Lactoferrin Inhibition of the Complex Formation between ACE2 Receptor and SARS CoV-2 Recognition Binding Domain

Piacentini et al., 13 May 2022, Italy, peer-reviewed, 10 authors. Contact: giacomo.parisi@iit.it (corresponding author), roberta.piacentini@uniroma1.it, centi.laura95@gmail.com, alberto.boffi@uniroma1.it, miottomattia1@gmail.com, edoardo.milanetti@uniroma1.it, lorenzo.dirienzo@iit.it, martina.pitea@iit.it, giancarlo.ruocco@iit.it, paolopiazza@edifinstruments.com.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

This Paper Lactoferrin All

Roberta Piacentini, Laura Centi, Mattia Miotto, Edoardo Milanetti, Lorenzo Di Rienzo, Martina Pitea, Paolo Piazza, Giancarlo Ruocco, Alberto Boffi, Giacomo Parisi

International Journal of Molecular Sciences, doi:10.3390/ijms23105436

The present investigation focuses on the analysis of the interactions among human lactoferrin (LF), SARS-CoV-2 receptor-binding domain (RBD) and human angiotensin-converting enzyme 2 (ACE2) receptor in order to assess possible mutual interactions that could provide a molecular basis of the reported preventative effect of lactoferrin against CoV-2 infection. In particular, kinetic and thermodynamic parameters for the pairwise interactions among the three proteins were measured via two independent techniques, biolayer interferometry and latex nanoparticle-enhanced turbidimetry. The results obtained clearly indicate that LF is able to bind the ACE2 receptor ectodomain with significantly high affinity, whereas no binding to the RBD was observed up to the maximum "physiological" lactoferrin concentration range. Lactoferrin, above 1 µM concentration, thus appears to directly interfere with RBD-ACE2 binding, bringing about a measurable, up to 300-fold increase of the K D value relative to RBD-ACE2 complex formation.

References

Baker, Baker, Molecular structure, binding properties and dynamics of Lactoferrin, Cell. Mol. Life Sci, doi:10.1007/s00018-005-5368-9

Berlutti, Pantanella, Natalizi, Frioni, Paesano et al., Antiviral Properties of Lactoferrin-A Natural Immunity Molecule, Molecules, doi:10.3390/molecules16086992

Bishop, Gagneux, Evolution of carbohydrate antigens-microbial forces shaping host glycomes?, Glycobiology, doi:10.1093/glycob/cwm005

Bò, Miotto, Di Rienzo, Milanetti, Ruocco, Exploring the Association Between Sialic Acid and SARS-CoV-2 Spike Protein Through a Molecular Dynamics-Based Approach, Front. Med Technol, doi:10.3389/fmedt.2020.614652

Campione, Cosio, Rosa, Lanna, Di Girolamo et al., Lactoferrin as Protective Natural Barrier of Respiratory and Intestinal Mucosa against Coronavirus Infection and Inflammation, Int. J. Mol. Sci, doi:10.3390/ijms21144903

Campione, Lanna, Cosio, Rosa, Conte et al., Lactoferrin Against SARS-CoV-2: In Vitro and In Silico Evidences, Front. Pharmacol, doi:10.3389/fphar.2021.666600

Chang, Ng, Sun, Lactoferrin as potential preventative and adjunct treatment for COVID-19, Int. J. Antimicrob. Agents, doi:10.1016/j.ijantimicag.2020.106118

Coletta, Amendola, Numerical Modelling of the Optical Properties of Plasmonic and Latex Nanoparticles to Improve the Detection Limit of Immuno-Turbidimetric Assays, Nanomaterials, doi:10.3390/nano11051147

Concepcion, Witte, Wartchow, Choo, Yao et al., Label-Free Detection of Biomolecular Interactions Using BioLayer Interferometry for Kinetic Characterization, Comb. Chem. High Throughput Screen, doi:10.2174/138620709789104915

Cölfen, Völkel, Eda, Kobold, Kaufmann et al., Mechanism of Nanoparticle-Enhanced Turbidimetric Assays Applying Nanoparticles of Different Size and Immunoreactivity, Langmuir

