Algal Metabolites as an Immune Booster against COVID-19: Comparison
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Algae and algae-derived products are rich sources of natural products or metabolites synthesized during metabolism. Algae are a rich source of compounds such as lectins and sulfated polysaccharides, which have potent antiviral and immunity-boosting properties. Moreover, Algae-derived compounds or metabolites can be used as antibodies and vaccine raw materials against COVID-19. Furthermore, some algal species can boost immunity, reduce viral activity in humans and be recommended for usage as a COVID-19 preventative measure.

  • algae
  • antiviral
  • COVID-19
  • metabolites
  • SARS-CoV-2

1. Introduction

Since ancient times, plants/plant parts/natural products (extracts and/or metabolites) have been directly or indirectly utilized in allopathic or Ayurveda to cure various human diseases [1][2][3][4]. According to published records, it has been estimated that approximately 40–50% of total known plant species have been used for medicinal purposes [5][6]. Furthermore, more than 25% of modern medicine and nearly 80% of the global population depend upon plant metabolites for primary health treatments [7][8][9]. Algae and algae-derived products are rich sources of natural products or metabolites synthesized during metabolism [10]. These metabolites possess various pharmacological activities, including antibacterial, analgesic, antiviral, etc. In addition, the structural diversity of compounds or constituents such as alkaloids, terpenes, polyphenols, sterols, lactones offers an opportunity for bioactivity and drug design [11][12].
Algae are among the most widespread aquatic, photosynthetic organisms present in both freshwater and marine water [13][14]. Algae are considered an excellent source of secondary metabolites or bioactive compounds [15][16][17]. The cultivation system, growth conditions and growth phases are some prime factors that limit the rate and amount of metabolite production [18][19][20]. Similar to other plant-derived molecules, algal metabolites constitute various compound classes, such as polyphenols, lipids, phytols, terpenes, pigments, sterols, free fatty acids, pigments, vitamins, amino acids, peptides, polysaccharides, chitooligosaccharide and halogenated compounds. These compounds possess a broad range of pharmacological activities [21]. Various authors reported algae-derived metabolites and their significant effect in treating human ailments [22]. These metabolites have also been investigated to enrich pharmaceutical properties to treat various human disorders. For instance, calcium-rich spirulina derived from Spirulina platensis possesses antiviral activity against many human diseases [23]. Similarly, nostoflan, derived from Nostoc flagelliforme, exhibited antiviral activity against the influenza A virus [24]. Cyanovirin-N (CV-N) is a protein derived from Nostoc ellipsosporum which also displayed antiviral action against severe viral diseases, such as human immunodeficiency and simian immunodeficiency [25][26][27]. However, more efforts are being undertaken to discover therapy methods that effectively combat the current COVID-19 pandemic triggered by Coronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Therefore, antiviral compounds in algae must be investigated to identify a viable treatment resource for SARS-CoV-2 [28]. The SARS-CoV-2 genome encodes a variety of structural (spike glycoprotein), non-structural (helicase, 3-chymotrypsin-like, papain-like protease, protease and RNA-dependent RNA polymerase) and auxiliary proteins [29]. It is thought that the spike glycoprotein is essential when viruses and host cell receptors interact. Therefore, much recent research has focused on this structural protein, since it is crucial for virus entrance into host cells [30].

