Mustard seed tops ‘cures’ for COVID-19
SCIENTISTS have continued to record major breakthroughs in the search for natural cures for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – the agent that causes coronavirus disease 2019 (COVID-19).
Top on the list of plant products are: citrus fruit peels, lemon, lime, grapefruit, grapevine, microalgae, celery, parsley, dill, sweet chamomile, dried oregano, red onion, turmeric, aloe vera, brown mustard seeds, horseradish, commercial wasabi powder, wall rocket, and wild rucola.
The researchers from Spain have identified plant extracts that may be of interest in the search for treatments of COVID-19 and serve as a basis for future chemical, in vivo, and clinical trials.
The team, from the Polytechnic University of Valencia, identified 17 plant products commonly used in current and traditional cuisine that have previously shown promise as inhibitors of a coronavirus protein called chymotrypsin-like protease (3CLPro).
This protein is required for successful replication of SARS-CoV-2 – the agent responsible for the ongoing COVID-19 pandemic. The analysis revealed that extracts of turmeric, mustard seed, and wall rocket exhibited significant inhibition of SARS-CoV-2 3CLPro activity.
As reported in the journal Foods, turmeric rhizome extracts were the most effective at inhibiting 3CLPro activity. The study also revealed that a derivative of sinigrin, which is found in mustard seeds, was also a potent inhibitor of SARS-CoV-2 3CLPro activity.
Carla Guijarro-Real and colleagues wrote: “Testing plant extracts can be considered a first approach in the search for natural compounds with antiviral activity, or even represent a basis for the development of prophylactic or therapeutic plant extracts against COVID-19.
“In addition, given the proven safety for human consumption of the plants from which extracts are obtained, their potential use against COVID-19 might be immediate and easily accessible.”
Since the SARS-CoV-2 outbreak began in late December 2019, intense research efforts have led to the development and emergency use authorization of several COVID-19 vaccines that are now being rolled out on a mass scale globally.
The researchers said: “Several of the first-generation vaccines already in use in vaccination campaigns have shown high levels of efficacy, albeit the level of protection is not complete and seems to be strain-dependent.”
Furthermore, vaccines are in short supply in some regions, and in many countries, vaccination against SARS-CoV-2 is neither compulsory nor indicated for some specific groups, such as children or people with certain health conditions.
The team said: “Obtaining effective treatments against SARS-CoV-2 is urgently needed because, in combination with vaccines, they may become a first-line therapy not only for current SARS-CoV-2 strains but also for new ones.”
Where does 3CLPro come in? The SARS-CoV-2 protein 3CLPro is required for the proteolytic processing of viral polyproteins during the maturation step and is therefore essential for successful viral replication.
Recent studies reviewing natural compounds that may have potential antiviral activity against SARS-CoV-2 have identified plant-based extracts such as glucosinolates, flavonoids, and other phenolic compounds as likely inhibitors of 3CLPro.
What did the researchers do? Based on these previous studies, the researchers used a targeted approach to identify 17 plant products as potential inhibitors of 3CLPro activity.
They said: “The materials selected constitute common food products in many cultures and are of easy access or, alternatively, grow profusely in many regions and are included in traditional cuisines.”
Meanwhile, the team evaluated methanolic extracts in vitro for inhibition of SARS-CoV-2 3CLPro activity using a quenched fluorescence resonance energy transfer (FRET) assay.
The inhibition of SARS-CoV-2 3CLPro activity was tested at a final extract concentration of 500 µg mL−1. The lime peel and chamomile extracts produced signal interferences and were therefore excluded from the analysis.
What did the study find? Seven of the plant products exhibited low inhibitory capacity against 3CLPro, for which the average residual activity was more than 70 per cent. These products included extracts of grapefruit, lemon, orange fruit peel, red onion, celery stalk, horseradish, and dill.
Five other materials exhibited an intermediate inhibitory capacity (35–55 per cent), including extracts of celery leaves, parsley, oregano herbs, aloe vera leaves, and wasabi powder.
Finally, three extracts exhibited high inhibitory capacity, including wall rocket, mustard seeds, and turmeric rhizomes, which resulted in residual 3CLPro activity of 14.9 per cent, 9.4 per cent, and 0.0 per cent, respectively.
