SARS-CoV-2 Inhibition Using Leek Extract And Lectins Including Concanavalin A.

COVID-19 News: As the world grapples with the prolonged challenges posed by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), scientists continue to explore innovative strategies to combat the virus responsible for the ongoing COVID-19 pandemic. Four years into this global health crisis, the glycosylated spike proteins on the surface of SARS-CoV-2 remain a significant obstacle. Not only do these spike proteins facilitate virion docking and entry into host cells, but they also create a glycan shield that makes the virus less susceptible to neutralizing antibodies.


Graphical Abstract - SARS-CoV-2 Inhibition Using Leek Extract And Lectins Including Concanavalin A.

The constant evolution of SARS-CoV-2, coupled with the emergence of immune escape variants, has fueled the exploration of novel approaches to target the glycan shield. One promising avenue involves carbohydrate-binding agents, and in particular, plant-derived lectins. A new study conducted by researchers from Heidelberg University in Germany covered in this COVID-19 News report sheds light on the antiviral potential of seven lectins and a crude leek extract against SARS-CoV-2. The findings offer new insights into the potential use of these natural compounds as effective agents for COVID-19 prevention and treatment.
 
The Glycan Shield and its Significance
The surface of SARS-CoV-2 is adorned with extensively glycosylated spike proteins, creating a glycan shield that serves a dual purpose. On one hand, it facilitates virion docking and entry into host cells; on the other, it shields the virus from neutralizing antibodies. This glycosylation is especially crucial in the receptor-binding domain (RBD) of the spike protein, affecting spike conformation and receptor binding. While the virus exhibits high mutation rates overall, glycosylation sites in the spike protein remain relatively conserved, underscoring their importance in virion infectivity.
 
Recent studies have highlighted the role of glycosylation during SARS-CoV-2 maturation in shaping virion morphology and influencing virus spread. Targeting the glycan shield using carbohydrate-binding agents, such as lectins, presents a promising strategy. Lectins are natural proteins found in plants and other living organisms that have evolved as part of the immune defense against pathogens. These lectins exhibit antiviral properties against various viruses, making them potential candidates for combating SARS-CoV-2.
 
Testing Lectins and Leek Extract
The research team focused on seven plant-derived lectins and one crude leek extract to evaluate their antiviral activity against SARS-CoV-2. Two human lung cell lines were utilized in the study: A549 cells ectopically expressing the ACE2 receptor and Calu-3 cells. These cell lines were chosen to reflect the physiological conditions of SARS-CoV-2 replication in the human respiratory system.
 
Among the tested lectins, Concanavalin A (Con A) emerged as the most potent inhibitor of SARS-CoV-2 infection. The lectin displayed a remarkably low half-maximal inhibitory concentratio n (IC50) at approximately 13 nanomolar, with minimal cytotoxicity, resulting in a high selectivity index (SI). Other lectins, including Hippeastrum hybrid agglutinin (HHA), Urtica dioica agglutinin (UDA), and Morus rubra lectin (MRL), also exhibited antiviral activity. Furthermore, the crude leek extract demonstrated a robust inhibitory effect on SARS-CoV-2.
 
Cell Type-Dependent Variability
The researchers observed significant differences in the inhibitory activity of lectins between the two tested lung cell lines. Calu-3 cells, known for being less responsive to antiviral treatments, showed reduced or undetectable inhibitory properties for most lectins. However, Con A, HHA, UDA (in some experiments), and the leek extract maintained their antiviral effects in Calu-3 cells. Con A, in particular, demonstrated a remarkable selectivity index, highlighting its potential efficacy across different cell types.
 
Broad Antiviral Activity Against Variants
To assess the potential of lectins against different SARS-CoV-2 variants, the study compared the effects of Con A and HHA against the original strain (B.1) and subsequent variants, including Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), and Omicron (B.1.1.529 BA.1 and BA.5). Con A exhibited broad antiviral activity against all tested variants, including the highly transmissible Omicron variant.
 
Remarkably, Con A required approximately 49-fold lower molar amounts to achieve half-maximal inhibitory effects compared to the antiviral drug remdesivir.
 
Mechanism of Action: Super-Resolution Microscopy Insights
The researchers employed multiplex super-resolution microscopy to investigate the interactions between lectins and SARS-CoV-2, providing detailed insights into their mechanism of action. Notably, Con A not only bound to SARS-CoV-2 virions and their host cells but also induced the aggregation of SARS-CoV-2. This dual mode-of-action, comprising both antiviral and virucidal mechanisms, establishes Con A and other plant lectins as promising candidates for COVID-19 prevention and potential bases for further drug development.
 
Discussion: Safety and Potential Applications
While lectins, particularly Con A, demonstrated significant inhibitory effects against SARS-CoV-2 in vitro with minimal cytotoxicity, considerations about their safety and potential applications in clinical settings are essential. Lectins are known for their diverse biological activities, including antiviral, anticancer, and immunomodulatory properties. However, their therapeutic use must be approached cautiously due to potential adverse effects, such as immunogenicity, gastrointestinal toxicity, and allergic reactions.
 
In the case of Con A, its potent mitogenic activity on T lymphocytes raises concerns about possible immunostimulatory effects, which could exacerbate inflammatory responses in COVID-19 patients. Additionally, the potential for lectins to interact with host glycans and disrupt normal cellular functions underscores the need for thorough safety evaluations. Future studies should explore the pharmacokinetics, tissue distribution, and long-term effects of lectin administration to elucidate their safety profiles fully.
 
Despite these challenges, the broad-spectrum antiviral activity of Con A and other lectins against SARS-CoV-2 variants holds promise for various applications in the prevention and treatment of COVID-19. One potential approach is the development of topical formulations for nasal or oral administration to prevent viral transmission at mucosal surfaces. Lectin-based nasal sprays or mouthwashes could serve as convenient and cost-effective adjuncts to vaccination, especially in high-risk settings such as healthcare facilities and crowded environments.
 
Furthermore, the synergistic effects of lectins with existing antiviral drugs, such as remdesivir and monoclonal antibodies, warrant investigation. Combination therapies that target different stages of the viral replication cycle could enhance efficacy while minimizing the risk of drug resistance. Additionally, the development of novel delivery systems, such as nanoparticles or liposomes, may improve the bioavailability and tissue targeting of lectins, enhancing their therapeutic potential.
 
Beyond COVID-19, lectins offer broader implications for antiviral drug discovery and development. Their ability to target viral envelope glycoproteins and inhibit viral entry highlights their potential utility against other enveloped viruses, including influenza, HIV, and hepatitis C. Moreover, the diversity of lectins derived from various plant sources presents opportunities for the identification of new lead compounds with unique antiviral properties.
 
Conclusion
In conclusion, the study provides compelling evidence of the antiviral activity of lectins, particularly Con A, against SARS-CoV-2 and its variants. While further research is needed to elucidate their mechanism of action, safety profile, and clinical efficacy, lectins represent a promising class of natural compounds for COVID-19 prevention and treatment. Continued exploration of lectins and other carbohydrate-binding agents may lead to the development of innovative antiviral therapies with broad-spectrum activity and reduced risk of viral resistance. As the world continues to combat the COVID-19 pandemic, harnessing the potential of plant lectins offers hope for a safer and more effective approach to managing viral infections.
 
The study findings were published in the peer reviewed journal: Antiviral Research.
https://www.sciencedirect.com/science/article/pii/S0166354224000640

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