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.
Highlights
Sialidases, or neuraminidases, are glycosidases responsible for the cleavage of terminal sialic acid residues from glycoproteins, glycolipids, and oligosaccharides (Monti et al, 2010)
NEU1 is required for elastogenesis and signal transduction through this receptor (Hinek et al, 2006; Duca et al, 2007; Rusciani et al, 2010) and for the biological effects mediated by the elastin-derived peptides on atherosclerosis (Gayral et al, 2014; Kawecki et al, 2019), thrombosis (Kawecki et al, 2014), insulin resistance (Blaise et al, 2013) and non-alcoholic steatohepatitis (Romier et al, 2018)
Two approaches were used in order to deliver the interfering peptides (IntPep) targeting the TM2 domain of human membrane NEU1 (mNEU1) into cells: (i) in the first one (“transactivator of transcription (TAT) approach”), IntPep was linked to the TAT peptide sequence, rich in lysine and arginine residues; (ii) in the second method (“lithium dodecyl sulfate (LDS) approach”), IntPep was solubilized into positively charged LDS micelles
Summary
Sialidases, or neuraminidases, are glycosidases responsible for the cleavage of terminal sialic acid residues from glycoproteins, glycolipids, and oligosaccharides (Monti et al, 2010). Recent findings have highlighted a critical role of NEU1 in immune thrombocytopenia induced by antiGPIbα autoantibodies by a mechanism involving Fc-independent platelet activation, NEU1 translocation to the plasma membrane, desialylation, and platelet clearance in the liver via hepatocyte Ashwell–Morell receptors (Li et al, 2015). Together, these recent findings make NEU1 a pharmacological target of high potential and inhibitors of human NEU1 are urgently needed
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