Guijarro-Real and colleagues said: “The turmeric extracts were, in fact, the most effective among all the plant-based extracts evaluated in the inhibitory activity.”
However, when the team tested commercial curcumin, (curcumin is the principal curcuminoid in turmeric) SARS-CoV-2 3CLPro activity was no longer fully inhibited, suggesting that other components in the turmeric extract must contribute to the inhibition.
The team wrote: “The inhibitor capacity of turmeric extracts might be the result of a synergistic activity of several compounds. Overall, our results indicate that extracts of turmeric are a strong candidate for being tested for inhibition of the in vivo replication of SARS-CoV-2.”
The study also revealed that a derivative of sinigrin – allyl isothiocyanate – potently inhibited 3CLPro activity. Sinigrin is a major glucosinolate present in mustard seed and wall rocket.
The team said the results suggest that this sinigrin derivative is also a good candidate molecule for in vivo testing against 3CLPro activity.
Guijarro-Real and colleagues said: “However, the high cytotoxicity of allyl isothiocyanate may preclude its practical use, which would depend on the concentration required.”
They concluded: “Further analysis of the methanolic extracts for mustard and wall rocket would increase the knowledge regarding the concentration at which these compounds are found, and the possible presence of other metabolites also exerting potential inhibitory activities.”
Also, researchers in the United Kingdom (U.K.) and Spain have used a novel drug screening approach to identify compounds that could serve as effective antivirals against SARS-CoV-2 – the agent that causes COVID-19.
The team used a quantum-inspired device in combination with a more traditional fingerprinting method to search for drugs that are similar to remdesivir, the only antiviral against SARS-CoV-2 that is currently approved for human use.
The team from Fujitsu Technology Solutions in Madrid and King’s College Hospital in London said: “The COVID-19 pandemic has accelerated the need to identify new therapeutics at pace, including through drug repurposing.”
While both models predicted the antiviral drug GS-6620 as the top compound, the quantum-based model predicted the antiviral BMS-986094 as second best. Both of these compounds were initially developed to treat the hepatitis C virus.
The more traditional Tanimoto model also predicted different forms of vitamin B12 as potential antiviral candidates. In vitro analyses revealed that BMS-986094 and the different types of B12 were effective at inhibiting the replication of SARS-CoV-2 variants.
Rocio Martinez-Nunez and colleagues wrote: “While BMS-986094 can cause secondary effects in humans as established by phase II trials, these findings suggest that vitamin B12 deserves consideration as a SARS-CoV-2 antiviral, particularly given its extended use and lack of toxicity in humans, and its availability and affordability.
“Our data illustrate the power of employing quantum-inspired computing for drug repurposing.” A pre-print version of the research paper is available on the bioRxiv server while the article undergoes peer review.
Finally, the researchers showed that these compounds were effective at inhibiting the replication of a number of SARS-CoV-2 variants, including B.1.1.7 (also called Alpha), B.1.351 (Beta), and B.1.617.2 (Delta).
What did the authors conclude? Martinez-Nunez and colleagues say the data revealed novel compounds that could inhibit SARS-CoV-2 replication, based on the QUBO model and the more traditional Tanimoto fingerprint.
“BMS warrants further investigation, while vitamin B12 is readily available from multiple sources. It is affordable, can be self-administered by patients, is available worldwide, and displays low-to-no toxicity at high doses,” they wrote.
“Our screening method can be employed in future searches for novel pharmacologic inhibitors, thus providing an approach for accelerating drug deployment,” the team concluded.
The study titled “Drug repurposing based on a Quantum-Inspired method versus classical fingerprinting uncovers potential antivirals against SARS-CoV-2 including vitamin B12” was published in the journal bioRxiv.
Meanwhile, flavonoids are a large class of phytochemicals that are commonly found in fruit and vegetables. They are well known to have pharmacological characteristics, including antiviral properties through their ability to inhibit viral pathogenesis at an early stage of the viral life cycle. This antiviral activity potentiates its use as a treatment against the SARS-CoV-2, the causative pathogen of the ongoing COVID-19 pandemic.
Previous reports on flavonoids have investigated their use on five RNA viruses, such as influenza, human immunodeficiency virus (HIV), severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and Ebola. To that end, a comprehensive review of flavonoids and their antiviral potential against SARS-CoV-2 has been undertaken by researchers in Iran and recently published in the MPDI journal Molecules.
