Capture and neutralization of SARS-CoV-2 and influenza virus by algae-derived lectins with high-mannose and core fucose specificities.

We first investigated the interactions between several algae-derived lectins and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We created lectin columns using high-mannose (HM)-type glycan-specific lectins OAA and KAA-1 or core fucose-specific lectin hypninA-2 and conducted binding experiments with SARS-CoV-2. The results showed that these lectins were capable of binding to the virus. Furthermore, when examining the neutralization ability of nine different lectins, it was found that KAA-1, ESA-2, and hypninA-2 were effective in neutralizing SARS-CoV-2. In competitive inhibition experiments with glycoproteins, neutralization was confirmed to occur through HM-type or core fucose-type glycans. However, neutralization was not observed with other lectins, such as OAA. This trend of KAA-1 and ESA-2 having the neutralizing ability and OAA not having it was also similar to influenza viruses. Electron microscopy observations revealed that KAA-1 and hypninA-2 strongly aggregated SARS-CoV-2 particles, while OAA showed a low degree of aggregation. It is believed that the neutralization of SARS-CoV-2 involves multiple factors, such as glycan attachment sites on the S protein, the size of lectins, and their propensity to aggregate, which cause inhibition of receptor binding or aggregation of virus particles. This study demonstrated that several algae-derived lectins could neutralize SARS-CoV-2 and that lectin columns can effectively recover and concentrate the virus.

Lectins from plants and algae act as anti-viral against HIV, influenza and coronaviruses.

BACKGROUND: Carbohydrate-lectin interactions are extremely specific as the lectin is capable of recognising monomeric and oligomeric sugars in a reversible manner. It has been known for a long time that lectins have antibacterial, antifungal, and insecticidal activities. Recently, it has been reported that many lectins can prevent the virus growth by interacting with the viral envelop surface glycoprotein. Spike protein, which is found on the surface of some enveloped viruses, is heavily mannosylated and will have strong affinity for mannose specific lectins. According to the findings, lectins have a high binding affinity for the glycans of the SARS-CoV-2 spike glycoprotein, which contains N-glycosylation sites. As a result, various lectins are being researched and developed as anti-viral agents. RESULTS: According to our in silico studies, the amino acid residues Asn487, Tyr489, Gln493, Lys417, and Tyr505 of the receptor binding domain (RBD) of SARS-CoV-2 formed an interaction with the model lectin Lablab purpureus lectin. Similar interaction for SARS-CoV-2 spike protein was observed with Griffithsin lectin (algal source) as well. These observations demonstrate that lectins could be one of the potential molecules for neutralising coronavirus infection. CONCLUSION: This review focuses on anti-viral lectins isolated and characterized from plants and algae (last 5 years) and showed anti-viral properties against HIV, Influenza, and coronaviruses.

A molecularly engineered, broad-spectrum anti-coronavirus lectin inhibits SARS-CoV-2 and MERS-CoV infection in vivo.

"Pan-coronavirus" antivirals targeting conserved viral components can be designed. Here, we show that the rationally engineered H84T-banana lectin (H84T-BanLec), which specifically recognizes high mannose found on viral proteins but seldom on healthy human cells, potently inhibits Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (including Omicron), and other human-pathogenic coronaviruses at nanomolar concentrations. H84T-BanLec protects against MERS-CoV and SARS-CoV-2 infection in vivo. Importantly, intranasally and intraperitoneally administered H84T-BanLec are comparably effective. Mechanistic assays show that H84T-BanLec targets virus entry. High-speed atomic force microscopy depicts real-time multimolecular associations of H84T-BanLec dimers with the SARS-CoV-2 spike trimer. Single-molecule force spectroscopy demonstrates binding of H84T-BanLec to multiple SARS-CoV-2 spike mannose sites with high affinity and that H84T-BanLec competes with SARS-CoV-2 spike for binding to cellular ACE2. Modeling experiments identify distinct high-mannose glycans in spike recognized by H84T-BanLec. The multiple H84T-BanLec binding sites on spike likely account for the drug compound's broad-spectrum antiviral activity and the lack of resistant mutants.

Lectins and lectibodies: potential promising antiviral agents.

