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Hydrophobic Derivatives of Glycopeptide Antibiotics as Inhibitors of Protein Kinases

G. Cozza1, M. Fortuna2, F. Meggio2, S. Sarno3, M. H. G. Kubbutat4, F. Totzke4, C. Schaechtele4, L. A. Pinna5, E. N. Olsufyeva6,a*, and M. N. Preobrazhenskaya6#

1Department of Molecular Medicine, University of Padova, 35131 Padova, Italy

2Department of Biological Chemistry, University of Padova, 35131 Padova, Italy

3Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy

4ProQinase GmbH, 79106 Freiburg, Germany

5Center for Neuroscience Research Neuroscience Institute, 35131 Padova, Italy

6Gause Institute of New Antibiotics, 119021 Moscow, Russia

* To whom correspondence should be addressed.

# Deceased.

Received December 26, 2017; Revision received May 17, 2018
As key regulators of cell signaling, protein kinases (PKs) are attractive targets for therapeutic intervention in a variety of diseases. Herein, we report for the first time the inhibitory activity of polycyclic peptides, particularly, derivatives of glycopeptide antibiotics teicoplanin and eremomycin, against a panel of 12 recombinant human protein kinases and two protein kinases (CK1 and CK2) isolated from rat liver. Several of the investigated compounds inhibited various PKs with IC50 values below 10 μM and caused >90% suppression of the enzyme activity at 10 µM concentration. Kinetic analysis of the protein kinase CK2α inhibition by the teicoplanin aglycon analogue (7) demonstrated the non-competitive mechanism of inhibition (with regard to ATP). Interestingly, the inhibitory activity of some investigated compounds correlated with the earlier described antiviral activity against HIV, HCV, and other corona- and flaviviruses.
KEY WORDS: polycyclic glycopeptide derivatives, protein kinases, antiviral activity

DOI: 10.1134/S0006297918100073