αVβ6 Integrin plays a fundamental role in the activation of transforming growth factor-β (TGF-β), the major profibrotic mediator; for this reason, αVβ6 ligands have recently been forwarded to clinical phases for the therapy of fibrotic diseases. Herein, we report the synthesis and in vitro biological evaluation as antifibrotic agents of three new covalent conjugates, constituted by c(AmpLRGDL), an αVβ6 integrin-recognizing small cyclopeptide, and nintedanib, a tyrosine kinase inhibitor approved for idiopathic pulmonary fibrosis (IPF) treatment. One of these conjugates recapitulates optimal in vitro antifibrotic properties of the two active units. The integrin ligand portion within the conjugate plays a role in inhibiting profibrotic stimuli, potentiating the nintedanib effect and favoring the selective uptake of the conjugate in cells overexpressing αVβ6 integrin. These results may open a new perspective on the development of dual conjugates in the targeted therapy of IPF.

Nintedanib-Containing Dual Conjugates Targeting αVβ6 Integrin and Tyrosine Kinase Receptors as Potential Antifibrotic Agents / Kelly Bugatti , Elena Andreucci, Noemi Monaco, Lucia Battistini, Silvia Peppicelli, Jessica Ruzzolini, Claudio Curti, Franca Zanardi, Francesca Bianchini, Andrea Sartori. - In: ACS OMEGA. - ISSN 2470-1343. - ELETTRONICO. - 7:(2022), pp. 17658-17669. [10.1021/acsomega.2c00535]

Nintedanib-Containing Dual Conjugates Targeting αVβ6 Integrin and Tyrosine Kinase Receptors as Potential Antifibrotic Agents

Elena Andreucci;Noemi Monaco;Silvia Peppicelli;Jessica Ruzzolini;Franca Zanardi;Francesca Bianchini
;
2022

Abstract

αVβ6 Integrin plays a fundamental role in the activation of transforming growth factor-β (TGF-β), the major profibrotic mediator; for this reason, αVβ6 ligands have recently been forwarded to clinical phases for the therapy of fibrotic diseases. Herein, we report the synthesis and in vitro biological evaluation as antifibrotic agents of three new covalent conjugates, constituted by c(AmpLRGDL), an αVβ6 integrin-recognizing small cyclopeptide, and nintedanib, a tyrosine kinase inhibitor approved for idiopathic pulmonary fibrosis (IPF) treatment. One of these conjugates recapitulates optimal in vitro antifibrotic properties of the two active units. The integrin ligand portion within the conjugate plays a role in inhibiting profibrotic stimuli, potentiating the nintedanib effect and favoring the selective uptake of the conjugate in cells overexpressing αVβ6 integrin. These results may open a new perspective on the development of dual conjugates in the targeted therapy of IPF.
2022
7
17658
17669
Kelly Bugatti , Elena Andreucci, Noemi Monaco, Lucia Battistini, Silvia Peppicelli, Jessica Ruzzolini, Claudio Curti, Franca Zanardi, Francesca Bianchini, Andrea Sartori
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1286680
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