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

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

doi:10.3389/fcell.2020.611121

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

Front Cell Dev Biol. 2020 Dec 16:8:611121. doi: 10.3389/fcell.2020.611121. eCollection 2020.

Authors

Camille Albrecht^{1

2}, Andrey S Kuznetsov^{3

4

5}, Aline Appert-Collin^{1

2}, Zineb Dhaideh^{1

2}, Maïté Callewaert^{1

6}, Yaroslav V Bershatsky^{3

5}, Anatoly S Urban^{3

5}, Eduard V Bocharov^{3

5}, Dominique Bagnard^{7

8}, Stéphanie Baud^{1

2}, Sébastien Blaise^{1

2}, Béatrice Romier-Crouzet^{1

2}, Roman G Efremov^{3

4

5}, Manuel Dauchez^{1

2

9}, Laurent Duca^{1

2}, Marc Gueroult^{1

2}, Pascal Maurice^{1

2}, Amar Bennasroune^{1

2}

Affiliations

¹ Université de Reims Champagne-Ardenne, Reims, France.
² CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Reims, France.
³ Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.
⁴ Higher School of Economics, Moscow, Russia.
⁵ Moscow Institute of Physics and Technology, National Research University, Dolgoprudny, Russia.
⁶ CNRS UMR 7312, Institut de Chimie Moléculaire de Reims, Reims, France.
⁷ Université de Strasbourg, Strasbourg, France.
⁸ INSERM U1119 Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, Labex Medalis, Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France.
⁹ Plateau de Modélisation Moléculaire Multi-échelle, Reims, France.

Abstract

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: interfering peptides; membrane protein dimerization; neuraminidase-1; sialidase activity; transmembrane domain.