Introduction

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which mainly affects the respiratory system. It was initially identified in December 2019 in Wuhan City, China. The World Health Organization declared COVID-19 as a pandemic disease in March 2020 due to the high spreading rate among 194 countries, including the USA, Africa, Europe, India, and Sri Lanka (WHO, 2020). To date, the WHO has estimated 423,437,674 globally confirmed COVID-19 cases with 5,878,328 deaths (WHO 2022). According to Sri Lankan statistics, 638,043 confirmed COVID-19 cases have been identified together with 16,024 deaths to date (Amaratunga et al. 2020.; Health Promotion Bureau 2022).

SARS-CoV-2 is an airborne disease that mainly affects the respiratory system and causes mild, moderate, to severe respiratory illness which can further progress into a life-threatening condition. The severity of the COVID-19 infection is linked with the secretion of a high level of inflammatory mediators such as cytokines, interleukins, tumor necrosis factor, and C-reactive proteins which, in turn, exacerbate the inflammatory reactions in the body. The high level of cytokines which refers to the “cytokine storm” is associated with the high mortality rate of COVID-19 infections among survivors and non-survivors (Hojyo et al. 2020; Tang et al. 2020). Beyond that, SARS-CoV-2 can cause damage to multiple systems which, in turn, lead to multiorgan failure and death (Lakhani et al. 2021; Morhtari et al. 2020). The infected people are suffering from shortness of breath, sore throat, cough, fatigue, headache, fever, myalgia, and diarrhea, and furthermore, it can lead to life-threatening conditions including pulmonary edema and severe pneumonia (Hojyo et al. 2020).

As vaccination is highly effective against infectious diseases, several vaccines are developed for the prevention of COVID-19 infection. Among them, eight vaccines including AstraZeneca–Oxford, Sinopharm, Sinovac Biotech, Pfizer–BioNTech, Gamaleya, CanSino Biologics, Janssen, and Moderna are authorized and approved for public use to date (Yim et al. 2021a, b). However, due to the limited availability of COVID-19 vaccines, it is very difficult to fulfill the requirement of global COVID-19 vaccination. Even though the developed countries have the capacity to achieve full coverage of COVID-19 vaccination, statistics showed that around 4% of people who are living in low-income countries are vaccinated yet (World Bank 2020). Therefore, in place of vaccination programs, it is very important to search for natural remedies to prevent or treat COVID-19 infection.

Among the natural resources, seaweeds are a rich source of bioactive compounds including polyphenols, flavonoids, sulfated polysaccharides, proteins, peptides, vitamins, and minerals. Macroalgae are extremely diverse groups of aquatic, eukaryotic, multicellular, photosynthetic organisms possessing chlorophyll a, ranging in size from a few millimeters to several meters (Adl et al. 2012; Baldauf 2008; Burki et al. 2016). The bioactive compounds in seaweeds have been reported to exhibit significant pharmacological effects such as antiviral (Wang et al. 2008; Gheda et al. 2016), antibacterial (Perez et al. 2016), antidiabetic (Gunathilaka et al. 2021a, b; Gunathilaka et al. 2020), anticancer (Gunathilaka et al. 2021c; Gutierrez-Rodriguez et al. 2018), anti-inflammatory (Barbalace et al. 2019), immunomodulatory (Palstra et al. 2018), and antioxidant (Farasat et al. 2014) effects. Recent research has confirmed that the sulfated polysaccharides in seaweeds have the potential ability to act against SARS-CoV-2 (Kwon et al. 2020). Further research proved that phlorotannins extracted from seaweeds have the ability to act against SARS-CoV-2 (Kandeel and Al-Nazawi 2020; Qamar et al. 2020). Therefore, the present review mainly focuses on the utilization of bioactive compounds in marine seaweeds as a promising defense against COVID-19 infection.

Structure and Mechanism of Action of SARS-CoV-2

Structure of SARS-CoV-2

The human coronavirus was first observed and studied by two scientists: June Almeida, a Scottish virologist, and David Tyrrell, a British virologist. In 1968, the word “coronavirus” was first published referring to the characteristic appearance of virion morphology (Almeida et al. 1968) and intracellular binding site (Kathryn 1999). The morphology of the coronavirus was suggested based on the surface viral proteins (Sturman and Holmes 1983). According to epidemiological studies, five SARS-CoV-2 variants have been identified since the beginning of the pandemic as alpha, beta, gamma, delta, and omicron (Cascella et al. 2022). Both COVID-19 and SARS-CoV-2 were officially published by the WHO in February 2020 (WHO, 2020).

