The current toolbox for APOBEC drug discovery

Michael J Grillo; Katherine F M Jones; Michael A Carpenter; Reuben S Harris; Daniel A Harki

doi:10.1016/j.tips.2022.02.007

The current toolbox for APOBEC drug discovery

Trends Pharmacol Sci. 2022 May;43(5):362-377. doi: 10.1016/j.tips.2022.02.007.

Authors

Michael J Grillo¹, Katherine F M Jones², Michael A Carpenter³, Reuben S Harris³, Daniel A Harki⁴

Affiliations

¹ Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
² Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
³ Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Howard Hughes Medical Institute, University of Minnesota, Minneapolis, MN 55455, USA.
⁴ Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA; Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA; Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: daharki@umn.edu.

Abstract

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.

Keywords: APOBEC; DNA deaminase inhibitors; chemical probes; drug discovery; screening.

Publication types

Review
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cytidine Deaminase* / genetics
Drug Discovery*
Humans
Mutation

Substances

Cytidine Deaminase

Abstract

Publication types

MeSH terms

Substances

Grants and funding