Abstract
Platelets have a well-established role in atherosclerosis and related diseases. Lebetins from the venom of Vipera lebetina, lacking the RGD sequence, emerged as a new family of platelet aggregation inhibitors. However, the interaction sites and precise mechanism between lebetin and its substrate remain unclear. Here, we successfully synthesized two peptide analogs, which differ only by one glycine residue at the N-terminus: lebetin 2α (sL2α residues) and lebetin 2β (sL2ββ residues) were produced in sufficient quantities for structural and functional studies. NMR structure determination showed that the sL2α peptide adopts a compact ring conformation stabilized by a disulfide bond, from which emerge one loop and two extended regions, the C- and N-termini. Interestingly, two RGD-like motifs were identified in the structure of the peptides, suggesting an anti-platelet aggregation effect of the two isoforms. Indeed, activity was demonstrated on human and rabbit platelet-rich plasma where sL2α and sL2β showed more potent inhibitory effect on platelet aggregation compared to the previously described native lebetin 1. Synthetic lebetin 2 peptides constitute promising candidates for drug design toward chimeric compounds with high anti-platelet and natriuretic effects. These findings contribute to a novel field of research triggering platelet activation and natriuretic action.
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Data Availability
Protein Data Bank accession number: The atomic coordinates of the 10 best sL2a structures have been deposited with RCSB Protein Data Bank as entry 1Q01 and the Bio Mag Res Bank (BMRB) BMRB-8546.
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Acknowledgements
The authors thank Dr. Harold de Pomyers for helpful discussion. IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain)., and is included in the CERCA Programme of the Catalan Government.
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Mosbah, A., Marrakchi, N., Mansuelle, P. et al. Lebetin Peptides, A New Class of Potent Platelet Aggregation Inhibitors: Chemical Synthesis, Biological Activity and NMR Spectroscopic Study. Int J Pept Res Ther 26, 21–31 (2020). https://doi.org/10.1007/s10989-019-09812-8
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DOI: https://doi.org/10.1007/s10989-019-09812-8