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

Research output: Contribution to journalArticlepeer-review

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

Bibliographical note

Funding Information:
NMR and mass spectrometry facilities at Massey University and the assistance of Dr. Patrick J. B. Edwards and David Lun are gratefully acknowledged. We are also thankful for the assistance in preparation of full-length A3G provided by Michele Krause and Chisu Song (Otago University). We thank Prof. Reuben S. Harris (University of Minnesota, USA) and members of his cancer research program for helpful discussions. We thank anonymous reviewers for the extensive and constructive feedback given to this manuscript. V.V.F., E.H., G.B.J., M.V.K., and S.H. are grateful for the financial support provided by the Worldwide Cancer Research (grant 16?1197), Palmerston North Medical Research Foundation, Massey University Research Fund (MURF 2015, 7003 and RM20734) and the School of Fundamental Sciences, Massey University. D.A.H. acknowledges the United States National Institutes of Health (P01-CA234228, R01-GM110129 and R01-GM118000) for financial support. K.F.J. acknowledges the National Science Foundation Graduate Research Fellowship Program for support. K.L.K. thanks the Health Research Council (10/050, 07/050A), Otago University and the Thrash Foundation. Funding for open access charge: Worldwide Cancer Research (APC19-0009) and School of Fundamental Sciences, Massey University.

Keywords

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

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