In nature, lectins are widely dispersed proteins that selectively recognize and bind to carbohydrates and glycoconjugates via reversible bonds at specific binding sites. Many viral diseases have been treated with lectins due to their wide range of structures, specificity for carbohydrates, and ability to bind carbohydrates. Through hemagglutination assays, these proteins can be detected interacting with various carbohydrates on the surface of cells and viral envelopes. This review discusses the most robust lectins and their rationally engineered versions, such as lectibodies, as antiviral proteins. Fusion of lectin and antibody's crystallizable fragment (Fc) of immunoglobulin G (IgG) produces a molecule called a "lectibody" that can act as a carbohydrate-targeting antibody. Lectibodies can not only bind to the surface glycoproteins via their lectins and neutralize and clear viruses or infected cells by viruses but also perform Fc-mediated antibody effector functions. These functions include complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cell-mediated phagocytosis (ADCP). In addition to entering host cells, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein S1 binds to angiotensin-converting enzyme 2 (ACE2) and downregulates it and type I interferons in a way that may lead to lung disease. The SARS-CoV-2 spike protein S1 and human immunodeficiency virus (HIV) envelope are heavily glycosylated, which could make them a major target for developing vaccines, diagnostic tests, and therapeutic drugs. Lectibodies can lead to neutralization and clearance of viruses and cells infected by viruses by binding to glycans located on the envelope surface (e.g., the heavily glycosylated SARS-CoV-2 spike protein).

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.

Betacoronaviruses, responsible for the "Severe Acute Respiratory Syndrome" (SARS) and the "Middle East Respiratory Syndrome" (MERS), use the spikes protruding from the virion envelope to attach and subsequently infect the host cells. The coronavirus spike (S) proteins contain receptor binding domains (RBD), allowing the specific recognition of either the dipeptidyl peptidase CD23 (MERS-CoV) or the angiotensin-converting enzyme ACE2 (SARS-Cov, SARS-CoV-2) host cell receptors. The heavily glycosylated S protein includes both complex and high-mannose type N-glycans that are well exposed at the surface of the spikes. A detailed analysis of the carbohydrate-binding specificity of mannose-binding lectins from plants, algae, fungi, and bacteria, revealed that, depending on their origin, they preferentially recognize either complex type N-glycans, or high-mannose type N-glycans. Since both complex and high-mannose glycans substantially decorate the S proteins, mannose-specific lectins are potentially useful glycan probes for targeting the SARS-CoV, MERS-CoV, and SARS-CoV-2 virions. Mannose-binding legume lectins, like pea lectin, and monocot mannose-binding lectins, like snowdrop lectin or the algal lectin griffithsin, which specifically recognize complex N-glycans and high-mannose glycans, respectively, are particularly adapted for targeting coronaviruses. The biomedical prospects of targeting coronaviruses with mannose-specific lectins are wide-ranging including detection, immobilization, prevention, and control of coronavirus infection.

Evidence that Maackia amurensis seed lectin (MASL) exerts pleiotropic actions on oral squamous cells with potential to inhibit SARS-CoV-2 infection and COVID-19 disease progression.

COVID-19 was declared an international public health emergency in January, and a pandemic in March of 2020. There are over 125 million confirmed COVID-19 cases that have caused over 2.7 million deaths worldwide as of March 2021. COVID-19 is caused by the SARS-CoV-2 virus. SARS-CoV-2 presents a surface "spike" protein that binds to the ACE2 receptor to infect host cells. In addition to the respiratory tract, SARS-Cov-2 can also infect cells of the oral mucosa, which also express the ACE2 receptor. The spike and ACE2 proteins are highly glycosylated with sialic acid modifications that direct viral-host interactions and infection. Maackia amurensis seed lectin (MASL) has a strong affinity for sialic acid modified proteins and can be used as an antiviral agent. Here, we report that MASL targets the ACE2 receptor, decreases ACE2 expression and glycosylation, suppresses binding of the SARS-CoV-2 spike protein, and decreases expression of inflammatory mediators by oral epithelial cells that cause ARDS in COVID-19 patients. In addition, we report that MASL also inhibits SARS-CoV-2 infection of kidney epithelial cells in culture. This work identifies MASL as an agent with potential to inhibit SARS-CoV-2 infection and COVID-19 related inflammatory syndromes.

Antiviral Cyanometabolites-A Review.

