The current toolbox for APOBEC drug discovery

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

doi:10.1016/j.tips.2022.02.007

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 journal › Review article › peer-review

17 Scopus citations

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 language	English (US)
Pages (from-to)	362-377
Number of pages	16
Journal	Trends in Pharmacological Sciences
Volume	43
Issue number	5
DOIs	https://doi.org/10.1016/j.tips.2022.02.007
State	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.tips.2022.02.007

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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.",

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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: {\textcopyright} 2022 The Authors",

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The current toolbox for APOBEC drug discovery

Abstract

Bibliographical note

Keywords

UN SDGs

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