Characterization of a selective CaMKII peptide inhibitor.

Authors:
Marina Sala
Marina Sala
University of Naples Federico II
Italy
Maria Rosaria Rusciano
Maria Rosaria Rusciano
University of Naples Federico II
Italy
Sara Monaco
Sara Monaco
University of Pittsburgh Medical Center
United States
Angela Serena Maione
Angela Serena Maione
University of Naples Federico II
Italy
Prof. Guido Iaccarino, MD, PhD
Prof. Guido Iaccarino, MD, PhD
Federico II University of Naples
Full Professor of Applied Medical Science and Technology
Cardiology
Napoli, Campania | Italy
Paolo Tortorella
Paolo Tortorella
"Sapienza" University of Rome
Italy

Eur J Med Chem 2013 Apr 22;62:425-34. Epub 2013 Jan 22.

Depart. of Pharmaceutical and Toxicological Chemistry, University of Naples Federico II, Naples, Italy.

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 (IC50 ∼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.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2012.12.053DOI Listing

Still can't find the full text of the article?

We can help you send a request to the authors directly.
April 2013
6 Reads
4 Citations
3.450 Impact Factor

Publication Analysis

Top Keywords

tat sequence
4
nmr indicated
4
fusion tat
4
v16 fusion
4
indicated α-helix
4
r14 v16
4
sequence generated
4
generated cell-penetrating
4
version tat-5
4
tat-5 tat-5
4
inhibitor version
4
cn17β nmr
4
cell-penetrating inhibitor
4
substitution r14
4
potency substitution
4
potency ala
4
ala substitution
4
retained inhibitory
4
sequence retained
4
shortest sequence
4

Similar Publications