The current toolbox for APOBEC drug discovery

Michael J. Grillo, Katherine F Jones, Michael A Carpenter, Reuben Harris, Daniel A. Harki

Research output: Contribution to journalReview articlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)362-377
Number of pages16
JournalTrends in Pharmacological Sciences
Volume43
Issue number5
DOIs
StatePublished - May 2022

Bibliographical note

Funding Information:
This work was supported by the NIH (P01-CA234228 to D.A.H. and R.S.H. and R37-AI064046 to R.S.H.). D.A.H. acknowledges funding from the Masonic Cancer Center at the University of Minnesota with resources from Minnesota Masonic Charities. Salary support for K.F.M.J. was provided by the National Science Foundation Graduate Research Fellowship Program. R.S.H. is the Margaret Harvey Schering Land Grant Chair for Cancer Research, a Distinguished University McKnight Professor, and an Investigator of the Howard Hughes Medical Institute. R.S.H. and D.A.H. were cofounders of ApoGen Biotechnologies, Inc. which closed operations in April 2021. The other authors declare no conflicts of interest.

Funding Information:
This work was supported by the NIH ( P01-CA234228 to D.A.H. and R.S.H., and R37-AI064046 to R.S.H.). D.A.H. acknowledges funding from the Masonic Cancer Center at the University of Minnesota with resources from Minnesota Masonic Charities . Salary support for K.F.M.J. was provided by the National Science Foundation Graduate Research Fellowship Program. R.S.H. is the Margaret Harvey Schering Land Grant Chair for Cancer Research, a Distinguished University McKnight Professor , and an Investigator of the Howard Hughes Medical Institute .

Publisher Copyright:
© 2022 The Authors

Keywords

  • APOBEC
  • DNA deaminase inhibitors
  • chemical probes
  • drug discovery
  • screening

PubMed: MeSH publication types

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

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