TREX1 Inhibitor Assays May Aid the Discovery Novel HIV Treatments

TREX1 Inhibitor assays could help move things forward for cancer and HIV treatments. – The immune system of humans is remarkable. Unlike the adaptive immune response, the innate immune response is quick and is considered the first line of defense against pathogens and foreign DNA. This foreign material can come from pathogens, tumor cells, or malfunctioning patient cells. The innate immune response relies on various cell types and proteins such as interferons (INFs) to be successful. There are three types of cytokines within this group, all of which aid in removing viral pathogens. When interferon regulatory factor 3 (IRF3) is activated, type I interferon is produced, which has an antiviral effect.¹ However, in the case of human immunodeficiency virus (HIV), three prime repair exonuclease I (TREX1) blocks antiviral activity. Researchers have found that experiments that block or knockout TREX1 allow HIV to trigger DNA sensors inducing the interferon response.²

Role of STING Pathway

When TREX1 fails to degrade DNA as it should, an accumulation of cytosolic DNA activates the STING (stimulator of interferon genes) signaling pathway. It is recognized by cGAS, allowing cGAMP, a cyclic di-nucleotide produced in the cytosol in response to double-stranded DNA (dsDNA), to bind to STING.²

Since it can control proteins like IFN- β, an inflammatory mediator, TBK1 is a key player in the initiation of inflammation. When TBK1 phosphorylates STING, it makes it easier for IRF3 to bind to it. TBK1 then phosphorylates IRF3, which then translocates to the nucleus and drives IFN-α and/or IFN-β transcription.³

The STING (stimulator of interferon genes) pathway contributes to IRF3 phosphorylation and activation, resulting in antiviral activity.

HIV

Currently, there is no cure for HIV, and if left untreated, it could lead to acquired immunodeficiency syndrome (AIDS), which increases the chances of other diseases since the immune system is highly compromised. Nowadays, there’s a combination of drugs to treat/slow HIV to the point of non-detection; however, like with other diseases, drug resistance becomes an issue after long-term use. Therefore, scientists are always searching for solutions. At present, the following classes of anti-HIV drugs that work in various ways are:

• Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
• Nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs)
• Protease inhibitors (PIs)
• Integrase inhibitors
• Entry or fusion inhibitors

TREX1 Inhibitor Assays

With the significant role that TREX1 plays in the HIV immune response, inhibitors have been considered for therapeutic potential. Researchers have already started discovering TREX1 inhibitors to combat HIV; however, there is much to learn and precautions to consider since TREX1 have other disease implications to consider; autoimmune disorders can be the result of too little TREX1. ² A TREX1 inhibitor could help nudge the immune system into helping fight cancer as well.

TREX1 activity assays capable of detecting enzymatic activity are ideal for screening possible inhibitors for therapeutic qualities. An assay that can test thousands of compounds at once is perfect for drug discovery and would further enhance research efforts. Currently, BellBrook Labs is working on an NIH-sponsored grant to develop a new HTS compatible assay for TREX1 inhibitors.

References

1. Wheeler, L. A., Trifonova, R. T., Vrbanac, V., Barteneva, N. S., Liu, X., Bollman, B., … Lieberman, J. (2016). TREX1 Knockdown Induces an Interferon Response to HIV that Delays Viral Infection in Humanized Mice. Cell Reports, 15(8), 1715–1727. https://doi.org/10.1016/j.celrep.2016.04.048
2. Junjie Qian. (2012). DISCOVERY OF SMALL-MOLECULE COMPOUNDS TARGETING TREX1 by Junjie Qian A Thesis Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree MASTER OF SCIENCE (BIOCHEMISTRY AND MOLECULE BIOLOGY) http://digitallibrary.usc.edu/cdm/ref/collection/p15799coll3/id/74180
3. Bowie, A. G. (2013). Removing the trex1 safety net: Oxidized DNA overcomes immune silencing by exonuclease TREX1. Immunity, 39(3), 423–425. https://doi.org/10.1016/j.immuni.2013.08.023