Dzimianski, Lorig-Roach, O'rourke, Alexander, Kimmey et al., Rapid and sensitive detection of SARS-CoV-2 antibodies by biolayer interferometry, Sci. Rep, doi:10.1038/s41598-020-78895-x

Giansanti, Panella, Leboffe, Antonini, Lactoferrin from Milk: Nutraceutical and Pharmacological Properties, Pharmaceuticals, doi:10.3390/ph9040061

Gurnani, Lunn, Perrier, Synthesis of mannosylated and PEGylated nanoparticles via RAFT emulsion polymerisation, and investigation of particle-lectin aggregation using turbidimetric and DLS techniques, Polymer, doi:10.1016/j.polymer.2016.08.093

Harmsen, Swart, De Béthune, Pauwels, De Clercq et al., Antiviral Effects of Plasma and Milk Proteins: Lactoferrin Shows Potent Activity against Both Human Immunodeficiency Virus and Human Cytomegalovirus Replication In Vitro, J. Infect. Dis, doi:10.1093/infdis/172.2.380

Hulswit, Lang, Bakkers, Li, Li et al., Human coronaviruses OC43 and HKU1 bind to 9-O -acetylated sialic acids via a conserved receptor-binding site in spike protein domain A, Proc. Natl. Acad. Sci, doi:10.1073/pnas.1809667116

Kamat, Rafique, Designing binding kinetic assay on the bio-layer interferometry (BLI) biosensor to characterize antibodyantigen interactions, Anal. Biochem, doi:10.1016/j.ab.2017.08.002

Kell, Heyden, Pretorius, The Biology of Lactoferrin, an Iron-Binding Protein That Can Help Defend Against Viruses and Bacteria, Front. Immunol, doi:10.3389/fimmu.2020.01221

Kumaraswamy, Tobias, Label-Free Kinetic Analysis of an Antibody-Antigen Interaction Using Biolayer Interferometry, doi:10.1007/978-1-4939-2425-7_10

Lang, Yang, Deng, Liu, Yang et al., Inhibition of SARS Pseudovirus Cell Entry by Lactoferrin Binding to Heparan Sulfate Proteoglycans, PLoS ONE, doi:10.1371/journal.pone.0023710

Langford-Smith, Day, Bishop, Clark, Complementing the Sugar Code: Role of GAGs and Sialic Acid in Complement Regulation, Front. Immunol, doi:10.3389/fimmu.2015.00025

Mahmood, Poma, Okazaki, Optimizing G ō-MARTINI Coarse-Grained Model for F-BAR Protein on Lipid Membrane, Front. Mol. Biosci, doi:10.3389/fmolb.2021.619381

Malatesta, The study of bimolecular reactions under non-pseudo-first order conditions, Biophys. Chem, doi:10.1016/j.bpc.2005.04.006

Martínez, Cooper, Poma, Guzman, Free Energies of the Disassembly of Viral Capsids from a Multiscale Molecular Simulation Approach, J. Chem. Inf. Model, doi:10.1021/acs.jcim.9b00883

Milanetti, Miotto, Di Rienzo, Monti, Gosti et al., Zernike polynomial expansion: Finding the protein-protein binding regions, Comput. Struct. Biotechnol. J, doi:10.1016/j.csbj.2020.11.051

Milanetti, Miotto, Di Rienzo, Nagaraj, Monti et al., In-Silico Evidence for a Two Receptor Based Strategy of SARS-CoV-2, Front. Mol. Biosci, doi:10.3389/fmolb.2021.690655

Miotto, Di Rienzo, Bò, Boffi, Ruocco et al., Molecular Mechanisms Behind Anti SARS-CoV-2 Action of Lactoferrin, Front. Mol. Biosci, doi:10.3389/fmolb.2021.607443

Miotto, Di Rienzo, Gosti, Milanetti, Ruocco, Does blood type affect the COVID-19 infection pattern?, PLoS ONE, doi:10.1371/journal.pone.0251535

