Selective Class I HDAC Inhibitors Based on Aryl Ketone Zinc Binding Induce HIV-1 Protein for Clearance

Area of Science:

• Molecular Biology
• Virology
• Drug Discovery

Background:

• HIV persistence in latent CD4+ T cells is a major obstacle to viral eradication.
• Latency-reversing agents (LRAs) aim to activate the HIV provirus for immune clearance.
• Histone deacetylase inhibitors (HDACi) are explored as LRAs due to their role in gene transcription regulation.

Purpose of the Study:

• To discover novel, selective, and potent class I HDAC inhibitors.
• To evaluate the efficacy of these inhibitors in reversing HIV latency.
• To identify a lead compound for potential HIV eradication therapies.

Main Methods:

• Designed and synthesized a series of aryl ketone-based class I HDAC inhibitors.
• Evaluated inhibitor potency and selectivity using biochemical assays.
• Assessed latency reversal in a Jurkat T cell model of HIV latency (2C4 cells).
• Tested the lead compound's ability to induce HIV gag P24 protein in patient-derived latent CD4+ T cells.

Main Results:

• Identified potent and selective class I HDAC inhibitors based on aryl ketone scaffolds.
• Structure-activity relationship (SAR) studies led to the discovery of compound 10.
• Compound 10 demonstrated excellent potency and selectivity for class I HDACs.
• HDAC inhibitor 10 effectively reversed HIV latency and induced HIV gag P24 protein expression in patient cells.

Conclusions:

• A novel series of selective class I HDAC inhibitors were discovered.
• Compound 10 is a highly potent inhibitor capable of reversing HIV latency.
• These findings support the development of HDAC inhibitors as LRAs for HIV eradication strategies.