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Differential Inhibition of APOBEC3 DNA‐Mutator Isozymes by Fluoro‐ and Non‐Fluoro‐Substituted 2′‐Deoxyzebularine Embedded in Single‐Stranded DNA
Author(s) -
Kvach Maksim V.,
Barzak Fareeda M.,
Harjes Stefan,
Schares Henry A. M.,
Kurup Harikrishnan M.,
Jones Katherine F.,
Sutton Lorraine,
Donahue John,
D'Aquila Richard T.,
Jameson Geoffrey B.,
Harki Daniel A.,
Krause Kurt L.,
Harjes Elena,
Filichev Vyacheslav V.
Publication year - 2020
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201900505
Subject(s) - apobec3g , cytidine deaminase , dna , oligonucleotide , deamination , biochemistry , cytosine , biology , cytidine , dna damage , microbiology and biotechnology , chemistry , mutagenesis , enzyme , mutation , gene
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 APOBEC3G CTD and in that of full‐length wild‐type APOBEC3G.