Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata, I-98168 Messina, Italy.
Antiviral Res. 2011 Oct;92(1):102-7. doi: 10.1016/j.antiviral.2011.07.005. Epub 2011 Jul 13.
In recent years several potent HIV-1 integrase (IN) inhibitors have been identified and after the successful clinical use of raltegravir, they have gained a definitive place in the treatment of HIV-1 infection. Yet, there is a continuous effort to design newer inhibitors that target different steps in the integration process. Furthermore, the increased understanding of IN structural biology has opened novel approaches to inhibit IN, such as targeting its multimerization or interaction with cellular cofactors. On these bases, we have concentrated our research on the identification of small molecules able to inhibit two different stages of the integration process: the IN strand-transfer phase and the IN-LEDGF/p75 interaction. We found that the 4-[1-(4-fluorobenzyl)-4-hydroxy-1H-indol-3-yl]-2-hydroxy-4-oxobut-2-enoic acid (CHI-1043) is an interesting anti-HIV agent exhibiting dual inhibitory effects. This work has suggested the possibility of also constructing an integration dual inhibitor using a design-in strategy.
近年来，已经鉴定出几种有效的 HIV-1 整合酶（IN）抑制剂，在拉替拉韦成功临床应用后，它们在 HIV-1 感染的治疗中占据了明确的地位。然而，人们仍在不断努力设计针对整合过程中不同步骤的新型抑制剂。此外，对 IN 结构生物学的深入了解为抑制 IN 提供了新的方法，例如针对其多聚化或与细胞辅助因子相互作用的抑制。在此基础上，我们专注于鉴定能够抑制整合过程中两个不同阶段的小分子：IN 链转移阶段和 IN-LEDGF/p75 相互作用。我们发现 4-[1-(4-氟苄基)-4-羟基-1H-吲哚-3-基]-2-羟基-4-氧代丁-2-烯酸（CHI-1043）是一种具有双重抑制作用的有趣的抗 HIV 药物。这项工作提出了使用设计策略构建整合双重抑制剂的可能性。
