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Highly Selective Cyclic Hexapeptides Antagonist of GPIIb-IIIa by Multiple N-Methylation

  • Jayanta Chatterjee
  • Oded Ovadia
  • Grit Zahn
  • Luciana Marinelli
  • Amnon Hoffman
  • Horst Kessler
Part of the Advances in Experimental Medicine and Biology book series (volume 611)

Introduction

N-methylation is a precious tool to modify lipophilicity, proteolytic stability, bioavailability and induce conformational rigidity to peptide backbone. Mono N-methylation of peptide ligands has been employed over the years to enhance potency, new receptor subtype selectivity and tuning of an agonist to antagonist. However, multiple N-methylation to our knowledge has never been reported, probably owing to difficult coupling, availability of N-methylated amino acid and unpredictable conformational change. We show here that a systematic multiple N-methyl scan can be employed to achieve surprisingly enhanced receptor selectivity. For that purpose, we envisioned a ‘Design Approach’ instead of the commonly used ‘Library Approach’. In this method, the prerequisite is the knowledge of the bioactive conformation of the stem peptide (lead structure). Then a systematic N-methylation of the externally oriented (solvent exposed) peptide bonds are carried out. Here, we employed cyclic...

Keywords

Aspartic Acid Cyclic Peptide Bioactive Conformation Conformational Rigidity Subtype Selectivity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We acknowledge Humboldt Foundation for the Max-Planck Forschungspreis to HK.

References

  1. 1.
    Pfaff, M. et al. J. Biol. Chem. 269, 20233–2023872 (1994).Google Scholar
  2. 2.
    Gurrath, M. et al. Eur. J. Biohem. 210, 911–921 (1992).CrossRefGoogle Scholar
  3. 3.
    Huang, Z. W. et al. J. Am. Chem. Soc. 114, 9390–9401 (1992).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Jayanta Chatterjee
    • 1
  • Oded Ovadia
    • 2
  • Grit Zahn
    • 3
  • Luciana Marinelli
    • 4
  • Amnon Hoffman
    • 2
  • Horst Kessler
    • 1
  1. 1.Department Chemie, Lehrstuhl II für Organische ChemieTechnische Universität MünchenGarchingGermany
  2. 2.Pharmaceutics and Organic Chemistry DepartmentsThe Hebrew University of JerusalemJerusalemIsrael
  3. 3.Jerini A.G.BerlinGermany
  4. 4.Farmaceutica e TossicologicaUniversità di Napoli ‘Federico II’NapoliItaly

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