G protein-coupled receptor kinase 2 (GRK2) is a relevant signaling node of the cellular transduction network, playing major roles in the physiology of various organs/tissues including the heart and blood vessels. Emerging evidence suggests that GRK2 is up regulated in pathological situations such as heart failure, hypertrophy and hypertension, and its inhibition offers a potential therapeutic solution to these diseases. We explored the GRK2 inhibitory activity of a library of cyclic peptides derived from the HJ loop of G protein-coupled receptor kinases 2 (GRK2). The design of these cyclic compounds was based on the conformation of the HJ loop within the X-ray structure of GRK2. One of these compounds, the cyclic peptide 7, inhibited potently and selectively the GRK2 activity, being more active than its linear precursor. In a cellular system, this peptide confirms the beneficial signaling properties of a potent GRK2 inhibitor. Preferred conformations of the most potent analog were investigated by NMR spectroscopy.
Design, synthesis and efficacy of novel G protein-coupled receptor kinase 2 inhibitors / Carotenuto, Alfonso; Cipolletta, Ersilia; GOMEZ MONTERREY, ISABEL MARIA; Sala, M.; Vernieri, E.; Limatola, Antonio; Bertamino, A.; Musella, S.; Sorriento, D.; Grieco, Paolo; Trimarco, Bruno; Novellino, Ettore; Iaccarino, G.; Campiglia, P.. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 69:(2013), pp. 384-392. [10.1016/j.ejmech.2013.08.039]
Design, synthesis and efficacy of novel G protein-coupled receptor kinase 2 inhibitors
CAROTENUTO, ALFONSOCo-primo
;CIPOLLETTA, ERSILIACo-primo
;GOMEZ MONTERREY, ISABEL MARIACo-primo
;LIMATOLA, ANTONIO;D. Sorriento;GRIECO, PAOLO;TRIMARCO, BRUNO;NOVELLINO, ETTORE;G. Iaccarino;
2013
Abstract
G protein-coupled receptor kinase 2 (GRK2) is a relevant signaling node of the cellular transduction network, playing major roles in the physiology of various organs/tissues including the heart and blood vessels. Emerging evidence suggests that GRK2 is up regulated in pathological situations such as heart failure, hypertrophy and hypertension, and its inhibition offers a potential therapeutic solution to these diseases. We explored the GRK2 inhibitory activity of a library of cyclic peptides derived from the HJ loop of G protein-coupled receptor kinases 2 (GRK2). The design of these cyclic compounds was based on the conformation of the HJ loop within the X-ray structure of GRK2. One of these compounds, the cyclic peptide 7, inhibited potently and selectively the GRK2 activity, being more active than its linear precursor. In a cellular system, this peptide confirms the beneficial signaling properties of a potent GRK2 inhibitor. Preferred conformations of the most potent analog were investigated by NMR spectroscopy.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.