Lentil lectin derived from Lens culinaris exhibit broad antiviral activities against SARS-CoV-2 variants

Abstract

The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutated continuously and newly emerging variants escape from antibody-mediated neutralization raised great concern. S protein is heavily glycosylated and the glycosylation sites are relatively conserved, thus glycans on S protein surface could be a target for development of anti-SARS-CoV-2 strategies against variants. Here, we collected twelve plant-derived lectins with different carbohydrate specificity and evaluated their anti-SARS-CoV-2 activity against mutant strains and epidemic variants using a pseudovirus based neutralization assay. The Lens culinaris derived lentil lectin which specifically bind to oligomannose-type glycans and GlcNAc at the non-reducing end terminus showed most potent and broad antiviral activity against a panel of mutant strains and variants, including the artificial mutants at N-/O-linked glycosylation site, natural existed amino acid mutants, as well as the epidemic variants B.1.1.7, B.1.351 and P.1. Lentil lectin also showed antiviral activity against SARS-CoV and MERS-CoV. We found lentil lectin could block the binding of ACE2 to S trimer and inhibit SARS-CoV-2 at the early steps of infection. Using structural information and determined N-glycan profile of S trimer, taking together with the carbohydrate specificity of lentil lectin, we provide a basis for the observed broad spectrum anti-SARS-CoV-2 activity. Lentil lectin showed weak hemagglutination activity at 1 mg/mL and no cytotoxicity activity, and no weight loss was found in single injection mouse experiment. This report provides the first evidence that lentil lectin strongly inhibit infection of SARS-COV-2 variants, which should provide valuable insights for developing future anti-SARS-CoV-2 strategies.

The glycosylation in SARS-CoV-2 and its receptor ACE2

“…442 Notably, Lentil lectin derived from Lens culinaris can bind specifically to oligomannose-type glycans and GlcNAc at the non-reducing end terminus of S protein, thus block the binding of ACE2 to S trimer, showing the strongly inhibit infection of SARS-COV-2, including epidemic variants B.1.1.7, B.1.351, and P.1. 443 …”

Legume Lectins with Different Specificities as Potential Glycan Probes for Pathogenic Enveloped Viruses

“…From experiments performed under in vitro and in vivo conditions, it follows that plant, algal, and cyanobacterial lectins with different carbohydrate-binding specificities represent well-adapted CBAs for blocking the entry of pathogenic enveloped viruses into the host cells. In this respect, Man-specific lectins of the Vicieae tribe, which specifically recognize the α1,6-fucosylated Man 3 GlcNAc 2 core of N-glycans of the complex-and hybrid-type, are particularly relevant as glycan probes for the beta-coronaviruses MERS-CoV, SARS-CoV, and SARS-CoV-2 [51,106]. However, Man-specific lectins are not considered as replication blockers for coronaviruses, since they do not interfere with the coronavirus replication within the cell.…”

“…The cyanobacterial lectin, cyanovirin-N (CV-N), also displayed similar inhibition towards Ebola virus [85]. Similarly, lentil lectin, LcA, inhibited the early steps of the host cell infection by SARS-CoV-2 and variants B.1.1.7 (α variant), B.1.351 (β variant), and P1 (γ variant), by blocking the recognition of their spike S protein by the ACE2 receptor [51].…”

“…The effects of plant lectins on other pathogenic enveloped viruses have been more scarcely investigated. Plant lectins were identified as blocking agents for the entry of IV [45,52,57], HSV [57], HCMV [47,53,54], EBOV [47,48], LASV [47], and the coronaviruses MERS-CoV [51], SARS-CoV [42,51,54,62,63,104], and SARS-CoV-2 [50][51][52]58,60,61,66] in their corresponding host cells. However, depending on the viruses, the envelope glycoprotein(s) targeted by plant lectins are extremely diverse as mentioned in Table 2.…”

Plant lectins as prospective antiviral biomolecules in the search for COVID-19 eradication strategies

“…The glucose/mannose-specific plant lectin FRIL, derived from Lablab purpureus, is effective both in-vivo and in-vitro for neutralizing SARS-CoV-2 binding to complex-type-N-glycans on viral glycoproteins [138] . Another plant lectin which is mannose-specific, lentil, isolated from Lens culinaris, showed strong inhibitory SARS-CoV-2 activity at the early steps of infections by blocking the ACE2-S trimer binding to oligomannose-type glycans and N-acetylglucosamine at glycosylation sites N165, N234, and N343, which are located around the receptor binding domain [139] .…”