TY - JOUR
T1 - Overcoming the Lack of Oral Availability of Cyclic Hexapeptides
T2 - Design of a Selective and Orally Available Ligand for the Integrin αvβ3
AU - Weinmüller, Michael
AU - Rechenmacher, Florian
AU - Kiran Marelli, Udaya
AU - Reichart, Florian
AU - Kapp, Tobias G.
AU - Räder, Andreas F.B.
AU - Di Leva, Francesco Saverio
AU - Marinelli, Luciana
AU - Novellino, Ettore
AU - Muñoz-Félix, José M.
AU - Hodivala-Dilke, Kairbaan
AU - Schumacher, Adi
AU - Fanous, Joseph
AU - Gilon, Chaim
AU - Hoffman, Amnon
AU - Kessler, Horst
N1 - Publisher Copyright:
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2017/12/18
Y1 - 2017/12/18
N2 - 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.
AB - 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.
KW - cyclic peptides
KW - drug design
KW - integrin ligands
KW - oral bioavailability
KW - prodrugs
UR - http://www.scopus.com/inward/record.url?scp=85034834765&partnerID=8YFLogxK
U2 - 10.1002/anie.201709709
DO - 10.1002/anie.201709709
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C2 - 29072809
AN - SCOPUS:85034834765
SN - 1433-7851
VL - 56
SP - 16405
EP - 16409
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 51
ER -