Lactoferrin Binds through Its N-Terminus to the Receptor-Binding Domain of the SARS-CoV-2 Spike Protein
Patrik Babulic, Ondrej Cehlar, Gabriela Ondrovičová, Tetiana Moskalets, Rostislav Skrabana, Vladimir Leksa
Pharmaceuticals, doi:10.3390/ph17081021
Since Coronavirus disease 2019 (COVID-19) still presents a considerable threat, it is beneficial to provide therapeutic supplements against it. In this respect, glycoprotein lactoferrin (LF) and lactoferricin (LFC), a natural bioactive peptide yielded upon digestion from the N-terminus of LF, are of utmost interest, since both have been shown to reduce infections of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus responsible for COVID-19, in particular via blockade of the virus priming and binding. Here, we, by means of biochemical and biophysical methods, reveal that LF directly binds to the S-protein of SARS-CoV-2. We determined thermodynamic and kinetic characteristics of the complex formation and mapped the mutual binding sites involved in this interaction, namely the N-terminal region of LF and the receptor-binding domain of the S-protein (RBD). These results may not only explain many of the observed protective effects of LF and LFC in SARS-CoV-2 infection but may also be instrumental in proposing potent and cost-effective supplemental tools in the management of COVID-19.
Author Contributions: Conceptualization, V.L. and R.S.; methodology, formal analysis, investigation, data curation, P.B., O.C., G.O., T.M., R.S., and V.L.; validation, R.S. and V.L.; writing-original draft preparation, V.L.; writing-review and editing, P.B., O.C., G.O., T.M., R.S., and V.L.; visualization, supervision, project administration, V.L.; resources; funding acquisition, V.L., R.S., T.M., and P.B. All authors have read and agreed to the published version of the manuscript.
Institutional Review Board Statement: Not applicable
Informed Consent Statement: Not applicable
Conflicts of Interest: The authors declare no conflicts of interest.
Abbreviations Angiotensin converting enzyme-2, ACE2; antibody, Ab; Coronavirus disease 2019, COVID-19; heparan sulphate proteoglycans, HSPG; (human/bovine) lactoferricin, (h/b)LFC; (human/bovine) lactoferrin, (h/b)LF; human serum albumin (HSA); mAb, monoclonal antibody; receptor-binding domain (RBD); severe acute respiratory syndrome coronavirus-2, SARS-CoV-2; sodium dodecyl sulfatepolyacrylamide gel electrophoresis, SDS-PAGE; blue native PAGE, BN-PAGE; surface plasmon resonance, SPR; TEMED, N,N,N',N'-tetramethylethylenediamine; transmembrane protease serine 2, TMPRSS2; synthetic peptides, pLF1, pLF3, pLF2 and pCTR.
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'abstract': '<jats:p>Since Coronavirus disease 2019 (COVID-19) still presents a considerable threat, it is '
'beneficial to provide therapeutic supplements against it. In this respect, glycoprotein '
'lactoferrin (LF) and lactoferricin (LFC), a natural bioactive peptide yielded upon digestion '
'from the N-terminus of LF, are of utmost interest, since both have been shown to reduce '
'infections of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus '
'responsible for COVID-19, in particular via blockade of the virus priming and binding. Here, '
'we, by means of biochemical and biophysical methods, reveal that LF directly binds to the '
'S-protein of SARS-CoV-2. We determined thermodynamic and kinetic characteristics of the '
'complex formation and mapped the mutual binding sites involved in this interaction, namely '
'the N-terminal region of LF and the receptor-binding domain of the S-protein (RBD). These '
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'SARS-CoV-2 infection but may also be instrumental in proposing potent and cost-effective '
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