Bromodomain-containing protein 4 (BRD4) inhibitors have been proven to be a promising option for anti-HIV-1 latency therapeutics. We herein describe the design, synthesis, and anti-HIV-1 latency bioevaluation of triazolopyridine derivatives as BRD4 inhibitors. Among them, compound 13d displayed favorable HIV-1 reactivation and prominent safety profile without triggering abnormal immune activation. It exerted strong synergism when combined with the PKC activator prostratin and has the same BRD4-targeting latency mechanism as observed with JQ1, by stimulating Tat-dependent HIV-1 elongation. Besides, it neither affected the antiviral efficacies of antiviral drugs nor caused secondary infections to uninfected cells and the latency reversing potency of 13d , in turn, was not affected by different classes of antiviral drugs.
Keyphrases
- hiv infected
- antiretroviral therapy
- hiv positive
- hiv testing
- human immunodeficiency virus
- hepatitis c virus
- hiv aids
- men who have sex with men
- south africa
- small molecule
- cell death
- immune response
- cancer therapy
- cell proliferation
- inflammatory response
- amino acid
- oxidative stress
- cell cycle arrest
- endoplasmic reticulum stress
- toll like receptor
- protein protein
- single molecule