Identification of 5-substituted 2-acylaminothiazoles that activate Tat mediated transcription in HIV-1 latency models

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 utilised a novel HEK293 derived FlpIn dual-reporter cell line, that quantifies specific HIV provirus reactivation (LTR promoter) relative to non-specific 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 increase unspliced HIV RNA in resting CD4+ T cells isolated from HIV-infected individuals on ART, demonstrating the potential of th...