SAR study and conformational analysis of a series of novel peptide G protein‐coupled receptor kinase 2 inhibitors |
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| Authors: | Marina Sala Ermelinda Vernieri Antonio Limatola Alessia Bertamino Simona Musella Paolo Grieco Bruno Trimarco Ettore Novellino Guido Iaccarino Pietro Campiglia |
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| Affiliation: | 1. Department of Pharmaceutical Science, University of Salerno, Italy;2. Department of Pharmacy, “Federico II” University of Naples, Naples, Italy;3. Department of Clinical Medicine and Cardiovascular and Immunological Science, “Federico II” University of Naples, Naples, Italy;4. Department of Medicine and Surgery, University of Salerno, Fisciano (SA), Italy;5. IRCCS, “Multimedica”, Milano, Italy |
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| 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. © 2013 Wiley Periodicals, Inc. Biopolymers 101: 121–128, 2014. |
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| Keywords: | GRK2 inhibitors cardiovascular system peptide Ala‐scan NMR conformational analysis |
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