TY - JOUR
T1 - Design, synthesis and efficacy of novel G protein-coupled receptor kinase 2 inhibitors
AU - Carotenuto, Alfonso
AU - Cipolletta, Ersilia
AU - Gomez-Monterrey, Isabel
AU - Sala, Marina
AU - Vernieri, Ermelinda
AU - Limatola, Antonio
AU - Bertamino, Alessia
AU - Musella, Simona
AU - Sorriento, Daniela
AU - Grieco, Paolo
AU - Trimarco, Bruno
AU - Novellino, Ettore
AU - Iaccarino, Guido
AU - Campiglia, Pietro
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
KW - Cardiovascular system
KW - Cyclic peptides
KW - GRK2 inhibitors
KW - NMR conformational analysis
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U2 - 10.1016/j.ejmech.2013.08.039
DO - 10.1016/j.ejmech.2013.08.039
M3 - Article
C2 - 24077529
AN - SCOPUS:84884612383
VL - 69
SP - 384
EP - 392
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -