Journal
CHEMBIOCHEM
Volume 16, Issue 2, Pages 312-319Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201402526
Keywords
CREB; inhibitors; nucleoside-peptide conjugates; phosphorylation; protein kinase A
Funding
- Estonian Research Council [IUT20-17]
- Archimedes Foundation
- Estonian Ministry of Education and Research
- Mohn Foundation [A20242]
- national scholarship program Kristjan Jaak
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Bisubstrate inhibitors of protein kinases associate simultaneously with two substrate-binding sites of the kinase and thus potentially possess better inhibitory potency and selectivity than inhibitors binding to only the conserved ATP-site of the kinase. We have previously used conjugates of adenosine analogues and arginine-rich peptides (ARCs) to develop proteolytically stable cell plasma membrane-permeable bisubstrate inhibitors whose biochemical affinities towards several basophilic protein kinases of the AGC group are in the picomolar range. The potency of bisubstrate inhibitors to affect the phosphorylation of proteins in living cells has been described in a limited number of publications. In this study, the effect of ARCs on the protein kinase A (PKA)-catalysed cAMP response element-binding protein (CREB) phosphorylation pathway was studied in living mammalian cells. Our results demonstrate that at low micromolar extracellular concentration N-myristoylated ARCs are capable of reducing the activity of transcription factor CREB through inhibition of PKA.
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