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

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)5148-5175
Number of pages28
JournalJournal of Medicinal Chemistry
Volume62
Issue number10
DOIs
Publication statusPublished - 23 May 2019

Cite this

Nguyen, William ; Jacobson, Jonathan ; Jarman, Kate E. ; Jousset Sabroux, Helene ; Harty, Leigh ; McMahon, James ; Lewin, Sharon R. ; Purcell, Damian F. ; Sleebs, Brad E. / Identification of 5-Substituted 2-Acylaminothiazoles That Activate Tat-Mediated Transcription in HIV-1 Latency Models. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 10. pp. 5148-5175.
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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.",
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Identification of 5-Substituted 2-Acylaminothiazoles That Activate Tat-Mediated Transcription in HIV-1 Latency Models. / Nguyen, William; Jacobson, Jonathan; Jarman, Kate E.; Jousset Sabroux, Helene; Harty, Leigh; McMahon, James; Lewin, Sharon R.; Purcell, Damian F.; Sleebs, Brad E.

In: Journal of Medicinal Chemistry, Vol. 62, No. 10, 23.05.2019, p. 5148-5175.

Research output: Contribution to journalArticleResearchpeer-review

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