The team focused on the potential use of flavonoids as a possible treatment for COVID-19, assessing the antiviral capabilities of these phytochemicals against SARS-CoV-2.
SARS-CoV-2 is predominantly a respiratory virus, with most symptomatic individuals usually exhibiting a fever, dry cough or shortness of breath – though some do exhibit other symptoms, like loss of smell or taste, muscle pain, gastrointestinal problems or a headache.
In critical COVID-19, the virus can result in ‘cytokine storms’ – where the immune system goes into overdrive and causes excessive inflammation – and severe acute respiratory distress syndrome (ARDS), often leading to multiple organ failure. These adverse reactions can all lead to a higher rate of mortality which was seen during the pandemic, with over 182 million confirmed cases over 3.9 million deaths recorded thus far.
The viral life cycle of the SARS-CoV-2 infection consists of processes such as, attachment, penetration, biosynthesis, maturation and release. Once the virus has attached to the host cell, the viral Ribo Nucleic Acid (RNA) uses the host cell’s metabolic machinery to initiate the replication process. The viral messenger-RNA (mRNA) begins to generate the viral structural proteins, which include the spike (S) protein, membrane, envelope and nucleocapsid proteins.
The angiotensin-converting enzyme 2 (ACE2) surface receptor is also involved in the interaction with the virus and has been shown to act as a co-receptor for the SARS-CoV-2 virus and is highly expressed in the lungs, making its interaction with the virus a contender for therapeutic targets.
Due to the lack of treatment for the SARS-CoV-2 virus, there has been an increase in research investigating different adjuvant therapies to rectify this. Flavonoids have been reported to have antiviral activity, and so this study has assessed its use for combating the COVID-19.
The antiviral effect of flavonoids can be categorized by their direct and indirect action. The direct effect includes the virus being directly affected by the flavonoid, and the indirect effect consists of the flavonoid improving the host’s defense mechanism against the virus.
Direct antiviral activity by flavonoids can include the inhibition of viral proteases. The SARS-CoV-2 virus generates three types of proteases, such as 3-chymotrypsin-like cysteine (3CLpro), papain-like protease (PLpro), and main protease (Mpro). These proteases are significant due to their role in cleaving viral polyprotein precursors in order to release functional proteins – this makes them an important target for therapies.
Flavonoids such as kaempferol, which is found abundantly in food, have been used in a previous study when investigating their effect on the enzymes 3CLpro and PLpro from SARS and MERS in Escherichia coli. The result of the study included the proteases being inhibited with the use of kaempferol, which may be due to the hydroxyl group within this flavonoid as it can cause more potential antiviral activity.
To this end, due to positive research into flavonoids against SARS, which share the same proteases as the SARS-CoV-2 virus, it has been suggested that using flavonoids to target these enzymes may be beneficial for antiviral therapeutics.
Indirect antiviral effect
Indirect antiviral activity can be perceived to be the most important method of modulating the immune system against SARS-CoV-2 to prevent severe complications of the infection. A flavonoid that can be used for indirect antiviral activity is epigallocatechin gallate (EGCG).
EGCG has been found to have antifungal, antibacterial as well as antiviral properties, with studies suggesting that this flavonoid can inhibit reverse transcription, protease activity and viral entry. This would be significant for viral infections such as SARS-CoV-2 as it could disrupt the virus from having an effect when being transmitted between individuals.
Other effects of flavonoids can include inhibiting RNA polymerase, which is important for catalyzing RNA replication, and so this possible disruption of mRNA translation would result in inhibition of viral replication and the consequent spread of the infection. A recent in vitro study included in this comprehensive review has illustrated the antiviral effect of baicalin and baicalein against SARS-CoV-2 infection in Vero CCL-81 cell line, resulting in inhibition of the RNA polymerase.
Indirect antiviral activity by flavonoids could be used as an adjuvant in order to regulate severe effects of the SARS-CoV-2 virus and the ‘cytokine storm’, which follows severe infections. In vitro and in vivo experiments that investigate the use of flavonoids against SARS-CoV-2 are limited. However, this plant-derived compound may be promising as an addition for managing the virus, and so further research investigating its potential – particularly in vivo – would be beneficial.
