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Design of superactive and selective integrin receptor antagonists containing the RGD sequence

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Summary

Integrins play a major role in cell-cell and cell-matrix interactions. The majority of the different types of integrins recognize the tripeptide sequence arginine-glycine-aspartic acid (RGD). To explore the spatial requirements of the pharmacophore for receptor selectivity and high activity, a new procedure, ‘spatial screening’, was used. The procedure is based on the experience that the conformation of small cyclic peptides is mainly determined by the chirality of the amino acids (and glycine or proline). For example, cyclic pentapeptides with one d and four l amino acids prefer a βII'/γ conformation. The sequence RGDFV was shifted around this spatial βII'/γ template by synthesis of five peptides in which one of the amino acids was used in d-configuration. It turned out that cyclo(-RGDfV-) is a selective inhibitor for the αvβ3 integrin, which is strongly expressed in cancer cells. Systematic variations with different turn mimetics, retro-inverso structures, modified peptide bonds and sugar amino acids are discussed.

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Authors and Affiliations

  1. Institut für Organische Chemie und Biochemie der TU München, Lichtenbergstrasse 4, D-85747, Garching, Germany

    Horst Kessler, Dirk Finsinger, Armin Geyer, Marion Gurrath, Simon L. Goodman, Roland Haubner, Gerhard Müller, Erich Graf von Roedern & Jochen Wermuth

  2. Merck KGaA, D-64271, Darmstadt, Germany

    Beate Diefenbach, Günter Hölzemann & Alfred Jonczyk

Authors
  1. Horst Kessler
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  2. Beate Diefenbach
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  3. Dirk Finsinger
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  4. Armin Geyer
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  5. Marion Gurrath
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  6. Simon L. Goodman
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  7. Günter Hölzemann
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  8. Roland Haubner
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  9. Alfred Jonczyk
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  10. Gerhard Müller
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  11. Erich Graf von Roedern
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  12. Jochen Wermuth
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Kessler, H., Diefenbach, B., Finsinger, D. et al. Design of superactive and selective integrin receptor antagonists containing the RGD sequence. Lett Pept Sci 2, 155–160 (1995). https://doi.org/10.1007/BF00119142

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  • DOI: https://doi.org/10.1007/BF00119142

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