靶向于APOBEC3G-Vif相互作用的苯并咪唑类衍生物的合成及活性探索

Synthesis and activity study of benzimidazole derivatives targeted on APOBEC3G-Vif interaction

APOBEC3G能使HIV-1病毒正链DNA超突变,影响病毒的复制,但Vif蛋白通过形成蛋白复合物的方式与APOBEC3G结合,导致APOBEC3G发生泛素化并使其降解,增强病毒的感染力。在以往的研究中发现了苯并咪唑类衍生物能够靶向作用于Vif和APOBEC3G复合物,有效保护APOBEC3G蛋白,但是活性化合物存在水溶性较差的问题。本研究设计合成了水溶性较好的糖基化苯并咪唑类衍生物C66,并发现C66能够降低细胞内APOBEC3G蛋白水平,但其另一构型C83无此活性。本研究为开发新的用于HIV-1研究的工具药提供了一种新的思路,也为靶向于APOBEC3G的不利生理作用提供了新的先导化合物结构。

APOBEC3 Gis lethal to HIV-1 by causing excessive mutation of viral genome in the process of viral replication,makes degradation of viral DNA.However,Vif can induce ubiquitination and mediate degradation of APOBEC3 Gvia Vif-APOBEC3 G protein complex,so the viral prevalence rate is increased.Based on our previous work,we have discovered benzimidazole derivatives targeting the interaction of Vif and APOBEC3 Gcomplex which can effectively protect APOBEC3 Gprotein,but the active compound has poor water solubility.Here,we have synthesized glycosylated benzimidazole derivative-C66,which can efficiently reduce APOBEC3 Gprotein level,but another configuration,C83,has not this activity.This work provides a new way to develop new tool medicine for HIV-1 research and a new lead compound to inhibit adverse physiological interaction targeting APOBEC3 G.