An ADAR1 inhibitor is a molecule engineered to block the activity of a protein known as ADAR1 (Adenosine Deaminase Acting on RNA 1). This strategy is prominent in oncology, where manipulating the interactions between cancer cells and the immune system is a primary goal.
The development of these inhibitors includes various types of molecules, such as small molecules and nucleic acid-based compounds. These are being investigated for their therapeutic benefit in treating complex diseases by targeting fundamental cellular mechanisms.
The Function of the ADAR1 Protein
The primary role of the ADAR1 protein is to edit double-stranded RNA (dsRNA). This process, known as A-to-I editing, chemically converts the RNA building block adenosine (A) into inosine (I). This modification is a normal event in human cells, and ADAR1 acts as a molecular proofreader, placing these tags on the body’s own dsRNA.
This editing function allows the immune system to distinguish the body’s own RNA from that of a foreign invader, such as a virus. Unedited dsRNA can be mistaken by cellular sensors as a sign of viral infection, triggering a defensive immune response. By marking native dsRNA with inosine, ADAR1 prevents these sensors from being activated inappropriately.
Without this editing process, the body would exist in a state of constant immune alert, leading to self-attack and inflammation. ADAR1 is produced in two main forms, p110 and p150, which are located in different parts of the cell. The p150 isoform is inducible by interferons, which are signaling molecules central to the immune response.
The Mechanism of Inhibition
An ADAR1 inhibitor disrupts the protein’s ability to perform A-to-I editing. By blocking this activity, the inhibitor prevents the conversion of adenosine to inosine on double-stranded RNA. The cell’s own dsRNA then begins to accumulate in its original, unedited form.
This accumulation of unmodified dsRNA is detected by cellular sensors designed to recognize foreign genetic material, such as melanoma differentiation-associated gene 5 (MDA5) and protein kinase R (PKR). While ADAR1’s normal activity keeps these sensors dormant, the buildup of unedited dsRNA activates them, initiating a cascade of signaling events.
The activation of MDA5 triggers a pathway that leads to the production of interferons, which are signaling proteins that orchestrate an immune response. Inhibiting ADAR1 tricks the cell into believing it is under viral attack, launching a localized immune reaction that turns the cell’s own RNA into a trigger for its potential destruction.
Application in Oncology
The mechanism of ADAR1 inhibition is a compelling strategy in cancer treatment. Cancer cells often have high levels of genomic instability, leading to an overproduction of double-stranded RNA (dsRNA). To survive, these cells upregulate the ADAR1 protein, which edits the dsRNA and effectively masks the tumor from immune surveillance.
Using an ADAR1 inhibitor removes this protective shield. This unmasking process exposes the cancer cells to the immune system, which can then recognize them as abnormal and mount an attack.
This approach transforms a tumor from an immunologically “cold” environment, where immune cells are inactive, to a “hot” one that is inflamed and infiltrated by immune cells. This induced response can lead to the direct killing of cancer cells and may make tumors more susceptible to other immunotherapies, like immune checkpoint inhibitors. Research into inhibitors like 8-Azaadenosine is in preclinical and clinical trial stages.
Relevance in Autoimmune and Viral Diseases
The function of ADAR1 extends beyond cancer to both autoimmune and viral diseases. Genetic mutations that impair the ADAR1 gene can lead to rare autoinflammatory disorders known as type I interferonopathies. A primary example is Aicardi-Goutières syndrome (AGS), an inherited condition where deficient ADAR1 editing causes the immune system to attack the body’s own tissues, particularly in the brain, due to chronic activation of the interferon response. This highlights how proper ADAR1 function is necessary for maintaining immune self-tolerance.
In virology, ADAR1’s role is complex, exhibiting both proviral and antiviral effects. The protein’s primary function of editing dsRNA can be co-opted by certain viruses to their advantage, helping them evade the host’s innate immune defenses. Conversely, its editing activity can also introduce mutations into the viral genome that inhibit replication.
Developing antiviral strategies therefore requires careful consideration. For example, inhibiting ADAR1 could boost the innate immune response against a virus, but it could also have unintended consequences depending on how a specific virus interacts with the RNA editing machinery.