The study titled “Flavonoids as Promising Antiviral Agents against SARS-CoV-2 Infection: A Mechanistic Review” was published in journal Molecules.
Meanwhile, researchers in Italy have shown that leaf extract from the common grapevine – Vitis vinifera – exhibits significant antiviral activity against SARS-CoV-2 – the agent that causes COVID-19.
Carla Zannella from the University of Campania and colleagues said: “Wines and winery bio-products, such as grape pomace, skins, and seeds, are rich in bioactive compounds against a wide range of human pathogens, including bacteria, fungi, and viruses.
“However, little is known about the biological properties of vine leaves.” Now, the team has evaluated the phenolic composition and antiviral activity of V. vinifera leaf extract against two human viruses: the herpes simplex virus type 1 (HSV-1) and the currently widespread SARS-CoV-2.
Polyphenols, such as flavonoids, are widespread plant compounds that are characterized by antioxidant, antimicrobial, anticancer, anti-inflammatory, and antiviral properties.
The analysis led to the identification of about 40 phenolic compounds and the characterization of 35 flavonoids, most of which were quercetin derivatives.
As reported in the journal Viruses, the grapevine leaf extract inhibited both HSV-1 and SARS-CoV-2 replication in the early stages of infection at a concentration of just 10 µg/mL.
The team says these promising findings demonstrate the potential of using natural extracts in the design of antiviral drugs and the development of future vaccines.
Grapevine is a major fruit crop globally in terms of economic value and cultivated area. However, it is also rich in bioactive compounds and has been intensively studied for its antioxidant, antibacterial, and antiviral activity – properties conferred by the high levels of polyphenols found in the skin, seeds, and stem.
One study previously reported the antiviral potential of grape seed extract (GSE) against the hepatitis C virus, while another showed the virucidal activity of GSE against the hepatitis A virus.
Another study showed that V. vinifera leaves exerted anti-herpetic and anti-para-influenza activities. In silico analyses using bioinformatics approaches have also demonstrated the activity of flavonoids against SARS-CoV-2 and other coronaviruses such as the MERS.
“These data are very promising, suggesting that grapevine extracts could be used as cheap and eco-friendly innovative antiviral agents,” said Zannella and colleagues.
What did the researchers do? The team used aqueous methanol solvent to prepare leaf extracts of V. vinifera and evaluated its phenolic composition and antiviral activity against HSV-1 and SARS-CoV-2.
Chemical profile analysis by high-performance liquid chromatography-mass spectrometry identified about 40 phenolic compounds. Most of the compounds were quercetin derivatives, while others included derivatives of luteolin, kaempferol, apigenin, isorhamnetin, myricetin, chrysoeriol, biochanin, isookanin, and scutellarein.
The V. vinifera leaf extract completely inhibited the replication of both HSV-1 and SARS-CoV-2 in the early stages of infection, at a concentration as low as 10 µg/mL.
The teams also says the data indicate that V. vinifera leaf extract possesses antiviral activity against SARS-CoV-2 that has never previously been reported.
Meanwhile, study explores lectins from plants, fungi, algae and cyanobacteria as pan-coronavirus inhibitors. In a recently published article in the journal Cells, scientists have provided a detailed description of the utility of mannose-specific lectins in preventing coronavirus infections. They have specifically explained how mannose-specific lectins derived from plants, algae, fungi, and bacteria selectively bind N-glycans present on the surface of viral spike protein and how such interactions can be medically utilized to control coronavirus transmission.
SARS-CoV-2, the causative pathogen of COVID-19, is an enveloped RNA virus belonging to the human beta-coronavirus family. The other two highly pathogenic members of the family include SARS-CoV and MERS-CoV – both of which responsible for earlier outbreaks this century in 2002 and 2012, respectively.
The common structural features shared by beta-coronaviruses include spike-like protrusions on the viral envelope that participate in viral entry into host cells. These spikes are composed of homotrimers of spike glycoprotein, which is a 130 kDa viral structural protein with two subunits (S1 and S2). The S1 subunit contains the receptor-binding domain (RBD) that targets and binds host cell receptors, which are angiotensin-converting enzyme 2 (ACE2) for SARS-CoV and SARS-CoV-2 and dipeptidyl peptidase 4 (DPP4) for MERS-CoV. On the other hand, the S2 subunit participates in viral envelop – host cell membrane fusion and subsequent entry of viral genome into the host cell.
