N-methylated cyclic RGD peptides as highly active and selective α(v)β3 integrin antagonists

Michael A. Dechantsreiter, Eckart Planker, Barbara Mathä, Elisabeth Lohof, Günter Hölzemann, Alfred Jonczyk, Simon L. Goodman, Horst Kessler

Research output: Contribution to journalArticlepeer-review

788 Scopus citations

Abstract

The ανβ3 integrin receptor plays an important role in human tumor metastasis and tumor-induced angiogenesis. The in vivo inhibition of this receptor by antibodies or by cyclic peptides containing the RGD sequence may in the future be used to selectively suppress these diseases. Here we investigate the influence of N-methylation of the active and selective ανβ3 antagonist cyclo(RGDfV) (L1) on biological activity. Cyclo(RGDf- N(Me)V-) (PS) was found to be even more active than L1 and is one of the most active and selective compounds in inhibiting vitronectin binding to the ανβ3 integrin. Its high-resolution, three-dimensional structure in water was determined by NMR techniques, distance geometry calculations, and molecular dynamics calculations, providing more insight into the structure- activity relationship.

Original languageEnglish
Pages (from-to)3033-3040
Number of pages8
JournalJournal of Medicinal Chemistry
Volume42
Issue number16
DOIs
StatePublished - 12 Aug 1999

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