SARS-CoV-2 belongs to the family of Coronaviridae, and it is a single-stranded positive-sense RNA virus (Neuman et al. 2006). The long single-stranded RNA is tightly packed at the center of the virus structure, and it is further encoded with capsid proteins called “nucleocapsid” (Wang et al. 2020). The RNA together with the nucleocapsid located at the core of the virus is further surrounded by an outer membrane that consists of lipids and three structural proteins including envelop proteins (E), membrane proteins (M), and spike proteins (S) as shown in Fig. 1 (Lai and Cavanagh 1997; Mittal et al. 2020). The spike proteins present in the outer membrane protrude from the viral surface and mediate the entry of coronavirus into host cells. The spike protein consists of two functional subunits called subunit 1 (S1) and subunit (S2). S1 is composed of the receptor-binding domain (RBD) and N-terminal domain (NTD) which facilitate the binding of coronavirus to the receptors of the host cells. The receptor-binding domain of S1 of spike protein can specifically recognize the angiotensin-converting enzyme 2 (ACE2) receptors (Figs. 1 and 2). Similarly, S2 is composed of several components such as transmembrane domain (TM), connector domain (CD), fusion peptide (FP), central helix (CH), heptad repeat 1 (HR1), heptad repeat 2 (HR2), and cytoplasmic tail (CT) that facilitate the fusion of viral membrane with the host cells (Fig. 2) (Wang et al. 2020). Other than the structural protein, SARS-CoV-2 consists of 16 non-structural proteins which facilitate viral replication, within the host cells via a series of mechanisms, and act as a potential source for vaccine synthesis (Yadav et al. 2021).

Fig. 1
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The structure of SARS-CoV-2

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Fig. 2
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Schematic diagrams of A SARS-CoV-2 binding to ACE2 receptors and B SARS-CoV-2 spike proteins. NDT, N-terminal domain; RBD, receptor-binding domain; FP, fusion peptide; HR1, heptad repeat 1; HR2, heptad repeat 2; TM, transmembrane domain; CT, cytoplasmic tail

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Mechanism of Action of SARS-CoV-2

SARS-CoV-2 enters the human lung cells via ACE2 receptors. Among the structural proteins, a spike protein present on the viral membrane binds with ACE2 receptors on lung cells and gains access to the entry of human lungs. During this process, human cells ingest viral cells via the process called “endocytosis” (Mittal et al. 2020). Once SARS-CoV-2 enters the host cells, S1 and S2 of spike proteins are cleaved by host proteases including trypsin and furin which release the FP present in S2 to activate the membrane fusion mechanisms within the endosome. As a result of the activation of membrane fusion mechanisms, viral RNA is released into the cytoplasm. With this process, viral RNA starts its replication process and produces thousands of viral RNA copies other than the structural and non-structural proteins and assembles into new virions within the endoplasmic reticulum-Golgi intermediate compartment. Ultimately, the synthesized new virions are transported via exocytosis and gain the capability to infect other body cells (Boopathi et al. 2021).

Therapeutic Targets for COVID-19

The therapeutic targets of SARS-CoV-2 can be discussed in three different steps as SARS-CoV-2 replication cycle, the spike protein during entry, the main protease during proteolytic activation, and RNA-dependent RNA polymerase during transcription (Krumm et al. 2021). Concerning the spike proteins present on the surface of SARS-CoV-2, angiotensin-converting enzyme 2 plays a major role as it is the major human receptor for the S protein and facilitates viral entry (Zhou et al. 2020; Li et al. 2020).

The SARS-CoV-2 gains access to the human body via ACE2 receptors that are mainly found in the alveolar epithelial type 2 cells. Therefore, the expression of ACE2 receptors in alveolar epithelial cells determines the most vulnerable individuals to SARS-CoV-2 infection. ACE2 receptors are involved in the regulation of blood pressure and inflammatory conditions via the renin-angiotensin system (Tamama 2021). Both angiotensin-converting enzyme (ACE) and ACE2 are involved in the renin-angiotensin system which regulates blood pressure. The ACE is a carboxypeptidase that catalyzes the conversion of angiotensin I into angiotensin II which stimulates vasoconstriction and inflammatory effects. In contrast, ACE2 converts angiotensin II into angiotensin (1–7) which stimulates vasodilatation and anti-inflammatory effects (Fig. 3). Therefore, ACE2 has protective effects against severe acute lung injuries in COVID-19 whereas ACE exacerbates the inflammatory conditions in lung tissues. Therefore, inhibition of the ACE leads to stimulating ACE2 which leads to producing angiotensin (1–7) that exerts protective effects against COVID-19 infection (Malha et al. 2020).