The spike protein is heavily glycosylated with both complex type and high-mannose type N-glucans that are highly exposed at the spike surface. Because of this structural feature, spike protein is a vital target for mannose-specific lectins, which are a group of heterogeneous proteins with potent antiviral and anticancer properties.
Mannose-specific lectins are widely distributed in viruses, bacteria, fungi, algae, plants, animals, and humans. Although highly diverse in structural features and phylogenetic relationship, mannose-specific lectins share a common functional feature of specifically targeting mannose and its derivatives, including complex and high-mannose N-glycans.
Regarding their antiviral properties, several in vitro studies have revealed that mannose-specific lectins prevent viral replication by specifically targeting mannose-containing N-glycans on the viral envelope, such as gp120 for HIV-1 and hemagglutinin for influenza virus.
N-glycans covering the coronavirus surface are highly diverse in nature. Different patterns of N-glycosylation have been observed at the glycosylation sites of SARS-CoV, SARS-CoV-2, and MERS-CoV. Moreover, studies have shown that spike proteins of SARS-CoV-2 and SARS-CoV share similar N-glycosylation patterns, which is significantly different than that of MERS-CoV.
In addition to N-glycosylation patterns, the distribution of high-mannose and complex N-glycans at the spike surface also differs significantly between coronaviruses. For instance, high-mannose N-glycans are predominantly present at the top of MERS-CoV spike protein, whereas complex glycans are highly distributed at the top of SARS-CoV and SARS-CoV-2 spike.
The distribution of both types of N-glycans differs between coronaviruses, particularly at the top of spike protein, indicating that N-glycans of SARS-CoV, SARS-CoV-2, and MERS-CoV are differentially accessible to mannose-specific lectins of plant, fungi, and bacterial origin. Interestingly, none of the mutations found in SARS-CoV-2 variants of concern, including B.1.1.7 and B.1.351, have been found to alter N-glycosylation sites of the spike protein.
To establish spike glycan interaction networks, glycan-binding assays and glycan array experiments have been performed in many studies. As suggested by these studies, mannose-specific single and two-chain lectins from higher plants interact with complex and high-mannose N-glycans of SARS-CoV, SARS-CoV-2, and MERS-CoV. Compared to single-chain lectins, two-chain lectins such as pea lectin and lentil lectin have a higher affinity for complex glycans.
Mannose-specific jacalin-related lectins (Morniga M) and GNA-related lectins with higher affinity for hybrid glycans and high-mannose glycans, respectively, are known to better interact with MERS-CoV-2 spike than SARS-CoV and SARS-CoV-2 spike.
Mannose-specific lectins derived from filamentous fungi, including Ascomycota and Basidiomycota, have a higher affinity for high-mannose glycans and complex glycans, respectively. Similarly, lectins from red algae and green algae recognize high-mannose glycans with high affinity. All these lectins are expected to recognize and interact with spike proteins of all human beta-coronaviruses.
Studies investigating direct interaction between mannose-specific lectins and coronavirus spike glycans have revealed antiviral efficacy of GNA-related lectins such as Cymbidium sp. lectin, Hippeastrum hybrid lectin, and Galanthus nivalis lectin against SARS-CoV. Specifically, two target proteins for Hippeastrum hybrid lectin have been identified, which are probably involved in virus-host cell attachment and release of mature virions from infected cells.
Recently, legume-derived mannose-specific lectin FRIL has been found to interfere with SARS-CoV-2 host cell entry by specifically binding spike complex glycans. This lectin has a higher affinity for flucosylated complex type N-glycans. Taken together, these observations highlight the importance of differential distribution patterns of N-glycans on the spike surface that are differentially accessible to and targeted by mannose-specific lectins of diverse origins.
Similar to mannose-specific lectins from plants, mannose-binding lectins of animal origin have been found to selectively inhibit SARS-CoV host cell entry. In contrast, certain membrane-associated mannose-specific human lectins have been found to promote infection and propagation of SARS-CoV by specifically recognizing spike glycans. Recently, inhibition of Galectin-3, a human lectin, has been proposed as a therapeutic intervention to prevent SARS-CoV-2 host cell attachment and suppress inflammation.
