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Biochemistry (Moscow)

, Volume 83, Issue 10, pp 1222–1230 | Cite as

Hydrophobic Derivatives of Glycopeptide Antibiotics as Inhibitors of Protein Kinases

  • G. Cozza
  • M. Fortuna
  • F. Meggio
  • S. Sarno
  • M. H. G. Kubbutat
  • F. Totzke
  • C. Schaechtele
  • L. A. Pinna
  • E. N. OlsufyevaEmail author
  • M. N. Preobrazhenskaya
Article
  • 54 Downloads

Abstract

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.

Keywords

polycyclic glycopeptide derivatives protein kinases antiviral activity 

Abbreviations

Aurora-A

serine/threonine protein kinase (PK)

Aurora-B

serine/threonine PK

AXL

tyrosine PK receptor UFO

B-RAF-V600E

serine/threonine PK proto-oncogene B-Raf

CDK2/Cyclin A

cyclin-dependent serine/threonine PK 2

CEM

host cells for HIV

CK1 and CK2

serine/threonine casein kinases 1 and 2

CK2α-1

serine/threonine CK2 catalytic subunit isoform

CRFK

host cells for FIPV

DENV-2

Dengue virus (flavivirus)

EC50

effective compound concentration required to inhibit host cell proliferation by 50%

FIPV

feline infectious peritonitis virus (coronavirus)

HCV

hepatitis C virus (flavivirus)

HIV

human immunodeficiency virus (coronavirus)

Huh

host cells for HIV

IC50

compound concentration required to inhibit enzyme ctivity by 50%

IGF1R

insulin-like growth factor 1 receptor (tyrosine PK receptor)

JEV

Japanese encephalitis virus (flavivirus)

MET

single pass tyrosine PK receptor

PLK1

serine/threonine polo-like PK 1

PRK1

serine/threonine PK N1

SARS-CoV

severe acute respiratory syndrome-associated coronavirus

SRC

proto-oncogene tyrosine PK c-Src (c-sarcoma)

TBEV

tickborne encephalitis virus (flavivirus)

VEGFR2

vascular endothelial growth factor tyrosine PK receptor

Vero-B

host cells for SARS-CoV, DENV-2, YFV-17D, JEV, and TBEV

YFV-17D

yellow fever virus (flavivirus)

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Copyright information

© Pleiades Publishing, Ltd. 2018

Authors and Affiliations

  • G. Cozza
    • 1
  • M. Fortuna
    • 2
  • F. Meggio
    • 2
  • S. Sarno
    • 3
  • M. H. G. Kubbutat
    • 4
  • F. Totzke
    • 4
  • C. Schaechtele
    • 4
  • L. A. Pinna
    • 5
  • E. N. Olsufyeva
    • 6
    Email author
  • M. N. Preobrazhenskaya
    • 6
  1. 1.Department of Molecular MedicineUniversity of PadovaPadovaItaly
  2. 2.Department of Biological ChemistryUniversity of PadovaPadovaItaly
  3. 3.Department of Biomedical SciencesUniversity of PadovaPadovaItaly
  4. 4.ProQinase GmbHFreiburgGermany
  5. 5.Center for Neuroscience Research Neuroscience InstitutePadovaItaly
  6. 6.Gause Institute of New AntibioticsMoscowRussia

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