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-KIINalpha is contained within a minimal region of 19 amino acids. Here, analysis of the homologous CaM-KIINbeta showed that a 17 mer peptide (CN17beta) was the shortest sequence that still retained useful inhibitory potency. Ala substitution of almost any residue of CN17beta 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) approximately 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 CN17beta by CD and NMR indicated an alpha-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.

Autore Pugliese

• Tortorella Paolo

Tutti gli autori

• TORTORELLA P.

Titolo volume/Rivista

Non Disponibile

Anno di pubblicazione

2013

ISSN

0223-5234

ISBN

Non Disponibile

Numero di citazioni Wos

11

Ultimo Aggiornamento Citazioni

Non Disponibile

Numero di citazioni Scopus

12

Ultimo Aggiornamento Citazioni

Non Disponibile

Settori ERC

Non Disponibile

Codici ASJC

Non Disponibile