Design, synthesis and efficacy of novel G protein-coupled receptor kinase 2 inhibitors.

Authors:
Alfonso Carotenuto
Alfonso Carotenuto
University of Naples Federico II
Italy
Ersilia Cipolletta
Ersilia Cipolletta
Department of Clinical Medicine
Italy
Marina Sala
Marina Sala
University of Naples Federico II
Italy
Ermelinda Vernieri
Ermelinda Vernieri
"Federico II" University of Naples
Italy
Antonio Limatola
Antonio Limatola
University of Naples Federico II
Italy
Alessia Bertamino
Alessia Bertamino
University of Naples Federico II
Italy
Simona Musella
Simona Musella
"Federico II" University of Naples
Italy

Eur J Med Chem 2013 Nov 13;69:384-92. Epub 2013 Sep 13.

Dipartimento di Farmacia, "Federico II" University of Naples, Italy.

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.

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http://dx.doi.org/10.1016/j.ejmech.2013.08.039DOI Listing

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November 2013
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