The current toolbox for APOBEC drug discovery

Mutational processes driving genome evolution and heterogeneity contribute to immune evasion and therapy resistance in viral infections and cancer. APOBEC3 (A3) enzymes promote such mutations by catalyzing the deamination of cytosines to uracils in single-stranded DNA. Chemical inhibition of A3 enzymes may yield an antimutation therapeutic strategy to improve the durability of current drug therapies that are prone to resistance mutations. A3 small-molecule drug discovery efforts to date have been restricted to a single high-throughput biochemical activity assay; however, the arsenal of discovery assays has significantly expanded in recent years. The assays used to study A3 enzymes are reviewed here with an eye towards their potential for small-molecule discovery efforts. APOBEC3 (A3) catalyzed cytosine-to-uracil deamination contributes to mutations in virus and cancer genomes that facilitate disease progression and the evolution of drug resistance.Chemical inhibition of A3-catalyzed mutation is a novel therapeutic strategy to prevent proevolutionary mutagenesis in virus and cancer genomes.Many biophysical, biochemical, and cellular assays have been developed to study A3 structure and function.