Blockade of TMPRSS2-mediated priming of SARS-CoV-2 by the N-terminal peptide of lactoferrin

Ohradanova-Repic, A.; Gebetsberger, L.; Tajti, G.; Ondrovicova, G.; Prazenicova, R.; Skrabana, R.; Barath, P.; Stockinger, H.; Leksa, V.

doi:10.1101/2021.12.20.473447

bioRxiv · 10.1101/2021.12.20.473447

Blockade of TMPRSS2-mediated priming of SARS-CoV-2 by the N-terminal peptide of lactoferrin

Ohradanova-Repic, A.·Gebetsberger, L.·Tajti, G.·Ondrovicova, G.·Prazenicova, R.·Skrabana, R.·Barath, P.·Stockinger, H.·Leksa, V.

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Abstract

In addition to vaccines, there is an urgent need for supplemental antiviral therapeutics to dampen the persistent COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The transmembrane protease serine 2 (TMPRSS2), which is responsible for the proteolytic processing of the SARS-CoV-2 spike protein as virus priming for cell entry, appears as a rational therapeutic target for the clearance of SARS-CoV-2 infection. Accordingly, selective inhibitors of TMPRSS2 represent potential tools for prevention and treatment of COVID-19. Here, we tested the inhibitory capacities of the human milk glycoprotein lactoferrin and its N-terminal peptide pLF1, which we identified as inhibitors of plasminogen, a serine protease homologous to TMPRSS2. In vitro proteolysis assays revealed that, unlike full-length lactoferrin, pLF1 significantly inhibited the proteolytic activity of TMPRSS2. pLF1 inhibited both the proteolytic processing of the SARS-CoV-2 spike protein and the SARS-CoV-2 infection of simian Vero cells. Because lactoferrin is a natural product and several biologically active peptides, such as the N-terminally derived lactoferricins, are produced naturally by pepsin-mediated digestion, natural or synthetic peptides from lactoferrin represent well-achievable candidates for supporting prevention and treatment of COVID-19.

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Ohradanova-Repic, A., Gebetsberger, L., Tajti, G., Ondrovicova, G., Prazenicova, R., Skrabana, R., Barath, P., Stockinger, H., Leksa, V.. 2021-12-22. Blockade of TMPRSS2-mediated priming of SARS-CoV-2 by the N-terminal peptide of lactoferrin. https://doi.org/10.1101/2021.12.20.473447

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