Global processes, such as climate change, frequent and distant travelling and population growth, increase the risk of viral infection spread. Unfortunately, the number of effective and accessible medicines for the prevention and treatment of these infections is limited. Therefore, in recent years, efforts have been intensified to develop new antiviral medicines or vaccines. In this review article, the structure and activity of the most promising antiviral cyanobacterial products are presented. The antiviral cyanometabolites are mainly active against the human immunodeficiency virus (HIV) and other enveloped viruses such as herpes simplex virus (HSV), Ebola or the influenza viruses. The majority of the metabolites are classified as lectins, monomeric or dimeric proteins with unique amino acid sequences. They all show activity at the nanomolar range but differ in carbohydrate specificity and recognize a different epitope on high mannose oligosaccharides. The cyanobacterial lectins include cyanovirin-N (CV-N), scytovirin (SVN), microvirin (MVN), Microcystisviridis lectin (MVL), and Oscillatoria agardhii agglutinin (OAA). Cyanobacterial polysaccharides, peptides, and other metabolites also have potential to be used as antiviral drugs. The sulfated polysaccharide, calcium spirulan (CA-SP), inhibited infection by enveloped viruses, stimulated the immune system's response, and showed antitumor activity. Microginins, the linear peptides, inhibit angiotensin-converting enzyme (ACE), therefore, their use in the treatment of COVID-19 patients with injury of the ACE2 expressing organs is considered. In addition, many cyanobacterial extracts were revealed to have antiviral activities, but the active agents have not been identified. This fact provides a good basis for further studies on the therapeutic potential of these microorganisms.

Lectins purified from medicinal and edible mushrooms: Insights into their antiviral activity against pathogenic viruses.

For thousands of years, fungi have been a valuable and promising source of therapeutic agents for treatment of various diseases. Mushroom is a macrofungus which has been cultivated worldwide for its nutritional value and medicinal applications. Several bioactive molecules were extracted from mushroom such as polysaccharides, lectins and terpenoids. Lectins are carbohydrate-binding proteins with non-immunologic origin. Lectins were classified according to their structure, origin and sugar specificity. This protein has different binding specificity with surface glycan moiety which determines its activity and therapeutic applications. A wide range of medicinal activities such as antitumor, antiviral, antimicrobial, immunomodulatory and antidiabetic were reported from sugar-binding proteins. However, glycan-binding protein from mushroom is not well explored as antiviral agent. The discovery of novel antiviral agents is a public health emergency to overcome the current pandemic and be ready for the upcoming viral pandemics. The mechanism of action of lectin against viruses targets numerous steps in viral life cycle such as viral attachment, entry and replication. This review described the history, classification, purification techniques, structure-function relationship and different therapeutic applications of mushroom lectin. In addition, we focus on the antiviral activity, purification and physicochemical characteristics of some mushroom lectins.

Nanoluciferase complementation-based bioreporter reveals the importance of N-linked glycosylation of SARS-CoV-2 S for viral entry.

The ongoing COVID-19 pandemic has highlighted the immediate need for the development of antiviral therapeutics targeting different stages of the SARS-CoV-2 life cycle. We developed a bioluminescence-based bioreporter to interrogate the interaction between the SARS-CoV-2 viral spike (S) protein and its host entry receptor, angiotensin-converting enzyme 2 (ACE2). The bioreporter assay is based on a nanoluciferase complementation reporter, composed of two subunits, large BiT and small BiT, fused to the S receptor-binding domain (RBD) of the SARS-CoV-2 S protein and ACE2 ectodomain, respectively. Using this bioreporter, we uncovered critical host and viral determinants of the interaction, including a role for glycosylation of asparagine residues within the RBD in mediating successful viral entry. We also demonstrate the importance of N-linked glycosylation to the RBD's antigenicity and immunogenicity. Our study demonstrates the versatility of our bioreporter in mapping key residues mediating viral entry as well as screening inhibitors of the ACE2-RBD interaction. Our findings point toward targeting RBD glycosylation for therapeutic and vaccine strategies against SARS-CoV-2.

The Potential of Algal Biotechnology to Produce Antiviral Compounds and Biopharmaceuticals.

The emergence of the Coronavirus Disease 2019 (COVID-19) caused by the SARS-CoV-2 virus has led to an unprecedented pandemic, which demands urgent development of antiviral drugs and antibodies; as well as prophylactic approaches, namely vaccines. Algae biotechnology has much to offer in this scenario given the diversity of such organisms, which are a valuable source of antiviral and anti-inflammatory compounds that can also be used to produce vaccines and antibodies. Antivirals with possible activity against SARS-CoV-2 are summarized, based on previously reported activity against Coronaviruses or other enveloped or respiratory viruses. Moreover, the potential of algae-derived anti-inflammatory compounds to treat severe cases of COVID-19 is contemplated. The scenario of producing biopharmaceuticals in recombinant algae is presented and the cases of algae-made vaccines targeting viral diseases is highlighted as valuable references for the development of anti-SARS-CoV-2 vaccines. Successful cases in the production of functional antibodies are described. Perspectives on how specific algae species and genetic engineering techniques can be applied for the production of anti-viral compounds antibodies and vaccines against SARS-CoV-2 are provided.