2. Antiviral Metabolites Generated from Algae against SARS-CoV-2

The antiviral activity of many marine algal species and their extracts and metabolites have been reviewed established as antiviral agents against many viruses [31][32]. Spirulina is a dietary supplement with many essential fatty acids, phenolic acids, vitamin B12 and sulfated polysaccharides. It has antiviral properties against pseudo-type coronaviruses because it binds to the 36 spikes of the S1 domain and prevents spikes from interacting with their receptor [33]. Therefore, red algal species Porphyridium sulfated polysaccharides are advocated to serve as promising antiviral medicines that could be utilized to coat sanitary products to prevent COVID-19 [34]. In addition, natural astaxanthin (nASX) extracted from microalgal species (Haematococcus Pluvialis) served as an adjuvant in combination with primary COVID-19 drugs by enhancing their immunity and shortening the period of patient recovery [35]. Similarly, an unusual diterpene derived from the Halimeda tuna possesses antiviral activity against murine coronavirus [36]. Red algae-derived Griffithsin has antiviral properties against MERS (Middle East respiratory disease)-CoV and SARS-CoV [37][38]. In vitro, Griffithsin inhibits a wide range of CoVs in SARS-CoV-infected mice, including HCoV-OC43, HCV-229E and HCV-NL63 [39], because it blocks virus entry and integrase activity, as well as protease and reverse transcriptase activities [40]. Other polysaccharides, such as ulvans (produced from green algae) and fucoidans (derived from brown algae), were also being investigated as potential SARS-CoV-2 therapeutic agents [41]. Arthrospira-derived phycoerythrobilin, phycocyanobilin and folic acid compete with SARS-CoV-2 for binding [42]. However, an in-silico experiment was conducted to screen therapeutic SARS-CoV targets using algae-derived compounds obtained from Gracilaria corticata, Laurencia papillosa and Grateloupia filicina, which have exhibited antiviral activities against SARS-CoV-2 [43]. Phlorotannins, alginates, luminaries, fucoidans, polyphenols, carotenoids, carrageenans and fatty acids are marine algae-derived bioactive chemicals that enhance the human gut microbiota and sustain host health by enhancing epithelial barrier integrity, immune system function and metabolism modulation [44][45]. Indeed, improving diets, mainly proteins, vitamins, minerals and a fiber-rich food, can help boost the immune system and is considered an effective strategy for combating COVID-19 [46]. 

2.1. Phycocyanobilins Antiviral Chromospheres against SARS-CoV-2

Phycocyanobilins (PCBs) are blue phycobilins, which are tetrapyrrole chromophores found in cyanobacteria and rhodophytes (Figure 1) [47]. The antioxidant, antiviral and NADPH-oxidase inhibitory activities of these light-capturing pigments are intensively investigated [48][49][50]. Potential SARS-CoV-2 infection inhibitors are made from PCBs (source: Spirulina sp.) [51]. The bioactive compounds were screened in silico to utilize anti-SARS-CoV-2 activity through the COVID-19 Docking Server. Phycocyanobilin has been found to have a strong affinity for binding two possible targets, RNA-dependent RNA polymerase (RdRp) and the Main protease (Mpro). Polyprotein digestion is carried out by the primary protease (translated from SARS-CoV-2 RNA), whereas the polymerase is responsible for viral RNA replication. The study found PCB binding target enzymes with substantial antiviral potential. However, as it is already known, in vitro or in vivo research is required to back up the docking results and discover PCBs’ true potential as a COVID-19 treatment [51]. Antioxidants 11 00452 g001
Figure 1. Bioactive metabolites extracted from algae and their possible approach to treating or preventing COVID-19.

2.2. Antiviral Therapies Based on Algal Glycan against SARS-CoV-2

Most algae are enriched with several pharmacologically active compounds with antiviral activities [52]. As a result, it was  postulated that antiviral medicines derived from cyanobacteria could be used to combat the virus that causes COVID-19 [53][54]. Glycoproteins are characterized by a broad spectrum of biological activities, including antiviral characteristics, shown in Table 1. The spike (S) glycoproteins interact with the glycans of the cell surface and make an initial connection with the glycoprotein of the host cell and virus envelope. The glycoprotein-based antiviral therapy is an emerging research paradigm [55][56].
Table 1. Algae-derived antiviral pharmacologically active compounds and their targeted viruses.
Marine Algal Source Lectin Designated Active against Viruses References
Griffiths Sp. GRFT SARS-CoV, HCV, HIV [57][58][59]
Amansia multifida, Hypnea musciformis, Bryothamnion seaforthii, Solieria filiformis, Meristiella echinocarpa AML, HML, BSL, Sfl, MEL HIV and influenza [60]
Nostoc ellipsosporum Cyanovirin HIV [61]
Microcystis aeruginosa Microvirin HIV-1 [62]
Microcystis Viridis MVL HIV-1 [63]
Eucheuma serrai ESA-2 Influenza [64]
Halimeda renschii HRL40 Influenza [65]
Kappaphycus alvarezii KAA-2 Influenza [64]
Scytonema varium Scytovirin HCV, HIV, Ebola [66][67]

