Frontiers in Cell and Developmental Biology (Dec 2020)

Transmembrane Peptides as a New Strategy to Inhibit Neuraminidase-1 Activation

  • Camille Albrecht,
  • Camille Albrecht,
  • Andrey S. Kuznetsov,
  • Andrey S. Kuznetsov,
  • Andrey S. Kuznetsov,
  • Aline Appert-Collin,
  • Aline Appert-Collin,
  • Zineb Dhaideh,
  • Zineb Dhaideh,
  • Maïté Callewaert,
  • Maïté Callewaert,
  • Yaroslav V. Bershatsky,
  • Yaroslav V. Bershatsky,
  • Anatoly S. Urban,
  • Anatoly S. Urban,
  • Eduard V. Bocharov,
  • Eduard V. Bocharov,
  • Dominique Bagnard,
  • Dominique Bagnard,
  • Stéphanie Baud,
  • Stéphanie Baud,
  • Sébastien Blaise,
  • Sébastien Blaise,
  • Béatrice Romier-Crouzet,
  • Béatrice Romier-Crouzet,
  • Roman G. Efremov,
  • Roman G. Efremov,
  • Roman G. Efremov,
  • Manuel Dauchez,
  • Manuel Dauchez,
  • Manuel Dauchez,
  • Laurent Duca,
  • Laurent Duca,
  • Marc Gueroult,
  • Marc Gueroult,
  • Pascal Maurice,
  • Pascal Maurice,
  • Amar Bennasroune,
  • Amar Bennasroune

DOI
https://doi.org/10.3389/fcell.2020.611121
Journal volume & issue
Vol. 8

Abstract

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Sialidases, or neuraminidases, are involved in several human disorders such as neurodegenerative, infectious and cardiovascular diseases, and cancers. Accumulative data have shown that inhibition of neuraminidases, such as NEU1 sialidase, may be a promising pharmacological target, and selective inhibitors of NEU1 are therefore needed to better understand the biological functions of this sialidase. In the present study, we designed interfering peptides (IntPep) that target a transmembrane dimerization interface previously identified in human NEU1 that controls its membrane dimerization and sialidase activity. Two complementary strategies were used to deliver the IntPep into cells, either flanked to a TAT sequence or non-tagged for solubilization in detergent micelles. Combined with molecular dynamics simulations and heteronuclear nuclear magnetic resonance (NMR) studies in membrane-mimicking environments, our results show that these IntPep are able to interact with the dimerization interface of human NEU1, to disrupt membrane NEU1 dimerization and to strongly decrease its sialidase activity at the plasma membrane. In conclusion, we report here new selective inhibitors of human NEU1 of strong interest to elucidate the biological functions of this sialidase.

Keywords