What Is an ADAR Inhibitor and How Does It Work?

Within our cells, a family of enzymes known as Adenosine Deaminases Acting on RNA (ADARs) constantly alters our genetic blueprint at the RNA level. They perform a function that helps cellular processes run smoothly, but disrupted activity can have significant consequences for human health. In response, scientists are developing ADAR inhibitors, molecules designed to block the action of these enzymes and explore their potential in medical treatments.

Understanding ADAR and RNA Editing

ADAR enzymes are proteins that chemically modify RNA, the molecule carrying genetic instructions from DNA to the cell’s protein-making machinery. The primary members of this family, ADAR1 and ADAR2, perform a specific modification called A-to-I RNA editing. They convert adenosine (A) into inosine (I) within double-stranded RNA structures, a change that is significant because cellular machinery reads inosine as guanosine (G).

This A-to-I editing is a form of post-transcriptional modification, meaning it occurs after the genetic message has been copied from DNA to RNA. By changing the RNA sequence, ADAR enzymes can diversify the information encoded by a single gene. This can result in the production of different protein variants from the same gene, expanding the functional toolkit available to the cell.

The functions of ADAR editing are widespread, influencing how RNA molecules are spliced, folded into their correct three-dimensional shapes, and their overall stability. The process also plays a role in modulating the immune system and ensuring proper neurological function.

ADAR Dysregulation and Disease

When ADAR activity is insufficient or excessive, it can lead to various diseases, including autoimmune disorders, neurological conditions, and cancer. In some conditions, the problem is hyperediting, where ADAR enzymes are overly active. This excessive editing can alter RNA molecules that encode for proteins, leading to malfunctioning proteins or changes in gene expression that promote disease. For example, hyperediting by the ADAR1 enzyme has been observed in certain cancers, helping tumor cells evade the body’s immune system.

Conversely, a lack of sufficient ADAR1 editing can cause severe health issues. Without proper editing, the immune system can incorrectly identify the body’s own RNA as a threat. This activates cellular sensors that normally detect viral RNA, leading to chronic inflammation and autoimmunity. Aicardi-Goutières syndrome, a rare genetic disorder, is linked to insufficient ADAR1 function and results in severe neurological damage from this inappropriate immune response.

Mechanisms of ADAR Inhibition

Researchers are exploring several strategies to block ADAR enzymes. The goal of these inhibitors is to reduce aberrant RNA editing and restore normal cellular function by interfering with the A-to-I editing process. These approaches range from small molecules that directly interact with the enzyme to technologies that prevent it from finding its target.

One approach involves small molecule inhibitors designed to fit into a specific part of the ADAR enzyme. Some of these molecules act as competitive inhibitors, binding directly to the enzyme’s active site. By occupying the space where RNA would normally attach, the inhibitor physically obstructs the enzyme’s function.

Other inhibitors bind to an allosteric site, a location on the enzyme away from the active site. This binding event causes a change in the enzyme’s shape, which reduces its ability to edit RNA. Another strategy employs antisense oligonucleotides, which are short strands of synthetic genetic material that bind to the target RNA sequences, shielding them from the enzyme.

Therapeutic Exploration of ADAR Inhibitors

The potential for ADAR inhibitors to treat human diseases is an active area of research, particularly in oncology and immunology. In cancer, inhibiting ADAR1 is being investigated as a way to make tumors more visible to the immune system. Some cancer cells use ADAR1’s editing function to hide from immune surveillance. By blocking ADAR1, researchers hope to unmask these cells, allowing the immune system to attack them. Combining ADAR inhibitors with existing immunotherapies could create a more powerful anti-tumor response.

For autoimmune diseases driven by ADAR1 deficiency, the goal is different, as inappropriate immune activation causes the pathology. Research suggests that ADAR inhibitors could help reduce this unwanted inflammation. By targeting mistakenly activated pathways, these inhibitors may help restore immune tolerance and reduce symptoms associated with conditions like systemic lupus erythematosus. Developing selective and potent ADAR inhibitors remains a focus for translating this research into viable treatments.