The Walter and Eliza Hall Institute for Medical Research , Parkville , Victoria 3052 , Australia.
Department of Medical Biology , University of Melbourne , Parkville , Victoria 3052 , Australia.
J Med Chem. 2019 May 23;62(10):5148-5175. doi: 10.1021/acs.jmedchem.9b00462. Epub 2019 Apr 29.
The persistent reservoir of cells latently infected with human immunodeficiency virus (HIV)-integrated proviral DNA necessitates lifelong suppressive antiretroviral therapy (ART). Epigenetic targeted compounds have shown promise as potential latency-reversing agents; however, these drugs have undesirable toxicity and lack specificity for HIV. We utilized a novel HEK293-derived FlpIn dual-reporter cell line, which quantifies specific HIV provirus reactivation (LTR promoter) relative to nonspecific host cell gene expression (CMV promoter), to identify the 5-substituted 2-acylaminothiazole hit class. Here, we describe the optimization of the hit class, defining the functionality necessary for HIV gene activation and for improving in vitro metabolism and solubility. The optimized compounds displayed enhanced HIV gene expression in HEK293 and Jurkat 10.6 latency cellular models and increased unspliced HIV RNA in resting CD4+ T cells isolated from HIV-infected individuals on ART, demonstrating the potential of the 2-acylaminothiazole class as latency-reversing agents.
潜伏感染人类免疫缺陷病毒 (HIV) -整合前病毒 DNA 的细胞库持续存在，需要终身抑制性抗逆转录病毒治疗 (ART)。表观遗传靶向化合物已显示出作为潜在潜伏逆转剂的潜力；然而，这些药物具有不理想的毒性，并且对 HIV 缺乏特异性。我们利用一种新型的源自 HEK293 的 FlpIn 双报告细胞系，该细胞系可定量测定特定的 HIV 前病毒激活（LTR 启动子）与非特异性宿主细胞基因表达（CMV 启动子）的相对水平，以鉴定 5 取代 2-酰氨基噻唑类命中化合物。在这里，我们描述了命中化合物的优化，确定了 HIV 基因激活所必需的功能，以及改善体外代谢和溶解度的功能。优化后的化合物在 HEK293 和 Jurkat 10.6 潜伏细胞模型中显示出增强的 HIV 基因表达，并增加了接受 ART 的 HIV 感染者静息 CD4+T 细胞中的未剪接 HIV RNA，表明 2-酰氨基噻唑类化合物作为潜伏逆转剂的潜力。
