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5‐aminomethyloxazolidine‐2,4‐dione hybrid α/β‐dipeptide scaffolds as inductors of constrained conformations: Applications to the synthesis of integrin antagonists
Author(s) -
De Marco Rossella,
Mazzotti Giacomo,
Dattoli Samantha D.,
Baiula Monica,
Spampinato Santi,
Greco Arianna,
Gentilucci Luca
Publication year - 2015
Publication title -
peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.22704
Subject(s) - peptidomimetic , chemistry , dipeptide , scaffold , integrin , stereochemistry , combinatorial chemistry , receptor , peptide , biophysics , biochemistry , medicine , biomedical engineering , biology
Peptidomimetics represent an attractive starting point for drug discovery programs; in particular, peptidomimetics that result from the incorporation of a heterocycle may take advantage of increased enzymatic stability and higher ability to reproduce the bioactive conformations of the parent peptides, resulting in enhanced therapeutic potential. Herein, we present mimetics of the α4β1 integrin antagonist BIO1211 (MPUPA‐Leu‐Asp‐Val‐Pro‐OH), containing a aminomethyloxazolidine‐2,4‐dione scaffold (Amo). Interestingly, the retro‐sequences PhCOAsp(OH)‐Amo‐APUMP including either (S)‐ or (R)‐configured Amo displayed significant ability to inhibit the adhesion of α4β1 integrin expressing cells, and remarkable stability in mouse serum. Possibly, the conformational bias exerted by the Amo scaffold determined the affinity for the receptors. These peptidomimetics could be of interest for the development of small‐molecule agents effective against inflammatory processes and correlated autoimmune diseases. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 104: 636–649, 2015.