Molecular Mechanisms Behind Anti SARS-CoV-2 Action of Lactoferrin

Miotto et al., Frontiers in Molecular Biosciences, doi:10.3389/fmolb.2021.607443

Feb 2021

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In Silico study of possible molecular mechanisms for anti-SARS-CoV-2 action of lactoferrin.

13 preclinical studies support the efficacy of lactoferrin for COVID-19:

10 In Vitro studies Alves, Andreu, Cutone, Kobayashi-Sakamoto, Mirabelli, Ostrov, Piacentini, Salaris, Yathindranath, Yazawa

1 In Vivo animal study Berkowitz

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1. Alves et al., Inhibition of SARS-CoV-2 Infection in Vero Cells by Bovine Lactoferrin under Different Iron-Saturation States, Pharmaceuticals, doi:10.3390/ph16101352.mdpi.com, doi.org.

2. Andreu et al., Liposomal Lactoferrin Exerts Antiviral Activity against HCoV-229E and SARS-CoV-2 Pseudoviruses In Vitro, Viruses, doi:10.3390/v15040972.mdpi.com, doi.org.

3. Berkowitz et al., Sigma Receptor Ligands Prevent COVID Mortality In Vivo: Implications for Future Therapeutics, International Journal of Molecular Sciences, doi:10.3390/ijms242115718.mdpi.com, doi.org.

4. Cutone et al., Lactoferrin binding to Sars-CoV-2 Spike glycoprotein protects host from infection, inflammation and iron dysregulation., Research Square, doi:10.21203/rs.3.rs-1605740/v1.researchsquare.com, doi.org.

5. Kobayashi-Sakamoto et al., Bovine lactoferrin suppresses the cathepsin-dependent pathway of SARS-CoV-2 entry in vitro, International Dairy Journal, doi:10.1016/j.idairyj.2023.105805.sciencedirect.com, doi.org.

6. Miotto et al., Molecular Mechanisms Behind Anti SARS-CoV-2 Action of Lactoferrin, Frontiers in Molecular Biosciences, doi:10.3389/fmolb.2021.607443.frontiersin.org, doi.org.

7. Mirabelli et al., Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19, Proceedings of the National Academy of Sciences, doi:10.1073/pnas.2105815118.pnas.org, doi.org.

8. Ostrov et al., Highly Specific Sigma Receptor Ligands Exhibit Anti-Viral Properties in SARS-CoV-2 Infected Cells, Pathogens, doi:10.3390/pathogens10111514.mdpi.com, doi.org.

9. Piacentini et al., Lactoferrin Inhibition of the Complex Formation between ACE2 Receptor and SARS CoV-2 Recognition Binding Domain, International Journal of Molecular Sciences, doi:10.3390/ijms23105436.mdpi.com, doi.org.

10. Salaris et al., Protective Effects of Lactoferrin against SARS-CoV-2 Infection In Vitro, Nutrients, doi:10.3390/nu13020328.mdpi.com, doi.org.

11. Yathindranath et al., Lipid Nanoparticle-Based Inhibitors for SARS-CoV-2 Host Cell Infection, International Journal of Nanomedicine, doi:10.2147/IJN.S448005.dovepress.com, doi.org.

12. Yazawa et al., Evaluation of SARS-CoV-2 isolation in cell culture from nasal/nasopharyngeal swabs or saliva specimens of patients with COVID-19, Research Square, doi:10.21203/rs.3.rs-2676422/v1.researchsquare.com, doi.org.

Miotto et al., 15 Feb 2021, peer-reviewed, 6 authors. Contact: mattia.miotto@roma1.infn.it.

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

This Paper Lactoferrin All

Molecular Mechanisms Behind Anti SARS-CoV-2 Action of Lactoferrin

Mattia Miotto, Lorenzo Di Rienzo, Leonardo Bò, Alberto Boffi, Giancarlo Ruocco, Edoardo Milanetti

Frontiers in Molecular Biosciences, doi:10.3389/fmolb.2021.607443

Despite the huge effort to contain the infection, the novel SARS-CoV-2 coronavirus has rapidly become pandemic, mainly due to its extremely high human-to-human transmission capability, and a surprisingly high viral charge of symptom-less people. While the seek for a vaccine is still ongoing, promising results have been obtained with antiviral compounds. In particular, lactoferrin is regarded to have beneficial effects both in preventing and soothing the infection. Here, we explore the possible molecular mechanisms with which lactoferrin interferes with SARS-CoV-2 cell invasion, preventing attachment and/or entry of the virus. To this aim, we search for possible interactions lactoferrin may have with virus structural proteins and host receptors. Representing the molecular iso-electron surface of proteins in terms of 2D-Zernike descriptors, we 1) identified putative regions on the lactoferrin surface able to bind sialic acid present on the host cell membrane, sheltering the cell from the virus attachment; 2) showed that no significant shape complementarity is present between lactoferrin and the ACE2 receptor, while 3) two high complementarity regions are found on the N-and C-terminal domains of the SARS-CoV-2 spike protein, hinting at a possible competition between lactoferrin and ACE2 for the binding to the spike protein.

AUTHOR CONTRIBUTIONS EM, AB, and GR conceived research; MM and LB performed molecular dynamics simulations. MM, LR, and EM performed calculations and computational analysis. All authors analyzed results; all authors wrote and revised the paper. Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Copyright © 2021 Miotto, Di Rienzo, Bò, Boffi, Ruocco and Milanetti. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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