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.
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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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Published in Russian in Biokhimiya, 2018, Vol. 83, No. 10, pp. 1523–1533.
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Cozza, G., Fortuna, M., Meggio, F. et al. Hydrophobic Derivatives of Glycopeptide Antibiotics as Inhibitors of Protein Kinases. Biochemistry Moscow 83, 1222–1230 (2018). https://doi.org/10.1134/S0006297918100073
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DOI: https://doi.org/10.1134/S0006297918100073