Taming the Mutators: Discovery of Small Molecule and Nucleic Acid Inhibitors Of APOBEC Cytosine Deaminase
Daniel A. Harki, PhD
University of Minnesota
Abstract: APOBEC enzymes are a family of 7 human DNA cytosine-to-uracil deaminases that degrade foreign DNA as part of the innate immune response to pathogen infection. However, cytosolic APOBEC enzymes, including APOBEC3G, have been implicated in promoting HIV-1 mutation, which contributes to viral genetic diversity, adaptability, and the evolution of drug resistance mutations. The nuclear enzyme, APOBEC3B, has been recently discovered as an endogenous source of mutation in >50% of all human cancers. Chemical modulators of APOBEC3B may be similarly useful in slowing or preventing the evolution of drug resistance mutations when co-administered during cancer therapy. Using a combination of high-throughput screening, computational design, organic synthesis, and biochemical assays, first-in-class chemical probes of APOBEC3G and APOBEC3B have been developed. This presentation will discuss our efforts to develop small molecule and nucleic acid probes of the APOBEC family of enzymes.