AUTHOR=Albrecht Camille , Kuznetsov Andrey S. , Appert-Collin Aline , Dhaideh Zineb , Callewaert Maïté , Bershatsky Yaroslav V. , Urban Anatoly S. , Bocharov Eduard V. , Bagnard Dominique , Baud Stéphanie , Blaise Sébastien , Romier-Crouzet Béatrice , Efremov Roman G. , Dauchez Manuel , Duca Laurent , Gueroult Marc , Maurice Pascal , Bennasroune Amar TITLE=Transmembrane Peptides as a New Strategy to Inhibit Neuraminidase-1 Activation JOURNAL=Frontiers in Cell and Developmental Biology VOLUME=8 YEAR=2020 URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2020.611121 DOI=10.3389/fcell.2020.611121 ISSN=2296-634X 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.