BREAKING! French Study Shows That Mannose-Specific Lectins From Plants, Fungi, Algae And Cyanobacteria Can Prevent Various Coronavirus Transmissions Including SARS-CoV-2

Coronavirus News: A new study by researcher from Université Paul Sabatier-France, Ecole Nationale Vétérinaire d’Alfort-France,  Université Grenoble Alpes-France and also involving scientist from Ghent University-Belgium has shown that mannose-specific lectins derived from plants, algae, fungi, and bacteria selectively bind N-glycans present on the surface of viral spike protein hnece preventing coronavirus infections. This process can be medically utilized to control coronavirus transmission including SARS-CoV-2 transmissions. 

According to the study team, “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 human 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.”
 
The study findings were published in the peer reviewed journal: Cells. https://www.mdpi.com/2073-4409/10/7/1619
 
SARS-CoV-2 coronavirus, the causative pathogen of the COVID-19 disease, 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 Middle East respiratory syndrome coronavirus (MERS-CoV) – both of which responsible for earlier outbreaks this century in 2002 and 2012, respectively.
 
It is already known that 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.
 
Studies have shown that 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.
 
Unknown to many, 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.
 
As for 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.
 
The 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.
 
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.
 
However 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.
Interaction between mannose-specific lectins and spike glycans
 
In order 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.
 
It should be noted that 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. 
 
However 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.
 
Research 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.
 
Most 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.
 
Just like 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.
 
Despite the limitation that 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.
 
As for the 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.
 
Also 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 team is further exploring the usage of these mannose-specific lectins in actual clinical settings to assess their efficacy in stopping SARS-CoV-2 transmission.
 
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