Characterization of a selective CaMKII peptide inhibitor

Isabel Gomez-Monterrey, Marina Sala, Maria Rosaria Rusciano, Sara Monaco, Angela Serena Maione, Guido Iaccarino, Paolo Tortorella, Anna Maria D'Ursi, Mario Scrima, Alfonso Carotenuto, Giuseppe De Rosa, Alessia Bertamino, Ermelinda Vernieri, Paolo Grieco, Ettore Novellino, Maddalena Illario, Pietro Campiglia

Research output: Contribution to journalArticle

Abstract

Analogs of potent CaMKinase II inhibitor, CaM-KNtide, were prepared to explore new structural requirements for the inhibitory activity. The full potency of CaMKII inhibition by CaM-KIINα is contained within a minimal region of 19 amino acids. Here, analysis of the homologous CaM-KIINβ showed that a 17 mer peptide (CN17β) was the shortest sequence that still retained useful inhibitory potency. Ala substitution of almost any residue of CN17β dramatically reduced potency, except for substitution of P3, R14, and V16. Fusion with the tat sequence generated the cell-penetrating inhibitor version tat-5. This tat-5 fusion peptide maintained selectivity for CaMKII over CaMKI and CaMKIV, and appeared to slightly further enhance potency (IC 50 ∼30 nM). Within a breast cancer cell line and in primary human fibroblasts, tat-5 inhibited the Erk signaling pathway and proliferation without any measurable cytotoxicity. Structural analysis of CN17β by CD and NMR indicated an α-helix conformation in the Leu6-Arg11 segment well overlapping with the crystal structure of 21-residue segment of CaM-KNtide bound to the kinase domain of CaMKII.

Original languageEnglish
Pages (from-to)425-434
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Volume62
DOIs
Publication statusPublished - Apr 2013

Keywords

  • Ca/calmodulin-dependent protein kinase
  • CaM-KNtide analogs
  • CaMKinase II inhibitor
  • Cell growth inhibition
  • Protein kinase

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

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  • Cite this

    Gomez-Monterrey, I., Sala, M., Rusciano, M. R., Monaco, S., Maione, A. S., Iaccarino, G., Tortorella, P., D'Ursi, A. M., Scrima, M., Carotenuto, A., De Rosa, G., Bertamino, A., Vernieri, E., Grieco, P., Novellino, E., Illario, M., & Campiglia, P. (2013). Characterization of a selective CaMKII peptide inhibitor. European Journal of Medicinal Chemistry, 62, 425-434. https://doi.org/10.1016/j.ejmech.2012.12.053