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Lebetin Peptides, A New Class of Potent Platelet Aggregation Inhibitors: Chemical Synthesis, Biological Activity and NMR Spectroscopic Study

  • Amor MosbahEmail author
  • Naziha Marrakchi
  • Pascal Mansuelle
  • Soumaya Kouidhi
  • Ernest Giralt
  • Mohamed El Ayeb
  • Gaëtan Herbette
  • Ameur Cherif
  • Didier Gigmes
  • Hervé Darbon
  • Kamel MabroukEmail author
Article
  • 22 Downloads

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.

Keywords

NMR structure Peptide Synthesis Anti-platelet Aggregation Natriuretic factor 

Notes

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.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10989_2019_9812_MOESM1_ESM.docx (713 kb)
Supplementary material 1 (DOCX 712 KB)

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Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Amor Mosbah
    • 1
    • 2
    • 3
    Email author
  • Naziha Marrakchi
    • 4
  • Pascal Mansuelle
    • 5
  • Soumaya Kouidhi
    • 1
  • Ernest Giralt
    • 6
    • 7
  • Mohamed El Ayeb
    • 4
  • Gaëtan Herbette
    • 8
  • Ameur Cherif
    • 1
  • Didier Gigmes
    • 3
  • Hervé Darbon
    • 2
  • Kamel Mabrouk
    • 3
    • 9
    Email author
  1. 1.Univ. Manouba, ISBST, BVBGR-LR11ES31, Biotechnopole Sidi ThabetArianaTunisia
  2. 2.UMR 7257, CNRS, Aix-Marseille Université, Architecture et Fonction des Macromolécules Biologiques (AFMB)MarseilleFrance
  3. 3.Aix Marseille Univ, CNRS, ICR, Institut de Chimie Radicalaire, UMRMarseilleFrance
  4. 4.Laboratoire des Venins et ToxinesInstitut Pasteur de TunisTunis-BelevédèreTunisia
  5. 5.Plate-forme Protéomique, Marseille Protéomique (MaP) IBiSA labelledInstitut de Microbiologie de la Méditerranée, FR 3479, CNRSMarseille Cedex 20France
  6. 6.Institute for Research in Biomedicine (IRB Barcelona)The Barcelona Institute of Science and TechnologyBarcelonaSpain
  7. 7.Department of Inorganic and Organic ChemistryUniversity of BarcelonaBarcelonaSpain
  8. 8.Aix Marseille Univ, Spectropôle, FR1739MarseilleFrance
  9. 9.Laboratoire de Chimie RadicalaireOrganique et Polymères de SpécialitéMarseilleFrance

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