Identification of 5-Substituted 2-Acylaminothiazoles That Activate Tat-Mediated Transcription in HIV-1 Latency Models
William Nguyen, Jonathan Jacobson, Kate E Jarman, Helene Jousset Sabroux, Leigh Harty, James McMahon, Sharon R Lewin, Damian F Purcell, Brad E Sleebs
JOURNAL OF MEDICINAL CHEMISTRY | AMER CHEMICAL SOC | Published : 2019
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 H..View full abstract
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Awarded by National Health and Medical Research Council of Australia
This work was funded by the National Health and Medical Research Council of Australia (development grant 1113712 to D.F.P., B.E.S., and S.RL.; project grant 1129320 to D.F.P. and B.E.S.; program grant 1052979 to D.F.P. and S.R.L.; Practitioner Fellowship to S.R.L.), the Australian Centre for HIV and Hepatitis Virology Research, the Australian Cancer Research Foundation, the Victorian State Government Operational Infrastructure Support, and Australian Government NHMRC IRIISS. B.E.S. is a Corin Centenary Fellow.