2. Academic Validation
  3. Identification of 5-Substituted 2-Acylaminothiazoles That Activate Tat-Mediated Transcription in HIV-1 Latency Models

Identification of 5-Substituted 2-Acylaminothiazoles That Activate Tat-Mediated Transcription in HIV-1 Latency Models

  • J Med Chem. 2019 May 23;62(10):5148-5175. doi: 10.1021/acs.jmedchem.9b00462.
William Nguyen 1 2,  Jonathan Jacobson 3,  Kate E Jarman 1 2,  Helene Jousset Sabroux 1 2,  Leigh Harty 3,  James McMahon 4,  Sharon R Lewin 4 5,  Damian F Purcell 3,  Brad E Sleebs 1 2
Affiliations

Affiliations

  • 1 The Walter and Eliza Hall Institute for Medical Research , Parkville , Victoria 3052 , Australia.
  • 2 Department of Medical Biology , University of Melbourne , Parkville , Victoria 3052 , Australia.
  • 3 Department of Microbiology and Immunology, Peter Doherty Institute of Infection and Immunity , University of Melbourne , Parkville , Victoria 3000 , Australia.
  • 4 Department of Infectious Diseases , Alfred Health and Monash University , Melbourne , Victoria 3004 Australia.
  • 5 The Peter Doherty Institute for Infection and Immunity , The University of Melbourne and Royal Melbourne Hospital , Parkville , Victoria 3000 , Australia.
PMID: 30973727 DOI: 10.1021/acs.jmedchem.9b00462
Abstract

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.

Figures