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 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.