title: SAR study and conformational analysis of a series of novel peptide G protein-coupled receptor kinase 2 inhibitors.
abstract: 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. These information can help the design of peptides and peptido-mimetics with enhanced GRK2 inhibition properties.
authors.affiliation: Department of Pharmacy, "Federico II" University of Naples, Naples, Italy.
authors.forename: Isabel
authors.initials: I
authors.lastname: Gomez-Monterrey
authors.forename: Alfonso
authors.initials: A
authors.lastname: Carotenuto
authors.forename: Ersilia
authors.initials: E
authors.lastname: Cipolletta
authors.forename: Marina
authors.initials: M
authors.lastname: Sala
authors.forename: Ermelinda
authors.initials: E
authors.lastname: Vernieri
authors.forename: Antonio
authors.initials: A
authors.lastname: Limatola
authors.forename: Alessia
authors.initials: A
authors.lastname: Bertamino
authors.forename: Simona
authors.initials: S
authors.lastname: Musella
authors.forename: Paolo
authors.initials: P
authors.lastname: Grieco
authors.forename: Bruno
authors.initials: B
authors.lastname: Trimarco
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Guido
authors.initials: G
authors.lastname: Iaccarino
authors.forename: Pietro
authors.initials: P
authors.lastname: Campiglia
mesh_terms: D054769:G-Protein-Coupled Receptor Kinase 2; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation; D017433:Protein Structure, Secondary
chemical_list: D010455:Peptides; D054769:G-Protein-Coupled Receptor Kinase 2
keywords: GRK2 inhibitors; NMR conformational analysis; cardiovascular system; peptide Ala-scan