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SAR study and conformational analysis of a series of novel peptide G protein‐coupled receptor kinase 2 inhibitors
Author(s) -
GomezMonterrey Isabel,
Carotenuto Alfonso,
Cipolletta Ersilia,
Sala Marina,
Vernieri Ermelinda,
Limatola Antonio,
Bertamino Alessia,
Musella Simona,
Grieco Paolo,
Trimarco Bruno,
Novellino Ettore,
Iaccarino Guido,
Campiglia Pietro
Publication year - 2014
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.22295
Subject(s) - beta adrenergic receptor kinase , chemistry , peptide , kinase , biochemistry , signal transduction , protein kinase a , amino acid , biophysics , computational biology , stereochemistry , g protein coupled receptor , biology
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. © 2013 Wiley Periodicals, Inc. Biopolymers 101: 121–128, 2014.