Small Molecule Inhibitors of Activation-Induced Deaminase Decrease Class Switch Recombination in B Cells

Juan Alvarez-Gonzalez, Adam Yasgar, Robert W. Maul, Amanda E. Rieffer, Daniel J. Crawford, Daniel J. Salamango, Dorjbal Dorjsuren, Alexey V. Zakharov, Daniel J. Jansen, Ganesha Rai, Juan Marugan, Anton Simeonov, Reuben S. Harris, Rahul M. Kohli, Patricia J. Gearhart

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Activation-induced deaminase (AID) not only mutates DNA within the immunoglobulin loci to generate antibody diversity, but it also promotes development of B cell lymphomas. To tame this mutagen, we performed a quantitative high-throughput screen of over 90 000 compounds to see if AID activity could be mitigated. The enzymatic activity was assessed in biochemical assays to detect cytosine deamination and in cellular assays to measure class switch recombination. Three compounds showed promise via inhibition of switching in a transformed B cell line and in murine splenic B cells. These compounds have similar chemical structures, which suggests a shared mechanism of action. Importantly, the inhibitors blocked AID, but not a related cytosine DNA deaminase, APOBEC3B. We further determined that AID was continually expressed for several days after B cell activation to induce switching. This first report of small molecules that inhibit AID can be used to gain regulatory control over base editors.

Original languageEnglish (US)
Pages (from-to)1214-1226
Number of pages13
JournalACS Pharmacology and Translational Science
Volume4
Issue number3
DOIs
StatePublished - Jun 11 2021
Externally publishedYes

Keywords

  • activation-induced deaminase
  • B cells
  • cellular assay
  • class switch recombination
  • high-throughput screen
  • small molecule inhibitors

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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