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

• GRK2 is a potential therapeutic target for cardiovascular diseases.
• A library of cyclic peptides able to inhibit GRK2 was developed.
• The most potent derivative was able to increase β2-adrenergic receptor density.
• It was also able to increase cAMP production in HEK-293 cells.
• Preferred conformations of the most potent analog were investigated by NMR.

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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