Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 26, Issue 59, Pages 13468-13475Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.202002554
Keywords
integrins; ligand design; peptidomimetics; RGD peptides; structure-activity relationships
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Funding
- Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR, PRIN) [20157WW5EH_002]
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In recognition of the key role played by integrins in several life-threatening dysfunctions, the search for novel small-molecule probes that selectively recognize these surface receptors is still open and widely pursued. Inspired by previously established aminoproline (Amp)-RGD based cyclopeptidomimetics with attracting alpha(V)beta(3)integrin affinity and selectivity, the design and straightforward synthesis of 18 new AmpRGD chemotypes bearing additional structural variants were herein implemented, to shift toward peptide-like alpha(V)beta(6)integrin targeted binders. The ligand competence of the synthesized products toward alpha(V)beta(6)was evaluated in competitive binding assays on isolated receptors, and alpha(V)beta(6)/alpha(V)beta(3)selectivity was determined for a subgroup of compounds, resulting in the identification of four very promising candidates. SAR considerations and docking simulations allowed us to appreciate the key structural features responsible for the observed activity.
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