The Walter and Eliza Hall Institute for Medical Research, Parkville, Victoria, 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3052, Australia.
Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute of Infection and Immunity, University of Melbourne, Parkville, Victoria, 3000, Australia.
Eur J Med Chem. 2020 Jun 1;195:112254. doi: 10.1016/j.ejmech.2020.112254. Epub 2020 Mar 20.
A persistent latent reservoir of virus in CD4 T cells is a major barrier to cure HIV. Activating viral transcription in latently infected cells using small molecules is one strategy being explored to eliminate latency. We previously described the use of a FlpIn.FM HEK293 cellular assay to identify and then optimize the 2-acylaminothiazole class to exhibit modest activation of HIV gene expression. Here, we implement two strategies to further improve the activation of viral gene expression and physicochemical properties of this class. Firstly, we explored rigidification of the central oxy-carbon linker with a variety of saturated heterocycles, and secondly, investigated bioisosteric replacement of the 2-acylaminothiazole moiety. The optimization process afforded lead compounds (74 and 91) from the 2-piperazinyl thiazolyl urea and the imidazopyridine class. The lead compounds from each class demonstrate potent activation of HIV gene expression in the FlpIn.FM HEK293 cellular assay (both with LTR ECs of 80 nM) and in the Jurkat Latency 10.6 cell model (LTR EC 220 and 320 nM respectively), but consequently activate gene expression non-specifically in the FlpIn.FM HEK293 cellular assay (CMV EC 70 and 270 nM respectively) manifesting in cellular cytotoxicity. The lead compounds have potential for further development as novel latency reversing agents.
潜伏在 CD4 T 细胞中的病毒持续存在是治愈 HIV 的主要障碍。使用小分子激活潜伏感染细胞中的病毒转录是正在探索的消除潜伏期的一种策略。我们之前描述了使用 FlpIn.FM HEK293 细胞测定法来鉴定并优化 2-酰氨基噻唑类化合物，以适度激活 HIV 基因表达。在这里，我们实施了两种策略来进一步提高该类化合物的病毒基因表达激活和物理化学性质。首先，我们探索了用各种饱和杂环刚性化中心氧-碳键合，其次，研究了 2-酰氨基噻唑部分的生物等排体取代。优化过程提供了来自 2-哌嗪基噻唑基脲和咪唑并吡啶类的先导化合物（74 和 91）。这两类的先导化合物均在 FlpIn.FM HEK293 细胞测定法中（LTR EC 均为 80 nM）和 Jurkat Latency 10.6 细胞模型中（LTR EC 分别为 220 和 320 nM）表现出有效的 HIV 基因表达激活，但随后在 FlpIn.FM HEK293 细胞测定法中（CMV EC 分别为 70 和 270 nM）非特异性激活基因表达，导致细胞毒性。这些先导化合物具有作为新型潜伏逆转剂进一步开发的潜力。
