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Pharmacological CURE strategy via targeting the human transcription factor RUNX1 for latent HIV reactivation and immune stimulation

Year: 2023
Type: dissertation
Abstract: The Runt-related transcription factor 1 (RUNX1) plays an essential role in silencing HIV transcription. The latently infected HIV cells remain an unresolved issue in people living with HIV (PLWH), since antiretroviral therapy (ART) cannot target these cells. The 'shock and kill strategy' aims to target these silenced HIV infected cells and reactivate them with a latency reversing agent (LRA). Our previous findings show that RUNX1 inhibition is an optimal target for HIV transcription reactivation and STAT5 activation. Herein, we have identified 43 potential RUNX inhibitor compounds that significantly activate the HIV promoter in vitro. We first showed the activation of STAT5 from several potential RUNX1 inhibitors analogues. Then we demonstrated their ability to activate latent HIV LTR activation in vitro. Our results showed that these compounds failed to activate HIV LTR in Jurkat T cells, containing the full HIV clone. Finally, we observed no toxicity among all 43 RUNX1 inhibitors. Based on computational docking studies, we analyzed 11 RUNX1 inhibitors for drug like properties, metabolic stability and toxicity and compared them to Alprazolam, where we observed that some of these compounds have better drug-like properties than Alprazolam. These findings collectively show that RUNX1 inhibition is a promising target for HIV reactivation in accordance with our previous findings. We have identified seven RUNX1 inhibitors that have shown a potent activity in STAT5 activation and RUNX1 inhibition. More studies are needed to identify the most potent RUNX1 inhibitor among the seven selected compounds and further confirm their latent HIV activation effect.
DOI: 10.17918/00001605
Language: English
Subfield: Virology
Open Access status: gold
OpenAlex ID: W4385368169
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