Fig. 3
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The involvement of the renin-angiotensin system in the prevention of inflammatory conditions in SARS-CoV-2 infection

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The infection of SARS-CoV-2 exacerbates the inflammatory condition in the body and leads to cause acute respiratory distress syndrome (ARDS) mainly by secreting high levels of cytokines which is refer to a cytokine storm. The high levels of cytokines such as chemokines, interferons, tumor necrosis factors, granulocyte–macrophage colony-stimulating factors, and interleukins are released as a result of the activation of innate immune mechanisms against the virus (Tamama 2021). The excessive secretion of cytokines attracts leukocytes via diapedesis by increasing vascular permeability and coagulability which stimulates the local inflammatory reactions and cell destruction. Furthermore, the cytokine storm induces cellular apoptosis and necrosis, lesions of the alveolar membrane, and fibrin deposition which leads to cause pulmonary fibrosis. Ultimately, all the mechanisms lead to cause multiorgan failure, ARDS, and death if inadequately treated (Krumm et al. 2021).

Similarly, reactive oxygen species act as the main stimulant in the activation of immune responses in COVID-19 infection. The SARS-CoV-2-infected lung tissues generate a high level of reactive oxygen species which stimulate the oxidation of phospholipids in pulmonary surfactants. The oxidized phospholipids stimulate alveolar macrophages to secrete cytokines mainly interleukin 6 (IL-6) via Toll-like receptor 4 that exacerbate acute lung injury (Jung and Lee 2021). Therefore, based on the literature, IL-6 together with other cytokines elevates the inflammatory condition in severe COVID-19.

Marine-derived Bioactive Compounds for the Treatment of COVID-19

Marine seaweeds have been identified as an important source of bioactive compounds comparable or superior to herbal medicines. In the last few years, marine seaweeds have been widely studied due to the presence of human-beneficial bioactive components (Gunathilaka et al. 2021a, b, c). Marine seaweeds are categorized into three groups as red algae (Rhodophyta), brown algae (Phaeophyta), and green algae (Chlorophyta) depending on the presence of accessory pigments. All groups of marine algae contain chlorophyll a, which assists in the process of photosynthesis. The characteristic color of different algal species is derived from accessory pigments. Marine green algae (Chlorophyta) have a characteristic green pigmentation mainly due to chlorophylls a and b that is approximately the same as in the amount present in higher plants. Phycoerythrin and phycocyanin are the pigments present in the marine red algae (Rhodophyta) which give a characteristic red color by masking the other pigments, such as chlorophyll a, beta-carotene, and xanthophylls. Xanthophyll pigments and fucoxanthin are responsible for the brown color of brown algae (Phaeophyta) by masking the other pigments, such as chlorophylls a and c, β-carotenes, and other xanthophylls.

Bioactive compounds present in marine seaweeds including polyphenols, flavonoids, alkaloids, tannins, sterols, proteins, enzymes, essential fatty acids, peptides, vitamins, and pigments are reported to exhibit different pharmacological activities. The composition of bioactive compounds varies depending on the environmental conditions including salinity, temperature, pH, level of sunlight, and availability of CO2 (Gunathilaka and Peiris 2022). This section mainly focuses on how marine-derived bioactive compounds are utilized for the treatment of COVID-19.

Effect of Marine-derived Polyphenolic Compounds Against COVID-19

Marine seaweeds are a rich source of polyphenols including flavonoids, phlorotannins, and bromophenols. Among different types of polyphenolic secondary compounds, phlorotannins are polyphenolic compounds that are mainly found in brown algae made up of phloroglucinol subunits. Depending on the number of phloroglucinol subunits, phlorotannins are categorized into six subunits as eckols, fucols, fuhalols, phlorethols, fucophlorethols, and carmalols. Phlorethols are made up of two phloroglucinol subunits whereas eckols are made up of three phloroglucinol subunits (Gunathilaka et al. 2020). Figure 4 shows the structure of the repeating unit phloroglucinol and the different groups of phlorotannins.

