1. Design, synthesis and efficacy of novel G protein-coupled receptor kinase 2 inhibitors.
- Author
-
Carotenuto A, Cipolletta E, Gomez-Monterrey I, Sala M, Vernieri E, Limatola A, Bertamino A, Musella S, Sorriento D, Grieco P, Trimarco B, Novellino E, Iaccarino G, and Campiglia P
- Subjects
- Dose-Response Relationship, Drug, G-Protein-Coupled Receptor Kinase 2 metabolism, Humans, Magnetic Resonance Spectroscopy, Models, Molecular, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Structure-Activity Relationship, Drug Design, G-Protein-Coupled Receptor Kinase 2 antagonists & inhibitors, Protein Kinase Inhibitors pharmacology
- Abstract
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., (Copyright © 2013. Published by Elsevier Masson SAS.) more...
- Published
- 2013
- Full Text
- View/download PDF