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Small Molecule Inhibitors of Activation-Induced Deaminase Decrease Class Switch Recombination in B Cells
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2021-05-07 , DOI: 10.1021/acsptsci.1c00064 Juan Alvarez-Gonzalez 1 , Adam Yasgar 2 , Robert W Maul 1 , Amanda E Rieffer 3, 4, 5 , Daniel J Crawford 6 , Daniel J Salamango 3, 4, 5 , Dorjbal Dorjsuren 2 , Alexey V Zakharov 2 , Daniel J Jansen 2 , Ganesha Rai 2 , Juan Marugan 2 , Anton Simeonov 2 , Reuben S Harris 3, 4, 5, 7 , Rahul M Kohli 6 , Patricia J Gearhart 1
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2021-05-07 , DOI: 10.1021/acsptsci.1c00064 Juan Alvarez-Gonzalez 1 , Adam Yasgar 2 , Robert W Maul 1 , Amanda E Rieffer 3, 4, 5 , Daniel J Crawford 6 , Daniel J Salamango 3, 4, 5 , Dorjbal Dorjsuren 2 , Alexey V Zakharov 2 , Daniel J Jansen 2 , Ganesha Rai 2 , Juan Marugan 2 , Anton Simeonov 2 , Reuben S Harris 3, 4, 5, 7 , Rahul M Kohli 6 , Patricia J Gearhart 1
Affiliation
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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.
中文翻译：
B细胞中激活诱导的脱氨酶减少类别转换重组的小分子抑制剂
激活诱导脱氨酶 (AID) 不仅会突变免疫球蛋白基因座内的 DNA 以产生抗体多样性，而且还会促进 B 细胞淋巴瘤的发展。为了驯服这种诱变剂，我们对超过 90,000 种化合物进行了定量高通量筛选，以查看是否可以减轻 AID 活性。在生化测定中评估酶活性以检测胞嘧啶脱氨，并在细胞测定中评估类转换重组。三种化合物通过抑制转化的 B 细胞系和鼠脾 B 细胞的转换显示出前景。这些化合物具有相似的化学结构，这表明了共同的作用机制。重要的是，这些抑制剂阻断了 AID，但不阻断相关的胞嘧啶 DNA 脱氨酶 APOBEC3B。我们进一步确定 AID 在 B 细胞激活后持续表达数天以诱导转换。第一份关于抑制 AID 的小分子的报告可用于获得对碱基编辑器的监管控制。
更新日期：2021-06-11
中文翻译：
B细胞中激活诱导的脱氨酶减少类别转换重组的小分子抑制剂
激活诱导脱氨酶 (AID) 不仅会突变免疫球蛋白基因座内的 DNA 以产生抗体多样性，而且还会促进 B 细胞淋巴瘤的发展。为了驯服这种诱变剂，我们对超过 90,000 种化合物进行了定量高通量筛选，以查看是否可以减轻 AID 活性。在生化测定中评估酶活性以检测胞嘧啶脱氨，并在细胞测定中评估类转换重组。三种化合物通过抑制转化的 B 细胞系和鼠脾 B 细胞的转换显示出前景。这些化合物具有相似的化学结构，这表明了共同的作用机制。重要的是，这些抑制剂阻断了 AID，但不阻断相关的胞嘧啶 DNA 脱氨酶 APOBEC3B。我们进一步确定 AID 在 B 细胞激活后持续表达数天以诱导转换。第一份关于抑制 AID 的小分子的报告可用于获得对碱基编辑器的监管控制。
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