Phlorotannins are reported to exhibit potential bioactivities including antioxidant, antimicrobial, antiviral, anti-allergic, antidiabetic, anti-inflammatory, anticancerous, and neuroprotection (Catarino et al. 2021). Further several studies have proved the anti-inflammatory activities of the phlorotannins isolated from marine seaweeds (Kwon et al. 2020; Ryu et al. 2021). Similarly, Bharathi et al. (2022) investigated the interactivity of algal molecules on SARS-CoV-2-RBD/ACE2 and SARS-CoV-2 spike/TMPRSS2 receptors using a silica model. Phlorotannins are reported to exhibit anti-inflammatory effects mainly by reducing the level of proinflammatory cytokines and reactive oxygen species (Catarino et al. 2021). Furthermore, phlorotannins have the ability to reduce cytokine storm in SARS-CoV-2 infection (Tamama 2021; Hu et al. 2021). Similarly, oxidative stress is one of the important mechanisms in the COVID-19 antiviral immune response (Wieczfinska et al. 2022). As phlorotannin exhibits several antioxidant mechanisms, it can be utilized to enhance the antiviral immune response in COVID-19 infection. Previous studies confirmed that phlorotannins exhibited potent antioxidant activity as determined by several mechanisms including DDPH and ABTS radical scavenging activity. Further studies reported that the phlorotannins isolated from Ecklonia stolonifera, Ecklonia kurome, and Eisenia bicyclis including phlorofucofuroeckol A, dieckol, and eckol exhibited potent antioxidant activity compared to the α-tocopherol, catechin, and ascorbic acid (Shibata et al. 2008). Phlorotannins extracted from Fucus vesiculosus, Fucus serratus, and Ascophyllum nodosum reduced the oxidative degradation of DNA in stress-induced cells (Kang et al. 2012). Other than that, phlorotannins have the ability to induce auto-antioxidant defenses present in cells by activating detoxifying enzymes including superoxide dismutase and catalase. Studies confirmed that the phlorotannin-rich extracts of F. vesiculosus, F. serratus, and A. nodosum activated superoxide dismutase and catalase (O’Sullivan et al. 2012). Similarly, phlorotannins exhibit anti-inflammatory effects mainly by reducing the levels of proinflammatory cytokines and also by inhibiting angiotensin-converting enzymes. Previous studies have proved that phlorotannin extract of Ecklonia cava reduced the levels of proinflammatory cytokines including interleukins (IL-6 and IL-1β) and tumor necrosis factor (TNF-α) (Kim et al. 2019). Furthermore, a previous study has confirmed that phlorotannins mainly dieckol isolated from E. cava have the ability to inhibit SARS-CoV competitively except for the monomeric phloroglucinol (Park et al. 2013). Therefore, phlorotannins in E. cava could be potential against SARS-CoV-2 as well. Correspondingly, phlorotannins inhibited ACE which is another target to reduce the inflammatory condition in COVID-19 infection. Phlorotannins extracted from brown seaweeds reduced inflammatory conditions by inhibiting ACE. Dieckol (IC50: 1.47 Mm) extracted from E. cava inhibited ACE in a non-competitive manner. Furthermore, phlorotannins extracted from Ecklonia stolonifera including eckol, dieckol, and phlorofucofuroeckol A exhibited a potent inhibitory activity on angiotensin-converting enzymes with IC50 values of 70:82 ± 0:25 μM, 34:25 ± 3:56 μM, and 12:74 ± 0:15 μM, respectively (Gunathilaka et al. 2021a, b, c). Among the isolated phlorotannins, dieckol inhibited the ACE non-competitively. Similarly, dieckol, 8,8-bieckol extracted from Ecklonia cava, acts as a protease inhibitor (Silva et al. 2020). Furthermore, phloroglucinol (IC50: 56.96 μg/ml) extracted from Sargassum wightii inhibited ACE compared to the reference drug captopril (IC50: 51.79 μg/ml) (Gunathilaka et al. 2021a, b, c).

Phlorotannins are unique compounds present in marine brown algae and can be extracted by several methods. Phlorotannin can be extracted by 30% ethanol–water solvent with a solid (freeze-dried seaweed powder/liquid ratio of 1:5 at a temperature of 25 °C for 30 min (Li et al. 2017).

