Abstract
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 language | American English |
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Pages (from-to) | 16405-16409 |
Number of pages | 5 |
Journal | Angewandte Chemie - International Edition |
Volume | 56 |
Issue number | 51 |
DOIs | |
State | Published - 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.
Keywords
- cyclic peptides
- drug design
- integrin ligands
- oral bioavailability
- prodrugs