Although the exact antiviral mechanism of mannose-specific lectins is still not known, there is evidence suggesting that multivalent lectins like FRIL interact with spike glycans to form virion – lectin aggregates outside host cells. Once endocytosed, these large aggregates are entrapped in the late endosome/lysosomes, which in turn prevent their nuclear import.
Regarding potential biomedical applications, large molecular weight mannose-specific lectins that create steric hindrance by interacting with spike glycans can be used as blocking agents to prevent spike – ACE2 interaction. These blocking agents can be immobilized in air-conditioned filters to entrap SARS-CoV-2 and prevent its transmission.
Moreover, mannose-specific lectins can be used as glycan probes to detect SARS-CoV-2 in the environment. Regarding therapeutic applications, some in vitro studies have shown that mannose-specific lectins can prevent viral entry into host cells but cannot inhibit viral replication within host cells.
The study titled “Man-Specific Lectins from Plants, Fungi, Algae and Cyanobacteria, as Potential Blockers for SARS-CoV, MERS-CoV and SARS-CoV-2 (COVID-19) Coronaviruses: Biomedical Perspectives” was published in the journal Cells.
Meanwhile, a new review article published in the journal Antibiotics reports the presence of a large number of bioactive compounds in microalgae that target chemical structures present only in their structure.
Marine algae already contribute almost a tenth of biomedical molecules, for some of which scientists depend entirely on these microcellular organisms. Secondly, microalgae proliferate abundantly at low energy costs, while producing high amounts of medicinal compounds.
Microalgae produce a variety of such chemicals, such as carbohydrate-binding proteins, called lectins, that bind directly to viral glycoproteins added post-translationally via specifically-oriented carbohydrate recognition domain (CRDs); polysaccharides with sulfate groups and acidic polysaccharides; pigments; peptides and proteins; flavonoids and polyphenols; and glycolipids.
Cyanobacterial lectins include Agglutinin OAA, Cyanovirin-N (CV-N), Microcystis Viridis Lectin (MVL), Microvirin, and Scytovirin, from species such as Oscillatoria agardhii strain NIES-204, Nostoc ellipsosporum and Microcystis aeruginosa PCC7806. These inhibit a range of viruses such as human immunodeficiency virus (HIV) 1 and 2, hepatitis C virus (HCV), the hemorrhagic fever virus ZEBOV, influenza A, B viruses, and herpes virus simplex (HSV).
Polysaccharides are produced by the well-known Spirulina and Porphyridium microalgae. Sulfate polysaccharides may occupy the viral attachment sites on the viral envelope via the negative charge on the sulfate group that binds to the positive charges on the envelope, creating a non-reversible complex.
Other promising sulfate-polysaccharides from Spirulina include the calcium-spirulan (Ca-SP), which is active against HIV1 and HSV, as well as the cytomegalovirus (CMV), mumps virus and influenza virus. Porphyridium is red, whereas the other is green. The former has an envelope rich in sulfate polysaccharides that inhibit tumor growth, bacterial and viral growth.
The Varicella zoster (HH3), murine leukemia virus and HSV are also inhibited by Porphyridium species. Other microalgae produce sulfate polysaccharides that inhibit picornaviruses (causing diverse conditions ranging from myocarditis and encephalitis, through neurological and reproductive diseases, to diabetes), and parainfluenza viruses, responsible for severe pediatric respiratory disease, as well as HIV, HSV, and mumps viruses.
A well-known acidic polysaccharide from this class of organisms includes Nostoflan from a Nostoc species, highly active against HSV by inhibiting the viral envelope glycoprotein synthesis.
Microalgal pigments such as pheoporbide and carotenoids are used in biomedical applications on a wide scale. These may inhibit viral entry as well as having post-viral entry effects.
Carotenoids, in particular, may counteract the cytokine storm implicated in severe COVID-19 by inhibiting the excessive production of antiviral reactive oxygen species (ROS) and reactive nitrogen-oxygen (RNS). While these are useful in reducing viral replication, they also activate transcription nuclear factor-KB (NF-KB), inducing the JAK/STAT inflammation pathway.
Since the cytokine storm also induces life-threatening acute respiratory distress syndrome (ARDS), and acute lung injury (ALI), associated with multi-organ damage, carotenoids may have a still higher utility beyond their direct effects on the virus.
