State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Acta Biochim Biophys Sin (Shanghai). 2022 May 25;54(5):725-735. doi: 10.3724/abbs.2022049.
APOBEC3G (A3G) is a member of cytosine deaminase family with a variety of innate immune functions. It displays activities against retrovirus and retrotransposon by inhibition of virus infectivity factor (Vif)-deficient HIV-1 replication. The interaction between A3G N-terminal domain and Vif directs the cellular Cullin 5 E3-ubiquitin ligase complex to ubiquitinate A3G, and leads to A3G proteasomal degradation, which is a potential target for anti-HIV drug. Currently, there are very few reports about stable small molecules targeting the interaction between A3G and Vif. In this study, we screened two series of small molecules containing carbamyl sulfamide bond or disulfide bond as bridges of two different aromatic rings. Five asymmetrical disulfides were successfully identified against interaction between A3G and Vif with the IC values close to or smaller than 1 μM, especially, not through covalently binding with A3G or Vif. They restore the A3G expression in the presence of Vif by inhibiting Vif-induced A3G ubiquitination and degradation. This study opens a way to the discovery of new anti-HIV drugs.
APOBEC3G（A3G）是胞嘧啶脱氨酶家族的成员，具有多种先天免疫功能。它通过抑制病毒感染因子（Vif）缺陷的 HIV-1 复制来显示针对逆转录病毒和逆转座子的活性。A3G N 端结构域与 Vif 的相互作用将细胞 Cullin 5 E3-泛素连接酶复合物导向泛素化 A3G，并导致 A3G 蛋白酶体降解，这是抗 HIV 药物的潜在靶点。目前，关于针对 A3G 和 Vif 相互作用的稳定小分子的报道很少。在这项研究中，我们筛选了含有氨基甲酰磺酰胺键或二硫键作为两个不同芳环桥的两个系列小分子。成功鉴定了五种不对称二硫化物，它们与 A3G 和 Vif 之间的相互作用具有接近或小于 1μM 的 IC50 值，特别是它们不与 A3G 或 Vif 发生共价结合。它们通过抑制 Vif 诱导的 A3G 泛素化和降解来恢复 Vif 存在下的 A3G 表达。这项研究为发现新的抗 HIV 药物开辟了道路。