2.3. Antiviral Therapies Based on Algal Sulfated Polysaccharides against SARS-CoV-2

A sulfated polymer derived from red algae, such as Gigartina, Chondrus, Eucheuma and Hypnea, prevented viruses from infecting host cells by preventing their binding or integration [68][69][70]. It prevented the dengue virus from replicating in the cells of mosquitoes and mammals. In addition, they work against a variety of human papillomavirus (HPV), a sexually transmitted strain that can cause genital warts and cervical cancer. Two fucoidans from Sargassum henslowianum, a brown macroalga, were purified and structurally characterized in a recent study [71]. SHAP-1 and SHAP-2 fucoidans were investigated for their ability to fight against HSV-1 and HSV-2 herpes simplex virus strains. The fucoidans were also involved in interrupting the adsorption of HSV to the host cell in the adsorption and penetration assays. As a result, fucoidans appear to be attractive candidates for inhibiting HSV-2 viruses and could be used successfully in various clinical settings.

2.4. Algal Polyphenols as Antiviral Therapeutics against SARS-CoV-2

Polyphenols derived from brown algae, commonly known as phlorotannins, have shown promising antiviral action against viruses. Phlorotannins 8,4-dieckol and 8,8-bieckol derivatives produced from Ecklonia cava showed significant inhibitory results on HIV-1 reverse transcriptase and protease activities [72]. 8,4-Dieckol has also been proven to prevent syncytia formation, the synthesis of viral antigen and HIV-1 lytic effects, making it an intriguing antiviral option for future investigation [73]. Polyphenols and their derivatives were abundant in extracts from different Mexican seaweeds. Polyphenols were discovered to limit the adsorption and penetration of the Measles virus into target cells. The synergistic effects of sulfated polysaccharides and polyphenols could be an efficient source of protective and curative therapies for the measles virus that causes viral illnesses [74].

2.5. Antioxidant Potential of Algal Metabolites and Therapeutics against SARS-CoV-2

In human beings, the optimum concentration of antioxidant molecules is always required to neutralize the free radicals generated through various metabolic processes of the body or stress conditions [75]. The antioxidant diversity of algal metabolites is well documented and this metabolic diversity serves as adaptive flexibility in extreme environments to cope with environmental fluctuations and various oxidative stress-related disorders. The physiological and metabolic activities of algae that produce different metabolites showed excellent antioxidant activity. For instance, Duan et al. [76] extracted brominated mono- and bis-phenol from Symphyocladia latiuscula having free radical scavenging activity. Choi et al. [77] reported cyclohexanonyl bromophenol from the same red alga Symphyocladia latiuscula with 1,1-diphenyl-2-picrylhydrazyl showed radical (DPPH) scavenging activity.

3. Conclusions

SARS-CoV-2 is an emerging pathogen and is the cause of a pandemic outbreak around the globe. Currently, the COVID-19 problem is causing significant morbidity, mortality and socioeconomic losses. Coronavirus SARS-CoV-2 causes respiratory diseases, leading to death in extreme situations. SARS-CoV-2 has many variants already and continued viral genome mutations may lead to a rise in the number of viral variations in the future, resulting in vaccine development failure. Algal metabolites have demonstrated multistep antiviral capability, including virus binding, cell-to-cell transmission, reproduction in host cells and cytopathic effects without causing significant harm to the host cells. New research sheds information on the antiviral activities of algal metabolites, both specific and broad spectrum, particularly on drug-resistant types, indicating the necessity for more research on COVID-19 using algal metabolites. Based on the current enstrudy, algal metabolites may provide new paths for forming new therapeutics methods for treating COVID-19 and other viral diseases that are prevalent around the world. Based on published findings, it is concluded that algal metabolites have remarkable potential for creating new antiviral therapies and are easily cultivable in controlled circumstances in any part of the world, regardless of geographical distribution.

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