Hydrophobic Derivatives of Glycopeptide Antibiotics as Inhibitors of Protein Kinases

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G. Cozza¹, M. Fortuna², F. Meggio², S. Sarno³, M. H. G. Kubbutat⁴, F. Totzke⁴, C. Schaechtele⁴, L. A. Pinna⁵, E. N. Olsufyeva^6,a*, and M. N. Preobrazhenskaya^6#

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

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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.

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KEY WORDS: polycyclic glycopeptide derivatives, protein kinases, antiviral activity

DOI: 10.1134/S0006297918100073

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