Development of APOBEC3 Cytosine Deaminase Inhibitors

Abstract

The APOBEC3 (A3) family of proteins degrade non-native or ‘foreign’ DNA in cells. We have hypothesized that blocking the enzymatic activity of A3 proteins could enhance the efficiency of foreign DNA introduction (transfection) into cells that are otherwise refractory to the process. APOBEC3 proteins degrade ‘foreign’ DNA by converting cytosines into uracils, which then triggers the cell to degrade the DNA due to the presence of a non-native DNA base (uracil). To identify small molecules that could inhibit A3 proteins, High Throughput Screening (HTS) was performed at the University of Minnesota and the Sanford-Burnham Medical Research Institute and over 350,000 compounds were tested for inhibition of A3A and A3G proteins. Follow-up studies by the Harris laboratory (University of Minnesota) have identifed hundreds of potential candidate molecules that can inhibit A3 activity in vitro. Three lead molecules from this study include MN152, MN184 and MN132. The Harki laboratory (University of Minnesota) is collaborating with the Harris laboratory to conduct detailed medicinal chemistry campaigns to optimize lead molecules for strong potency and minimal toxicity. Preliminary results from our synthesis studies of these chemotypes are presented here.