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.
Highlights
APOBEC3 (A3) enzymes are important components of the innate immune system that protect against pathogens by catalysing the deamination of cytosine residues in the singlestranded DNA of the invading viral genome to form uracil residues (Scheme 1 A).[1]
Our results indicate subtleties in inhibition of cytosine deamination catalysed by different A3 enzymes, and support our general strategy of using known inhibitors of cytidine deaminase (CDA) to guide the design of singlestranded DNA (ssDNA) as inhibitors of A3 enzymes
We demonstrated that dZ does not inhibit A3 enzymes when present as the free nucleoside, but becomes a low-micromolar inhibitor if, and only if, it is incorporated into ssDNA
Summary
APOBEC3 (A3) enzymes are important components of the innate immune system that protect against pathogens by catalysing the deamination of cytosine residues in the singlestranded DNA (ssDNA) of the invading viral genome to form uracil residues (Scheme 1 A).[1]. These data are in line with previous findings that 3dadU, as an individual ribosebased single nucleoside, is a very weak inhibitor of human liver CDA (Ki = 100 mm).[10] higher concentrations of 3dadU-oligo might result in inhibition of A3BCTD-AL1, the use of such concentrations would provide a weaker basis than our www.chembiochem.org
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