Overcoming the lack of oral availability of cyclic hexapeptides: design of a selective and orally available ligand for the integrin alpha v beta 3
| Title | Overcoming the lack of oral availability of cyclic hexapeptides: design of a selective and orally available ligand for the integrin alpha v beta 3 |
| Publication Type | Journal Article |
| Year of Publication | 2017 |
| Authors | Weinmueller, M, Rechenmacher, F, Marelli, UKiran, Reichart, F, Kapp, TG, Raeder, AFB, Di Leva, FSaverio, Marinelli, L, Novellino, E, Munoz-Felix, JM, Hodivala-Dilke, K, Schumacher, A, Fanous, J, Gilon, C, Hoffman, A, Kessler, H |
| Journal | Angewandte Chemie-International Edition |
| Volume | 56 |
| Issue | 51 |
| Pagination | 16405-16409 |
| Date Published | DEC |
| Type of Article | Article |
| Abstract | Ahighly systematic approach for the development of both orally bioavailable and bioactive cyclic N-methylated hexapeptides as high affinity ligands for the integrin alpha v beta 3 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 Nmethylated analogues of the stem peptide cyclo(d-Ala-Ala(5)); 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) finetuning 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. |
| DOI | 10.1002/anie.201709709 |
| Type of Journal (Indian or Foreign) | Foreign |
| Impact Factor (IF) | 11.994 |
Divison category:
Central NMR Facility
Organic Chemistry
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