Effect of Marine-derived Proteins and Peptides Against COVID-19

Most edible marine seaweeds are rich in proteins and peptides that exhibit an inhibitory effect on ACE. Therefore, marine-derived proteins and peptides can also be utilized to reduce inflammatory conditions in COVID-19 infection. Enteromorpha clathrata is an edible green seaweed that can be utilized to inhibit ACE by the action of its protein-derived hydroxylate (Gunathilaka et al. 2021a, b, c). Furthermore, protein-derived hydroxylate of the red seaweed Palmaria palmata inhibited ACE, thereby reducing inflammatory conditions in COVID-19 (Admassu et al. 2018). Furthermore, a protein hydroxylate of Gracilariopsis lemaneiformis, Porphyra dioica, Neopyropia yezoensis, Pyropia columbina, Palmaria palmata, Bangia fuscopurpurea, Sargassum maclurei, Laminaria japonica, Undaria pinnatifida, Ulva intestinalis, Ulva rigida, Ulva lactuca, Enteromorpha clathrata, and Caulerpa lentillifera inhibited ACE, thereby reducing the inflammatory conditions in severe COVID-19 infection (Echave et al. 2022). Marine peptides are present in all three types of marine algae and extracted mainly by using bioassay-guided fractionation using methanol or ethyl acetate which has been subjected to partition with hexane or dichloromethane. The partially purified extract was subjected to silica gel column chromatography, and final purification was conducted using the reverse-phase HPLC technique (Cheung et al. 2015).

Effect of Marine-derived Sulfated Polysaccharides Against COVID-19

The sulfated polysaccharides are present in the cell walls of marine seaweeds and possess human-beneficial biological activities including anticoagulant, antiviral, antioxidant, anticancer, and anti-inflammation, hence utilized in many industries of cosmetics, foods, and pharmaceuticals. The unique properties of sulfated polysaccharides are based on the chemical structure, molecular weight, and chain conformations. The brown algae contain fucoidan, alginates, and laminaran as sulfated polysaccharides with beneficial biological effects (Gunathilaka et al. 2021a, b, c). Similarly, red seaweeds contain carrageenans and agarans as sulfated polysaccharides while ulvan is present in green seaweeds. The chemical structure of repeating dimeric units of fucoidan, carrageenan, and ulvan are shown in Fig. 5.

Fig. 4
figure 4

Chemical structure of phloroglucinol and groups of phlorotannin

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Fig. 5
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The chemical structure of repeating dimeric units of fucoidan, carrageenan, and ulvan

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Marine-derived sulfated polysaccharides are found in the cell wall of marine seaweeds and are reported to exhibit antiviral activity. Fucoidan is a sulfated polysaccharide that exhibits antiviral activity by reducing the secretion of proinflammatory cytokines mainly interleukins (Tamama 2021). Further studies proved that fucoidan reduced lung fibrosis in a mouse model (Yu et al. 2018). Therefore, it can be utilized to prevent pulmonary fibrosis in severe COVID-19 infection. Furthermore, a study conducted by Kwon et al. (2020) reported that fucoidan isolated from Saccharina japonica exhibited potent antiviral activity against SARS-CoV-2 by binding with spike glycoprotein of the virus which inhibits the binding of spike glycoprotein with ACE2 receptors of host cells. Furthermore, fucoidan extracted from Adenocystis utricularis, Cystoseira indica, Fucus vesiculosus, and Undaria pinnatifida exhibited anti-inflammatory activity by inhibiting adhesion and blocking reverse transcriptase enzyme (Kuznetsova et al. 2020; Krylova et al. 2020). Similarly, galactans are the main polysaccharide found in different marine seaweeds (Kumar et al. 2022a, b). Galactans extracted from Agardhiella tenera, Schizymenia binderi, and Callophyllis variegate exhibited antiviral activity by blocking the viral adhesion and replication into host cells (Ohta et al. 2009). Carrageenan, a sulfated polysaccharide found in marine red seaweeds, has the ability to inhibit viral infections mainly by obstructing the entry of viral particles into the host cells (Singh et al. 2021). Another study has reported that the carrageenan nasal spray was effective against the common cold caused by a human coronavirus (Koenighofer et al. 2014). Furthermore, lozenges (medicinal tablets) prepared using carrageenan were effective for throat problems caused by the human coronavirus OC43. This study has further proved that carrageenan has effectively inactivated the viral glycoproteins (Morokutti-Kurz et al. 2017). Moreover, carrageenan extracted from Gigartina skottsbergii exhibited antiviral activity via the inhibition of binding or internalization of viruses into host cells (Nagle et al. 2020; Grassauer et al. 2011). Therefore, based on the previous studies, carrageenan can be effective against SARS-CoV-2 as well.

