DNA-based inhibitors of the human APOBEC3B DNA cytosine deaminase

Barzak F1, Kvach MV1, Harjes S1, Jameson GB1,2, Aihara H4, Harris RS4,5, Filichev VV1,2, Harki DA3 and Harjes E1,2

  1. Institute of Fundamental Sciences, Massey University, Private Bag 11 222, Palmerston North, New Zealand.
  2. Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, New Zealand.
  3. Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
  4. Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
  5. Howard Hughes Medical Institute, University of Minnesota, Minneapolis, MN 55455, USA.

The APOBEC3 (A3) protein subfamily of seven proteins (A3A-H) are cytidine deaminases that attack retroviruses and other pathogens by hypermutating cytidine residues of single-stranded DNA [1] while, at the same time some APOBEC3 family members are involved in carcinogenesis [2]. In particular, one member of the family, APOBEC3B promotes mutagenesis in several cancers and contributes to tumor evolution including the detrimental outcomes of metastasis and drug resistance [3-7]. Inhibition of APOBEC3B may therefore be used to augment existing anticancer therapies [8]. We designed and tested chemically modified APOBEC3 DNA substrates for their inhibitory potential and obtained the first DNA-based inhibitors of APOBEC3 enzymes with low micromolar inhibition constants. We found that neighbouring nucleotides in the DNA sequence influence the specificity of our inhibitor which, led to the development of the first inhibitor selectively targeting APOBEC3B. This provides a platform for further development of APOBEC3B inhibitors with cellular activity. REFERENCES 1. Harris, R.S. and J.P. Dudley, APOBECs and virus restriction. Virology, 2015. 479: p. 131-145. 2. Swanton, C., et al., APOBEC enzymes: mutagenic fuel for cancer evolution and heterogeneity. Cancer discovery, 2015. 5(7): p. 704-712. 3. Burns, M.B., et al., APOBEC3B is an enzymatic source of mutation in breast cancer. Nature, 2013. 494(7437): p. 366-370. 4. Burns, M.B., N.A. Temiz, and R.S. Harris, Evidence for APOBEC3B mutagenesis in multiple human cancers. Nature Genetics, 2013b. 45(9): p. 977-983. 5. Law, E.K., et al., The DNA cytosine deaminase APOBEC3B promotes tamoxifen resistance in ER-positive breast cancer. Science advances, 2016. 2(10): p. e1601737. 6. Sieuwerts, A.M., et al., Elevated APOBEC3B correlates with poor outcomes for estrogen-receptor-positive breast cancers. Hormones and Cancer, 2014. 5(6): p. 405-413. 7. Ding, Q., et al., APOBEC3G promotes liver metastasis in an orthotopic mouse model of colorectal cancer and predicts human hepatic metastasis. The Journal of clinical investigation, 2011. 121(11). 8. Olson, M.E., R.S. Harris, and D.A. Harki, APOBEC Enzymes as Targets for Virus and Cancer Therapy. Cell chemical biology, 2017.