Overcoming the Lack of Oral Availability of Cyclic Hexapeptides: Design of a Selective and Orally Available Ligand for the Integrin αvβ3

Michael Weinmüller, Florian Rechenmacher, Udaya Kiran Marelli, Florian Reichart, Tobias G. Kapp, Andreas F.B. Räder, Francesco Saverio Di Leva, Luciana Marinelli, Ettore Novellino, José M. Muñoz-Félix, Kairbaan Hodivala-Dilke, Adi Schumacher, Joseph Fanous, Chaim Gilon, Amnon Hoffman, Horst Kessler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


A highly systematic approach for the development of both orally bioavailable and bioactive cyclic N-methylated hexapeptides as high affinity ligands for the integrin αvβ3 is based on two concepts: a) screening of systematically designed libraries with spatial diversity and b) masking of the peptide charge with a lipophilic protecting group. The key steps of the method are 1) initial design of a combinatorial library of N-methylated analogues of the stem peptide cyclo(d-Ala-Ala5); 2) selection of cyclic peptides with the highest intestinal permeability; 3) design of sublibraries with the bioactive RGD sequence in all possible positions; 4) selection of the best ligands for RGD-recognizing integrin subtypes; 5) fine-tuning of the affinity and selectivity by additional Ala to Xaa substitutions; 6) protection of the charged functional groups according to the prodrug concept to regain intestinal and oral permeability; 7) proof of biological effects in mice after oral administration.

Original languageAmerican English
Pages (from-to)16405-16409
Number of pages5
JournalAngewandte Chemie - International Edition
Issue number51
StatePublished - 18 Dec 2017

Bibliographical note

Funding Information:
This work was supported by the Reinhart Koselleck Grant of the Deutsche Forschungsgemeinschaft (DFG KE 147/42-1) and by CIPSM to H.K. The ex vivo and in vivo studies were supported by Worldwide Cancer Research (16-0390) and Cancer Research UK C8218/A18673, PI KHD. We also acknowledge MIUR-PRIN 2015 (Grant ID: FCHJ8E; L.M.).

Publisher Copyright:
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.


  • cyclic peptides
  • drug design
  • integrin ligands
  • oral bioavailability
  • prodrugs


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