Alginates are natural anionic polymers extracted from brown seaweed (Serrano-Aroca et al. 2021). Based on the previous studies, alginate extracted from Laminaria japonica and Laminaria digitata exhibited antiviral activity by inhibiting inverse transcriptase in the RNA virus (Tran et al. 2014). As SARS-CoV-2 is an RNA virus, alginate can be effectively utilized to inhibit the action of SARS-CoV-2.

Sulfated polysaccharides present in red, green, and brown algae were extracted using several methods. Sulfated polysaccharides present in brown seaweeds, mainly fucoidan, were extracted by precipitating with ethanol followed by different steps including acid precipitation, size-exclusive chromatography, or filtration to obtain pure fucoidan. Similarly, sulfated polysaccharides present in red algae, mainly carrageenan, were extracted using two conventional extraction procedures separately to extract refined carrageenan and semi-refined carrageenan. The refined carrageenan was extracted by solubilizing in hot water containing alkali whereas semi-refined carrageenan was extracted by boiling in hot potassium chloride (Jonsson et al. 2020).

Effect of Marine-derived Carotenoids Against COVID-19

Marine seaweeds are rich in carotenoids that include zeaxanthin, neoxanthin, α-carotene, β-carotene, lutein, fucoxanthin, astaxanthin, and siphonaxanthin and are reported to exhibit potent antioxidant and antiviral activities. Fucoxanthin is the most abundant type mainly found in brown algae including Undaria pinnatifida, Laminaria japonica, Sargassum sp., and Fucus sp. Similarly, astaxanthin and siphonaxanthin are mainly present in green algae such as Codium cylindricum, Caulerpa lentillifera, and Codium fragile (Yim et al. 2021a, b). Previous studies have confirmed that fucoxanthin exhibited potent anti-inflammatory activity mainly by reducing the levels of proinflammatory cytokines including interleukins (Tamama 2021). Furthermore, a molecular docking simulation study conducted by Yim et al. (2021) reported that fucoxanthin extracted from Undaria pinnatifida and siphonaxanthin extracted from Codium fragile have the ability to bind with the ACE2 receptors which is the binding site of SARS-CoV-2 spike protein with host cells (Yim et al. 2021a, b). During COVID-19 infection, SARS-CoV-2 induces oxidative stress that assists their replication inside the host cell. As marine algae are a rich source of natural antioxidants, it can be utilized against COVID-19 infection to maintain redox homeostasis in the body. Fucoxanthin, a natural carotenoid present in brown algae, has the ability to scavenge free radicals due to the presence of a specific allenic bond in its structure. Furthermore, studies reported that fucoxanthin extracted from Sargassum siliquastrum inhibited oxidative DNA damage by increasing the production of glutathione peroxidase (Singh et al. 2021).

Carotenoids present in marine seaweeds can be extracted using different methods including ultrasound-assisted extraction, pressurized liquid extraction, and supercritical fluid extraction. Among the different techniques, the Soxhlet extraction method is a conventional method that delivers the highest yield of carotenoids (Ramesh and Young, 2018).

Effect of Marine-derived Omega-3 and Omega-6 Against COVID-19

Seaweeds are rich in both omega-3 and omega-6 which are long-chain polyunsaturated fatty acids. Previous studies reported that both omega-3 and omega-6 fatty acids are involved in the regulation of inflammatory conditions. Omega-3 fatty acids play a key role in regulating the membrane fluidity of neutrophils by incorporating omega-3 fatty acids into the phospholipid bilayer which stimulates the secretion of prostaglandins and leukotrienes to enhance the immune response. Furthermore, it enhances the phagocytic function of macrophages and induces an antiviral response by inhibiting viral replication through the secretion of interferon. Similarly, omega-6 fatty acids stimulate the secretion of cytokines and leukotrienes which enhance the immune response against pathogen invasion (Hathaway et al. 2020). Previous studies have reported that both red and brown seaweeds are rich in omega-3 fatty acids that include linolenic acid, linoleic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Further research proved that brown algae Undaria pinnatifida, Calliblepharis jubata, Bifurcaria bifurcata, and Durvillaea antarctica; red algae Agarophyton chilense; and green algae Ulva lactuca are rich in omega-3 polyunsaturated fatty acids including EPA and DHA which are beneficial to reduce oxidative stress and acute respiratory distress in COVID-19 (Schwalfenberg 2006; Penalver et al. 2020).

