Laboratory for Molecular Virology and Gene Therapy, Division of Molecular Medicine, KU Leuven, Kapucijnenvoer 33, 3000 Leuven, Belgium.
Virology. 2013 Jan 5;435(1):102-9. doi: 10.1016/j.virol.2012.09.033.
To accomplish their viral life cycle, lentiviruses such as HIV highjack host proteins, the so-called cellular co-factors of replication. Lens Epithelium-derived Growth factor (LEDGF/p75), a transcriptional co-activator, is a co-factor of HIV-integrase (IN) and is required for the tethering and correct integration of the viral genome into the host chromatin. Due to its important role in HIV-replication the LEDGF/p75-IN interaction is an attractive antiviral novel target for the treatment of HIV/AIDS. Intensive drug discovery efforts over the past years have validated the LEDGF/p75-IN interaction as a drugable target for antiviral therapy and have resulted in the design and synthesis of LEDGINs, small molecule inhibitors binding to the dimer interface of HIV-integrase and inhibiting viral replication with a dual mechanism of action: potent inhibition of the LEDGF/p75-IN protein-protein interaction and allosteric inhibition of the catalytic function. Furthermore they inhibit both early and late steps of the replication cycle which increases their potential for further clinical development. In this review we will highlight the research validating the LEDGF/p75-IN interaction as a target for anti-HIV drug discovery and the recent advances in the design and development of LEDGINs.
为了完成它们的病毒生命周期，慢病毒如 HIV 劫持宿主蛋白，即所谓的复制的细胞辅助因子。晶状体上皮衍生的生长因子 (LEDGF/p75)，一种转录共激活因子，是 HIV 整合酶 (IN) 的辅助因子，是病毒基因组与宿主染色质正确整合所必需的。由于 LEDGF/p75-IN 相互作用在 HIV 复制中的重要作用，它是治疗 HIV/AIDS 的一种有吸引力的新型抗病毒靶点。过去几年中，药物研发的努力已经验证了 LEDGF/p75-IN 相互作用是一种可用于抗病毒治疗的药物靶点，并导致了 LEDGINs 的设计和合成，这些小分子抑制剂结合 HIV 整合酶的二聚体界面，通过双重作用机制抑制病毒复制：强烈抑制 LEDGF/p75-IN 蛋白-蛋白相互作用和变构抑制催化功能。此外，它们还抑制复制周期的早期和晚期步骤，从而增加了它们进一步临床开发的潜力。在这篇综述中，我们将重点介绍验证 LEDGF/p75-IN 相互作用作为抗 HIV 药物发现靶点的研究进展，以及 LEDGINs 的设计和开发的最新进展。