Other pigments with antioxidant and antiviral activity include phycobiliproteins and astaxanthin. The latter is reported to reduce both ARDS and ALI.
Some microalgae produce peptides that show antiviral activity in aquaculture and in silkworms. Flavonoids have potent antiviral activity, such as marennine, a bluish-grey pigment from Haslea ostrearia, active against HIV and HSV. This can be manufactured in a bioreactor and is used in food, coloring agents and cosmetics. It
Glycolipids are also produced by microalgae, and some show potent virucidal effects against HSV2 and HIV, using different mechanisms of action such as DNA polymerase inhibition or damaging the viral envelope to promote viral lysis.
Potential for vaccine production
Apart from microalgal compounds, they have the ability to act as vectors expressing double-stranded RNA in viruses and thus interfere with viral mRNA to inhibit viral replication. One example is the green microalga Chlamydomonas reinhardtii, used against a shrimp virus, the yellow head virus.
Microalgal supplements could be used in the diet to counteract SARS-CoV-2 infection. Spirulina, already known for its high nutritional value, also activates the immune system by virtue of its Braun-type lipoproteins that trigger Toll-like receptors. A spirulina-rich diet may help fight HIV infection, which may be linked to the lower incidence of HIV infection in some parts of the world, including Asia, where spirulina is consumed in larger amounts.
Spirulina improves the leukocyte count. Its fatty acids are generally linked to a higher number of immune cells and may also help to degrade the viral lipid membrane and envelope.
Additionally, spirulina enhances insulin sensitivity because of the antioxidant effects of the phycobiliproteins, thus regulating interleukin-6, a mediator in insulin signaling, and increasing lipoprotein lipase activity, which is typically abnormal in these patients. Moreover, it may prevent side effects following vaccination. Finally, its antioxidant content is high.
An asthaxanthin-rich diet could also help modulate cytokine release and improve the outcomes in SARS-CoV-2 infection. Increased immune activity, especially an increase in lymphocytes, is also seen with this nutrient, and is relevant in this infection, typically characterized by lymphopenia.
A diet enriched with Chlorella and Hematococcus pluvialis could also help prevent severe symptomatic COVID-19, therefore. Chlamydomonas reinhardtii also improves gut health via its phenolic compounds, again benefiting patients with COVID-19 who frequently have an altered gut microbiome.
Other microalgal products already used in foods, such as chitosan and carrageenan, are also worth further examination for their activity against SARS-CoV-2. The former regulates cholesterol levels.
Overall, therefore, microalgae “display eco-friendly and eco-sustainable characteristics, produce a high variety of antiviral compounds, and can be used as a supplement in diets without collateral effects. Moreover, these organisms are considered very good candidates for the genetic engineering approach.”
Meanwhile, in a recent study published in Antioxidants, a group of researchers in Mexico evaluated the use of antioxidants as potential adjuvants for the treatment of COVID-19, with a specific interest in the utility of these agents in reducing or preventing the neurological symptoms of this disease.
Both the transmission of SARS-CoV-2 and its anti-viral treatments can influence the virus’s genetic variability, which can affect the load, virulence, and neuropathological variability of SARS-CoV-2. An example of this can be found within a prevalent variant of the spike (S) protein, D614G, which is associated with a higher viral load in the upper respiratory tract. Notably, however, this variant does not appear to increase the severity of the infection by SARS-CoV-2.
To date, over 5,775 genome variants of the SARS-CoV-2 have been identified. Combined with the fact that new variants are on the rise, more research is required to understand what is responsible for the severe symptoms of COVID-19.
The main symptoms of COVID-19 include fever, shortness of breath, cough, fatigue, and headaches. Some systemic complications of COVID-19 can include adverse respiratory distress syndrome, cardiac injury, acute kidney injury, as well as additional damage to the central nervous system (CNS).
During the initial neurological characterization of COVID-19 during a Wuhan study, a low incidence of neurological complications was reported, which included headaches, nausea, and vomiting, to name a few. However, recent COVID-19 studies have found that neurological symptoms can affect more than 35 per cent of COVID-19 patients, thus demonstrating the possible neuro-invasive side effects of the infection.