Effect of Marine-derived Vitamins Against COVID-19

Seaweeds are a rich source of vitamins including vitamins A, C, D, E, B, and K. As reported, vitamins D, B12, and C have been reported to reduce the inflammatory conditions in COVID-19 infection. Vitamin D3, known as cholecalciferol, modulates the inflammatory responses by reducing the secretion of proinflammatory cytokines. Jayewardena et al. (2021) have reported a significant positive correlation between vitamin D deficiency and COVID-19 infection (Jayawardena et al. 2021). Similarly, previous studies have reported that vitamin B12 inhibited RNA-dependent RNA polymerase activity of SARS-CoV-2 (Narayanan and Nair 2020). Furthermore, vitamin C has the ability to scavenge reactive oxygen species which, in turn, enhances the cellular immune responses and vascular integrity to minimize the severe respiratory infections in COVID-19 (Uddin et al. 2021). Among the edible seaweeds, Fucus spiralis and Gelidiella acerosa are reported to exhibit high vitamin D3 content whereas Ascophyllum nodosum, Laminaria digitata, Undaria pinnatifida, Palmaria palmata, Porphyra umbilicalis, and Ulva sp. are rich in vitamin B12 (Leandro et al. 2020). Seaweeds including Himanthalia elongate, Crassiphycus changii, and Ecklonia arborea are reported to exhibit high vitamin C content (Simat et al. 2020).

Effect of Marine-derived Minerals Against COVID-19

Seaweeds are a rich source of essential minerals including calcium, magnesium, zinc, selenium, sulfate, phosphorus, chloride, sodium, and potassium which are acquired from the marine environment (Penalver et al. 2020). Among the available minerals, zinc is associated with the regulation of immune responses during SARS-CoV-2 infections. Previous studies have reported that zinc level is important to maintain lung integrity to prevent respiratory distress conditions in COVID-19 infections. Furthermore, it was reported that Zn inhibited the entry of SARS-CoV-2 into cells by downregulating the ACE2 receptors and also by inhibiting the fusion of SARS-CoV-2 with the host cell membrane. Furthermore, Zn has the ability to conquer RNA-dependent RNA polymerase of the SARS-CoV-2 (Jahromi et al. 2021). Therefore, seaweeds rich in Zn including Caulerpa lentillifera, Ulva rigida, Chondrus crispus, Palmaria palmata, Porphyra umbilicalis, Fucus vesiculosus, and Himanthalia elongate can be utilized for the treatment of COVID-19 infection (Penalver et al. 2020).

Effect of Marine-derived Prebiotics and Probiotics Against COVID-19

Furthermore, the gut microbiota is also important to prevent gastrointestinal infections associated with COVID-19 infection. SARS-CoV-2 gains access through the ACE receptors on intestinal endothelial cells and cause gastrointestinal infections. Both prebiotics and probiotics are involved in the maintenance of commensal gut microbiota by producing short-chain fatty acids through fermentation which exhibit anti-inflammatory effects. Similarly, soluble dietary fibers present in marine seaweeds are produced from short-chain fatty acids through fermentation by gut microbiota. Previous studies have reported that oral administration of fucoidan increased gut microbiota including Lactobacillus and Bifidobacterium. Similarly, laminarin, alginate, and agar serve as prebiotics (Kurian et al. 2021). Therefore, seaweeds rich in soluble dietary fibers can be utilized to reduce gastrointestinal infections associated with SARS-CoV-2. These findings are summarized in Table 1.

Table 1 Summary of tested algae and possible active agents responsible for the anti-inflammatory/antiviral properties
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Furthermore, sulfolipids and glycolipids present in marine seaweeds are reported to exhibit antiviral activities against the SARS-CoV-2 infection (Kumar et al. 2022a, b).

Conclusion

Marine seaweeds are a rich source of bioactive metabolites that exhibited potent antioxidant, antiviral, and anti-inflammatory effects. Among the bioactive compounds present in marine seaweeds, phlorotannins; fucoidans; fucoxanthin; astaxanthin; omega-3 and omega-6 fatty acids; vitamins B12, D, and C; minerals including zinc and selenium; and soluble dietary fibers exhibited direct or indirect antiviral effects against SARS-CoV-2 infection. Therefore, the present mini-review mainly focused on the contribution of marine bioactive compounds to lower the severity of SARS-CoV-2 infection.