Design, synthesis and efficacy of novel G protein-coupled receptor kinase 2 inhibitors

Alfonso Carotenuto, Ersilia Cipolletta, Isabel Gomez-Monterrey, Marina Sala, Ermelinda Vernieri, Antonio Limatola, Alessia Bertamino, Simona Musella, Daniela Sorriento, Paolo Grieco, Bruno Trimarco, Ettore Novellino, Guido Iaccarino, Pietro Campiglia

Research output: Contribution to journalArticle


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.

Original languageEnglish
Pages (from-to)384-392
Number of pages9
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - 2013



  • Cardiovascular system
  • Cyclic peptides
  • GRK2 inhibitors
  • NMR conformational analysis

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

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., & Campiglia, P. (2013). Design, synthesis and efficacy of novel G protein-coupled receptor kinase 2 inhibitors. European Journal of Medicinal Chemistry, 69, 384-392.