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Updated: Dec 20, 2025
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Structure-Activity Relationship Analysis of Benzotriazine Analogues as HIV-1 Latency-Reversing Agents
Eric S Sorensen1, Amanda B Macedo1, Rachel S Resop1
1Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington, DC, USA.
Abstract:
"Shock and kill" therapeutic strategies toward HIV eradication are based on the transcriptional activation of latent HIV with a latency-reversing agent (LRA) and the consequent killing of the reactivated cell by either the cytopathic effect of HIV or an arm of the immune system. We have recently found several benzotriazole and benzotriazine analogues that have the ability to reactivate latent HIV by inhibiting signal transducer and activator of transcription 5 (STAT5) SUMOylation and promoting STAT5 binding to the HIV long terminal repeat and increasing its transcriptional activity. To understand the essential structural groups required for biological activity of these molecules, we performed a systematic analysis of >40 analogues. First, we characterized the essential motifs within these molecules that are required for their biological activity. Second, we identified three benzotriazine analogues with similar activity. We demonstrated that these three compounds are able to increase STAT5 phosphorylation and transcriptional activity. All active analogues reactivate latent HIV in a primary cell model of latency and enhance the ability of interleukin-15 to reactivate latent HIV in cells isolated from aviremic participants. Third, this family of compounds also promote immune effector functions in vitro in the absence of toxicity or global immune activation. Finally, initial studies in mice suggest lack of acute toxicity in vivo A better understanding of the biological activity of these compounds will help in the design of improved LRAs that work via inhibition of STAT5 SUMOylation.
Insights
New compounds targeting signal transducer and activator of transcription 5 (STAT5) SUMOylation show promise for HIV eradication. These latency-reversing agents (LRAs) reactivate latent HIV and enhance immune functions without toxicity, aiding in the development of novel HIV therapies.
Area of Science:
- Virology
- Immunology
- Medicinal Chemistry
Background:
- "Shock and kill" strategies aim for HIV eradication by reactivating latent virus and eliminating infected cells.
- Latency-reversing agents (LRAs) are crucial for transcriptional activation of latent HIV.
- Signal transducer and activator of transcription 5 (STAT5) SUMOylation is a novel target for LRA development.
Purpose of the Study:
- To systematically analyze benzotriazole and benzotriazine analogues for HIV reactivation potential.
- To identify key structural motifs responsible for the biological activity of these compounds.
- To evaluate the efficacy and safety of promising analogues in preclinical models.
Main Methods:
- Synthesis and characterization of over 40 benzotriazole and benzotriazine analogues.
- Assay of compounds for their ability to inhibit STAT5 SUMOylation and promote STAT5 binding to the HIV long terminal repeat.
- Evaluation of viral reactivation in primary cell models of latency and assessment of immune effector functions in vitro.
- In vivo toxicity studies in mice.
Main Results:
- Identification of essential structural motifs for biological activity in benzotriazole and benzotriazine analogues.
- Three benzotriazine analogues demonstrated significant STAT5 phosphorylation and transcriptional activity.
- Active analogues reactivated latent HIV and enhanced interleukin-15-mediated reactivation in cells from aviremic participants.
- Compounds promoted in vitro immune effector functions without toxicity or global immune activation; initial in vivo studies showed no acute toxicity.
Conclusions:
- Benzotriazole and benzotriazine analogues targeting STAT5 SUMOylation are effective LRAs.
- These compounds represent a promising new class of agents for HIV eradication strategies.
- Further understanding of these compounds will facilitate the design of improved LRAs for HIV therapy.
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