

Coronavirus biology and replication: implications for SARS-CoV-2

Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry

The antiviral activities and mechanisms of marine polysaccharides: an overview

Inhibition of influenza A virus infection by fucoidan targeting viral neuraminidase and cellular EGFR pathway

Inhibition of Influenza A Virus Infection by Fucoidan Targeting Viral Neuraminidase and

Sulfated polysaccharides extracted from sea algae as potential antiviral drugs

Activity of a sulfated polysaccharide extracted from the red seaweed Aghardhiella tenera against human immunodeficiency virus and other enveloped viruses

The antioxidant, immunomodulatory, and anti-inflammatory activities of Spirulina: an overview

Antiviral effects of sulfated exopolysaccharide from the marine microalga Gyrodinium impudicum strain KG03

Inhibition of SARS-CoV-2 virus entry by the crude polysaccharides of seaweeds and Abalone viscera in vitro

Inhibition of SARS-CoV-2 Virus Entry by the Crude Polysaccharides of Seaweeds and