State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China.
Biochem Biophys Res Commun. 2013 Jul 12;436(4):650-4. doi: 10.1016/j.bbrc.2013.06.009. Epub 2013 Jun 13.
HIV-1 integrase (IN) plays an important role in integrating viral DNA into human genome, which has been considered as the drug target for anti-AIDS therapy. The appearance of drug-resistance mutants urgently requires novel inhibitors that act on non-active site of HIV-1 IN. Nanoparticles have such unique geometrical and chemical properties, which inspires us that nanoparticles like nanotubes may serve as better HIV-1 IN inhibitors than the conventional inhibitors. To test this hypothesis, we performed molecular dynamics (MD) simulation to study the binding of a carbon nanotube (CNT) to a full-length HIV-1 IN. The results showed that the CNT could stably bind to the C-terminal domain (CTD) of HIV-1 IN. The CNT also induced a domain-shift which disrupted the binding channel for viral DNA. Further MD simulation showed that a HIV-1 IN inhibitor, 5ClTEP was successfully sealed inside the uncapped CNT. These results indicate that the CNT may serve as a potential dual-functional HIV-1 IN inhibitor, not only inducing conformation change as an allosteric inhibitor but also carrying small-molecular inhibitors as a drug delivery system.
HIV-1 整合酶（IN）在将病毒 DNA 整合到人类基因组中起着重要作用，它一直被认为是抗艾滋病治疗的药物靶点。耐药突变体的出现迫切需要新型抑制剂作用于 HIV-1 IN 的非活性位点。纳米颗粒具有独特的几何和化学性质，这启发我们，纳米管等纳米颗粒可能比传统抑制剂更能作为 HIV-1 IN 的抑制剂。为了验证这一假设，我们进行了分子动力学（MD）模拟，以研究碳纳米管（CNT）与全长 HIV-1 IN 的结合。结果表明，CNT 可以稳定地结合到 HIV-1 IN 的 C 端结构域（CTD）。CNT 还诱导了构象位移，破坏了病毒 DNA 的结合通道。进一步的 MD 模拟表明，HIV-1 IN 抑制剂 5ClTEP 成功地被密封在未封闭的 CNT 内。这些结果表明，CNT 可能作为一种潜在的双重功能 HIV-1 IN 抑制剂，不仅可以诱导构象变化作为别构抑制剂，还可以作为药物输送系统携带小分子抑制剂。
