Differential Inhibition of APOBEC3 DNA-Mutator Isozymes by Fluoro- and Non-Fluoro-Substituted 2′-Deoxyzebularine Embedded in Single-Stranded DNA

Maksim V. Kvach, Fareeda M. Barzak, Stefan Harjes, Henry A.M. Schares, Harikrishnan M. Kurup, Katherine F. Jones, Lorraine Sutton, John Donahue, Richard T. D'Aquila, Geoffrey B. Jameson, Daniel A. Harki, Kurt L. Krause, Elena Harjes*, Vyacheslav V. Filichev

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

The APOBEC3 (APOBEC3A-H) enzyme family is part of the human innate immune system that restricts pathogens by scrambling pathogenic single-stranded (ss) DNA by deamination of cytosines to produce uracil residues. However, APOBEC3-mediated mutagenesis of viral and cancer DNA promotes its evolution, thus enabling disease progression and the development of drug resistance. Therefore, APOBEC3 inhibition offers a new strategy to complement existing antiviral and anticancer therapies by making such therapies effective for longer periods of time, thereby preventing the emergence of drug resistance. Here, we have synthesised 2′-deoxynucleoside forms of several known inhibitors of cytidine deaminase (CDA), incorporated them into oligodeoxynucleotides (oligos) in place of 2′-deoxycytidine in the preferred substrates of APOBEC3A, APOBEC3B, and APOBEC3G, and evaluated their inhibitory potential against these enzymes. An oligo containing a 5-fluoro-2′-deoxyzebularine (5FdZ) motif exhibited an inhibition constant against APOBEC3B 3.5 times better than that of the comparable 2′-deoxyzebularine-containing (dZ-containing) oligo. A similar inhibition trend was observed for wild-type APOBEC3A. In contrast, use of the 5FdZ motif in an oligo designed for APOBEC3G inhibition resulted in an inhibitor that was less potent than the dZ-containing oligo both in the case of APOBEC3GCTD and in that of full-length wild-type APOBEC3G.

Original languageEnglish (US)
Pages (from-to)1028-1035
Number of pages8
JournalChemBioChem
Volume21
Issue number7
DOIs
StatePublished - Apr 1 2020

Keywords

  • APOBEC3
  • antitumor agents
  • enzyme catalysis
  • fluorodeoxyzebularine
  • inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

Fingerprint Dive into the research topics of 'Differential Inhibition of APOBEC3 DNA-Mutator Isozymes by Fluoro- and Non-Fluoro-Substituted 2′-Deoxyzebularine Embedded in Single-Stranded DNA'. Together they form a unique fingerprint.

  • Cite this

    Kvach, M. V., Barzak, F. M., Harjes, S., Schares, H. A. M., Kurup, H. M., Jones, K. F., Sutton, L., Donahue, J., D'Aquila, R. T., Jameson, G. B., Harki, D. A., Krause, K. L., Harjes, E., & Filichev, V. V. (2020). Differential Inhibition of APOBEC3 DNA-Mutator Isozymes by Fluoro- and Non-Fluoro-Substituted 2′-Deoxyzebularine Embedded in Single-Stranded DNA. ChemBioChem, 21(7), 1028-1035. https://doi.org/10.1002/cbic.201900505