Müller-Esparza, Osorio-Valeriano, Steube, Thanbichler, Randau, Bio-Layer Interferometry Analysis of the Target Binding Activity of CRISPR-Cas Effector Complexes, Front. Mol. Biosci, doi:10.3389/fmolb.2020.00098

Nedyalkova, Vasighi, Sappati, Kumar, Madurga et al., Inhibition Ability of Natural Compounds on Receptor-Binding Domain of SARS-CoV2: An in Silico Approach, Pharmaceuticals, doi:10.3390/ph14121328

Odolczyk, Marzec, Winiewska-Szajewska, Pozna Ński, Zielenkiewicz, Native Structure-Based Peptides as Potential Protein-Protein Interaction Inhibitors of SARS-CoV-2 Spike Protein and Human ACE2 Receptor, Molecules, doi:10.3390/molecules26082157

Petersen, Strategies Using Bio-Layer Interferometry Biosensor Technology for Vaccine Research and Development, Biosensors, doi:10.3390/bios7040049

Puddu, Borghi, Gessani, Valenti, Belardelli et al., Antiviral effect of bovine lactoferrin saturated with metal ions on early steps of human immunodeficiency virus type 1 infection, Int. J. Biochem. Cell Biol, doi:10.1016/S1357-2725(98)00066-1

Rascón-Cruz, Espinoza-Sánchez, Siqueiros-Cendón, Nakamura-Bencomo, Arévalo-Gallegos et al., Lactoferrin: A Glycoprotein Involved in Immunomodulation, Anticancer, and Antimicrobial Processes, Molecules, doi:10.3390/molecules26010205

Redwan, Uversky, El-Fakharany, Al-Mehdar, Potential lactoferrin activity against pathogenic viruses, Comptes Rendus Biol, doi:10.1016/j.crvi.2014.08.003

Richards, Areas, volumes, packing and protein structure, Annu. Rev. Biophys. Bioeng, doi:10.1146/annurev.bb.06.060177.001055

Rosa, Cutone, Lepanto, Paesano, Valenti, Lactoferrin: A Natural Glycoprotein Involved in Iron and Inflammatory Homeostasis, Int. J. Mol. Sci, doi:10.3390/ijms18091985

Rosa, Tripepi, Naldi, Aimati, Santangeli et al., Ambulatory COVID-19 Patients Treated with Lactoferrin as a Supplementary Antiviral Agent: A Preliminary Study, J. Clin. Med, doi:10.3390/jcm10184276

Saponaro, Rutigliano, Sestito, Bandini, Storti et al., ACE2 in the Era of SARS-CoV-2: Controversies and Novel Perspectives, Front. Mol. Biosci, doi:10.3389/fmolb.2020.588618

Superti, Siciliano, Rega, Giansanti, Valenti et al., Involvement of bovine lactoferrin metal saturation, sialic acid and protein fragments in the inhibition of rotavirus infection, Biochim. Biophys. Acta, doi:10.1016/S0304-4165(01)00178-7

Tortorici, Walls, Lang, Wang, Li et al., Structural basis for human coronavirus attachment to sialic acid receptors, Nat. Struct. Mol. Biol, doi:10.1038/s41594-019-0233-y

Varki, Biological roles of glycans, Glycobiology, doi:10.1093/glycob/cww086

Wang, Wang, Wang, Luo, Wan et al., Lactoferrin for the treatment of COVID-19 (Review), Exp. Ther. Med, doi:10.3892/etm.2020.9402

Yan, Zhang, Li, Xia, Guo et al., Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2, Science, doi:10.1126/science.abb2762

Yi, Kaneko, Yu, Murakami, Hepatitis C virus envelope proteins bind lactoferrin, J. Virol

Zhou, Yang, Wang, Hu, Zhang et al., A pneumonia outbreak associated with a new coronavirus of probable bat origin, Nature, doi:10.1038/s41586-020-2012-7

Zhu, Zhang, Wang, Li, Yang et al., A Novel Coronavirus from Patients with Pneumonia in China, N. Engl. J. Med, doi:10.1056/NEJMoa2001017

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