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

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.

Identification and Evaluation of New Potential Inhibitors of Human Neuraminidase 1 Extracted from Olyra latifolia L.: A Preliminary Study

“…That is why several strategies have been envisaged to disturb the activation of NEU-1 to prevent the progression of various diseases. Among these, chemical compounds [ 22 , 45 ] or transmembrane peptides as inhibitors of NEU-1 dimerization/activation [ 24 ] are currently under development. During the last years, different selective inhibitors of human NEU-1 have been notably developed based on the DANA chemical structure [ 22 , 23 ].…”

“…In fact, C9-BA-DANA not only blocks NEU-1 sialidase activity but also its bioactivities in human lung in vitro and murine lung in vivo [ 45 ]. Furthermore, a recent study has also shown that interfering peptides targeting the transmembrane domain of NEU-1 are able to decrease both NEU-1 dimerization and sialidase activity [ 24 ]. The aim of this study was to identify plant-derived natural products that share analogy with the DANA molecule and to evaluate their bioactivity against plasma membrane NEU-1 sialidase activity.…”

“…Only two selective inhibitors specific of human NEU-1, the C5-hexanamido-C9-actetamido-DANA [ 22 ] and the C9-amido analogue of DANA [ 23 ], have been identified. Recently, a promising strategy has been developed using transmembrane peptides to inhibit dimerization and the activation of NEU-1 [ 24 , 25 ]. Thus, identifying new compounds with selective inhibition activity against NEU-1 remains a very exciting challenge.…”

Is It Possible to Find an Antimicrobial Peptide That Passes the Membrane Bilayer with Minimal Force Resistance? An Attempt at a Predictive Approach by Molecular Dynamics Simulation

“…The difference between our work and that done in [ 37 ] is that we built peptides with a linear (rather than α-helical) conformation.…”

The Elastin Receptor Complex: An Emerging Therapeutic Target Against Age-Related Vascular Diseases

“…From these results, we developed an original strategy based on the use of interfering peptides to target this dimerization interface. We showed that these interfering peptides were able to interact with NEU1 TM2, to disrupt membrane NEU1 dimerization and to inhibit its sialidase activity (89). In vivo application of these new promising selective NEU1 inhibitors is currently under investigation.…”