The pineapple-derived jacalin-related lectin as a potential anti-SARS-CoV-2 agent

In a recent study posted to the bioRxiv* preprint server, scientists demonstrated that the pineapple-derived jacalin-related lectin (AcmJRL/AnLec) could be an anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) agent.

Study: The Glycan-Specificity of the Pineapple Lectin AcmJRL and its Carbohydrate-Dependent Binding of the SARS-CoV-2 Spike Protein. Image Credit: Shulevskyy Volodymyr/Shutterstock
Study: The Glycan-Specificity of the Pineapple Lectin AcmJRL and its Carbohydrate-Dependent Binding of the SARS-CoV-2 Spike Protein. Image Credit: Shulevskyy Volodymyr/Shutterstock

Background

With approximately 529 million global SARS-CoV-2 cases identified to date, the current CoV disease 2019 (COVID-19) pandemic has emerged as one of the substantially challenging global health risks. Complementary to COVID-19 vaccines, innovative medications have been the topic of studies and development. SARS-CoV-2's highly glycosylated spike (S) protein is a primary focus for antiviral medicines since it aids in infection. 

The AcmJRL is found in substantial amounts in the drug bromelain and is known to attach mannosides. Further, an Ananas comosus (pineapple) stem extract, bromelain, is an authorized fibrinolytic, anti-inflammatory, and anti-edematous agent used to treat trauma-triggered swelling.

About the study

In the present work, the scientists ascribed the ligand selectivity of AcmJRL using glycan array assessment, characterized its contact with carbohydrates, and confirmed high-mannose glycans as AcmJRL's favored ligands. The AcmJRL's ligand selectivity was elucidated using two glycan arrays, Semiotik and Consortium for Functional Glycomics (CFG) glycan arrays. In addition, the engagement of AcmJRL with carbohydrates was evaluated in a competitive binding assessment. The authors evaluated the attachment of AcmJRL to recombinantly generated S protein and its derived receptor-binding domain (RBD) because the SARS-CoV-2 S protein was found previously to include a large proportion of high-mannose N-glycans.

The mannophilic lectin AcmJRL was extracted using affinity chromatography from a mannosylated stationary phase containing bromelain based on Azarkan et al. documented method. Before purification, bromelain's soluble protein portion was derived by aqueous extraction in the context of S-methyl methanethiosulfonate to suppress the high proteolytic function of bromelain. Mass spectrometry (MS) and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was used to validate the identity of the extracted protein. The team also employed dynamic light scattering (DLS) to calculate AcmJRL's hydrodynamic diameter in the buffered solution.

Results and conclusions

The study results reported that AcmJRL possesses carbohydrates such as glucooligosaccharides and glucose, which could react with primary protein amines to generate Schiff-bases, followed by a permanent Amadori rearrangement to a stable alpha-amino ketone matching to advanced glycation end-products. An increase in mass (162 Da) was seen in the MS spectra following this glycation. The existence of two +324 Da and +162 Da signals indicates that this interaction occurred two times on a maltose disaccharide reacted or the protein.

Rather than tetramers or monomers, the reported hydrodynamic diameter correlated to the dimer's radius. The differential scanning fluorimetry analyses revealed two unfolding incidents, possibly caused by dimer dissociation followed by protein denaturation.

Consistent with its established mannose specificity, the lectin demonstrated a strong affinity for numerous alpha-mannosides, including CFG-GLYCAN ID 310. Monovalent glycans had lower evident binding affinities to AcmJRL than tri- and bi-antennary mannosides. In solution, AcmJRL generates a dimer that can engage up to two mannosides per attaching site. The gap among the anomeric carbons of two mannosides inside one binding site was around 14 Å, close to the gap between two mannoses within mannopentaose, implying that this ligand may chelate. The binding of monovalent alpha-glucosides was significantly low but considerable.

Semiotik glycan array research confirmed mannopentaose and poly-Man-α-1,6 as AcmJRL ligands. However, the smaller mannotriose demonstrated no binding, presumably associated with a shorter linker length limiting protein accessibility. Compared to the CFG glycan array, the Semiotik chip has a multivalent alpha-glucoside that was significantly identified by the lectin, demonstrating AcmJRL's affinity for alpha-glucosides. Surprisingly, two non-related bacterial O-antigens were identified.

AcmJRL was used to titrate fluorescein-labeled alpha-D-mannoside 1, yielding a Kd of 58.9 ± 5.9 254 µM. Compared to AcmJRL's reported affinity for the priorly best-known ligand mannobiose Manα1-3Man, the lectin's high affinity for this alpha-mannoside was astonishing. The glycosidic bond in glucosides was critical for AcmJRL identification, as evidenced by single point inhibition investigations: maltobiose (Glc-285 1,4-Glc) demonstrated the strongest inhibition, whereas cellobiose (Glc-1,4-Glc) had no impact.

The authors discovered that the low µM attaching of AcmJRL and SARS-CoV-2 S protein was carbohydrate-reliant and might be hindered by the addition of mannotriose. Furthermore, AcmJRL decreased the S RBD's tight binding affinity for the human angiotensin-converting enzyme 2 (ACE2) receptor. As a result, bromelain and its component AcmJRL could be used as a new antiviral medication to neutralize SARS-CoV-2 after viral exposure.

Conclusions

Overall, in the present study, the researchers illustrated that the AcmJRL attaches the SARS-CoV-2 S protein in a carbohydrate-dependent manner with a low micromolar Kd, implying that it might be a robust SARS-CoV-2 neutralizing proxy.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Shanet Susan Alex

Written by

Shanet Susan Alex

Shanet Susan Alex, a medical writer, based in Kerala, India, is a Doctor of Pharmacy graduate from Kerala University of Health Sciences. Her academic background is in clinical pharmacy and research, and she is passionate about medical writing. Shanet has published papers in the International Journal of Medical Science and Current Research (IJMSCR), the International Journal of Pharmacy (IJP), and the International Journal of Medical Science and Applied Research (IJMSAR). Apart from work, she enjoys listening to music and watching movies.

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