The neurological effects of COVID-19 such as anosmia, or lack of smell, can be frequent. However, more severe neurological manifestations such as strokes and encephalopathies have also been reported, although this has been less frequent.
In the current study, the researchers discuss that viruses like SARS-CoV-2 can cause alveolar gas exchange disorders. As a result, this complication can be associated with hypoxia in the CNS through an increase in anaerobic metabolism and edema. The researchers also refer to studies that claim that COVID-19 has also been associated with a low level of red blood cells, which can be linked with reports of abnormal findings of blood vessel damages in various brain areas, which have resulted in the occurrence of strokes.
In severe cases of COVID-19, treatment can include mechanical ventilation with intensive care supervision. Due to vascular inflammation being the most common neurological effect of this COVID-19, anticoagulants are often administered for patients who have coagulopathies in order to reduce their risk of stroke.
Reactive oxygen species (ROS), which are more reactive derivatives of molecular oxygen, include free radicals and non-radicals such as hydrogen peroxide. This derivative of oxygen is integral in viral infections through its role in stimulating the innate immune response by allowing inflammatory cells to migrate through the endothelial barrier.
This can lead to excessive ROS production and is essential for inflammatory diseases to progress within the body. The increase of ROS has also been reported to be associated with severe viral infections due to the role they play in inflammatory processes and the widespread influence of viruses.
The reduced expression and/or activity of antioxidant enzymes can lead to a redox imbalance during viral infections, which can result in oxidative cell damage. This response has been identified in SARS-CoV-2, where increased oxidative stress may arise as a result of an increased movement of neutrophils to infected areas.
This provides evidence for patients who experience more severe symptoms of the COVID-19 infection exhibiting an increase in neutrophil levels and a reduction in lymphocyte levels. This reduction of lymphocyte levels has also been associated with oxidative stress, which further suggests the significance of this factor in the severity levels of SARS-CoV-2 infections.
Several possible reasons for the higher ROS levels in COVID-19 patients have been described. The activation of enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, for example, is usually regulated by the binding of angiotensin II to angiotensin I. However, this pathway is disrupted by SARS-CoV-2, which acts directly on angiotensin II. Other factors that can lead to ROS production may include the release of iron into the bloodstream and mitochondrial dysfunction.
The use of antioxidants in Chinese herbal medicine has been widely studied, with some antiviral effects reported to occur when using these agents following infection by SARS-CoV-2. The antiviral effect of flavonoids, which are secondary plant phenolics, as well as other antioxidants has been explored for their effect on SARS-CoV-2.
These antioxidants have been found to have a positive effect with different antioxidants working in various ways. An example of this is nigellone, which was found to bind parts of the SARS-CoV-2 virus such as the S protein, as well as block inflammatory markers such as interleukin-1 (IL-1) and IL-6. Other effects of antioxidants in the treatment of SARS-CoV-2 include, but are not limited to, the inhibition of viral replication as well as preventing the entry of the virus into the host cell.
As there are no specific antiviral drugs available for SARS-CoV-2, adjuvant therapies can be useful in treating COVID-19. Antioxidant compounds also have the potential to improve the prognosis of COVID-19 infections. With the ability to reduce inflammation, the researchers discuss the potential utility of incorporating dietary antioxidants into a COVID-19 patient’s treatment plan.
Some of the specific dietary antioxidants that could have a therapeutic effect include vitamins A, C, D, B6, and B12, folate, zinc, iron, copper, and selenium, as each of these micronutrients have a role in the immune response. These vitamins, particularly vitamin C, have also been shown to have an effect on COVID-19 infections.
Other antioxidants such as melatonin, which is a neuro-hormone, have been suggested to be effective in the treatment of the neurological manifestations of COVID-19. More specifically, melatonin has been shown to act as a protectant for neurons and exert anti-inflammatory effects. Other neurological protectants can also help the recovery after brain injuries due to ischemia.
Neurological management is an essential component of COVID-19 treatment. To this end, the use of antioxidants to reduce the inflammatory response while simultaneously working as a neuro-protectant could support their use as adjuvants in treating SARS-CoV-2, especially as new variants of SARS-CoV-2 continue to emerge around the world.
The study titled “Use of Antioxidants for the Neuro-Therapeutic Management of COVID-19” was published in the journal Antioxidants.