APOBEC3 proteins are a two-edged sword. On one side, APOBEC3 proteins provide a key part of our defences against viral pathogens by attacking single-stranded viral DNA (ssDNA) and rendering it nonsensical by mutating the cytidines. On the other side, several members of the family are implicated in carcinogenesis. In particular, one member of the family, APOBEC3B, promotes mutational activity in breast cancer, contributing to drug resistance, rapid disease development and poor survival prognosis. Therefore, inhibition of APOBEC3B will benefit breast cancer patients, noting the non-essential nature of APOBEC3B. We propose to design and screen chemically changed APOBEC3B substrates for their inhibitory potential. Our long-term goal is to optimise the best inhibitors for potential breast cancer treatment. We will structurally and thermodynamically characterize APOBEC3B-(modified) ssDNA complexes to understand the molecular basis of APOBEC3B-inhibitor/substrate interactions. This information will enable structurally-informed drug design targeting APOBEC3B and other APOBEC proteins.