Researchers found that they were able to use a small molecule called ZL0580 to modify bromodomain-containing protein 4 to suppress HIV.
While antiretroviral therapy (ART) can effectively lower the amount of HIV infection to undetectable levels, dormant HIV still remains. To date, researchers have struggled to effectively cure people of HIV, but researchers say they have discovered a potential new approach that can further suppress infection.
According to the researchers, the study offers proof of concept that the approach could complement ART regimens in suppressing the silent virus that these regimens struggle to combat. The researchers were able to show that the bromodomain-containing protein 4 (BRD4) plays and integral role in regulating the production of new copies of the HIV gene after the virus integrates into a person’s genetic coding.
They then were able to design, synthesize, and evaluate a series of small molecules to selectively program the protein to suppress HIV. In the process, they found a small molecule called ZL0580 that significantly delayed dormant HIV reactivation after a patient stopped taking their ART regimen.
“We are the first to show that human BRD4 protein and its associated machinery can be harnassed to suppress dormant HIV,” Haitao Hu, assistant professor in the Department of Microbiology and Immunology at the University of Texas Medical Branch (UTMB), and senior author of the study, said in a statement. “Our findings are exciting because they not only improve our understanding of the biology of HIV epigenetic regulation, they also present a promising approach for the development of probes and/or therapeutic agents for silencing HIV, hopefully leading to a cure of the virus eventually.”
The researchers collected peripheral blood mononuclear cells from people living with HIV as well as healthy donors that were stored at the UTMB blood bank and the US Military HIV Research Program.
The data showed that ZL0580 was able to more selectively bind to BRD4 than JQ1, the BRD4-pan inhibitor, and that the small molecule can suppress both induced and basal HIV transcription. According to the researchers, ZL0580 promotes HIV suppression by inhibiting Tat-mediated transcription elongation and inducing a repressive chromatin structure at the HIV promoter.
“We will continue to optimize the chemical structure and effectiveness of this class of molecules and conduct safety testing in cellular and animal studies,” said Jia Zhou, professor in the Department of Pharmacology and Toxicology at UTMB, and co—senior author of the study. “We look forward to the time when we can begin clinical trials so that this approach can begin to help HIV-infected individuals.”
Niu Q, Liu Z, Alamer E, et al. Structure-guided drug design identifies a BRD4-selective small molecule that suppresses HIV [published online July 22, 2019]. J Clin Invest. doi: 10.1172/JCI120633.