[en] The immune system depends on integrins for adhesion and migration during leukocyte trafficking and for intracellular signalling. There is a causal relationship between dysregulation of integrin expression and the onset of pathological conditions, such as autoimmune diseases, inflammation, cancer, and infections. Therefore, integrins, such as α4β1, are considered important therapeutic targets. In this study, a series of novel compounds were synthesized and evaluated for affinity and potency towards α4β1, and selectivity towards α5β1, and αMβ2 integrins. Three compounds 3, 4, and 8 showed excellent binding affinities (Ki < 10 nM) for α4β1. In cell adhesion assays these three ligands behaved as antagonists of α4β1, as confirmed by integrin-mediated intracellular signalling with a functional selectivity over ERK1/2 signalling pathway. Notably, compound 4, a proline derivative, was an antagonist against α4β1 (IC50 15 ± 3 nM) and an agonist against αMβ2 integrin (EC50 23 ± 5 nM). Compound 2, a fluorinated β-lactam derivative, was a selective and potent agonist of α5β1 (EC50 45.98 ± 7.92 nM). Compound 5, although it seems to bind to a different site compared to LDV in α4β1 integrin, showed an agonist behaviour in cell adhesion mediated by α4β1 and α5β1 integrin (EC50 25 ± 3 and 4.8 ± 3.4 nM, respectively) and in activating α4β1 integrin-mediated ERK1/2 and Akt phosphorylation. Compound 8 was the most potent agonist of the series against αMβ2 (EC50 1.4 ± 0.2 nM). Overall, the present study provides new insights into the effects of new integrin ligands that could be considered as potential lead compounds for therapeutic applications in inflammatory diseases and cancer.
Disciplines :
Chemistry
Author, co-author :
Giraldi, Valentina; Department of Chemistry "Giacomo Ciamician" University of Bologna, Via Piero Gobetti, 85, 40129, Bologna, Italy
Maurizio, Andrea; Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio, 48, 40126, Bologna, Italy
Cirillo, Martina; Department of Chemistry "Giacomo Ciamician" University of Bologna, Via Piero Gobetti, 85, 40129, Bologna, Italy
Magnone, Paolo; Department of Chemistry "Giacomo Ciamician" University of Bologna, Via Piero Gobetti, 85, 40129, Bologna, Italy
Fedele, Emanuela ; Université de Liège - ULiège > GIGA ; Department of Chemistry "Giacomo Ciamician" University of Bologna, Via Piero Gobetti, 85, 40129, Bologna, Italy
Bedini, Andrea; Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio, 48, 40126, Bologna, Italy
Baiula, Monica ; Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio, 48, 40126, Bologna, Italy. Electronic address: monica.baiula@unibo.it
Giacomini, Daria ; Department of Chemistry "Giacomo Ciamician" University of Bologna, Via Piero Gobetti, 85, 40129, Bologna, Italy. Electronic address: daria.giacomini@unibo.it
Language :
English
Title :
Targeting α4β1 integrin: from cyclic to linear ligands, effects of chemical modifications.
MIUR - Ministero dell'Istruzione, dell'Università e della Ricerca UNIBO - Università di Bologna MIUR - Ministero dell'Istruzione, dell'Università e della Ricerca
Funding text :
This work was supported by the University of Bologna RFO 2023\u201324 and by The Project \u201CSynthesis and biomedical applications of tumor targeting peptidomimetics and conjugates\u201D by Ministero dell\u2019Istruzione, dell\u2019Universit\u00E0 e della Ricerca ( MIUR , PRIN2020), funding number 2020833Y75.
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