APOBEC enzymes are a family of zinc metalloproteins that catalyze the hydrolytic deamination of single-stranded (ss)DNA cytosines to uracils. The seven APOBEC3 enzymes normally function as part of an overlapping innate immune response to pathogenic DNA infection. However, viruses and tumor cells can exploit the mutagenic capacities of endogenous APOBEC3 enzymes to promote favorable viral and cancer genome mutations that confer resistance to drug therapies. Consequently, chemical modulators of APOBEC3 enzymes may ultimately confer anti-mutation drugs that slow or prevent the evolution of drug resistance mutations when used in concert with existing therapies. Therefore, we have focused on the discovery of first-in-class APOBEC3 inhibitors to serve as mechanistic chemical probes. Utilizing high-throughput screening and rational design, we have developed small molecule and nucleic acid inhibitors of APOBEC3 enzymes. Covalent inhibitors of APOBEC3G, which restricts HIV-1 infection, have been identified that target Cys321 in the APOBEC3G active site. ssDNA oligonucleotides targeting APOBEC3A and APOBEC3B have also been reported by our team using a variety of biophysical- and activity-based assays, as well as x-ray co-crystallography analysis. These studies and ongoing efforts to develop novel APOBEC3-binding compounds will be presented.

Chemical modulation of APOBEC-catalyzed mutation

2019 Spring National Meeting

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