SAR study and conformational analysis of a series of novel peptide G protein-coupled receptor kinase 2 inhibitors

G protein-coupled receptor kinase 2 (GRK2) plays a central role in the cellular transduction network. In particular, during chronic heart failure GRK2 is upregulated and believed to contribute to disease progression. Thereby, its inhibition offers a potential therapeutic solution to several pathological conditions. In the present study, we performed a SAR study and a NMR conformational analysis of peptides derived from HJ loop of GRK2 and able to selectively inhibit GRK2. From Ala-scan and d-Ala point replacement, we found that Arg residues don't affect the inhibitory properties, while a d-amino acid at position 5 is key to the activity. Conformational analysis identified two β-turns that involve N-terminal residues, followed by a short extended region