Researchers from Scripps Research have developed a small molecule that can effectively block the activity of a protein linked to autoimmune diseases, such as systemic lupus erythematosus (SLE) and Crohn’s disease. The protein, called SLC15A4, has been considered difficult to target, as its structure and function have been elusive. However, the scientists were able to isolate the protein and develop a compound that successfully reduced inflammation in mouse models and cells from lupus patients.
SLC15A4 was first identified in 2010 by Bruce Beutler, a geneticist at Scripps Research, who discovered that higher levels of the protein are associated with inflammation. Beutler also found that removing the SLC15A4 gene from lupus mice improved their symptoms. Subsequent studies confirmed the presence of elevated levels of SLC15A4 in lupus and Crohn’s disease patients, as well as the protective effects of SLC15A4 mutations against these diseases.
Despite the strong correlation between SLC15A4 and autoimmune diseases, researchers have faced challenges in studying the protein. SLC15A4 is embedded in specific membranes within immune cells, making it difficult to isolate and study outside of its cellular environment. However, the researchers at Scripps Research developed a method to study the protein within living cells, without removing it from its natural environment. Using this approach, they discovered several molecular fragments that bound to SLC15A4 proteins in human immune cells.
One of these fragments, called FFF-21, was found to physically attach to SLC15A4 and inhibit its function in promoting inflammation. The researchers further modified FFF-21 and found that one variation, AJ2-30, effectively blocked SLC15A4 and reduced inflammation in various cell types, including immune cells from lupus patients. When the SLC15A4 gene was absent, AJ2-30 no longer had an effect, confirming its specific interaction with SLC15A4.
The researchers believe that the ability to block SLC15A4 could have implications beyond lupus and may be effective in other autoimmune diseases. However, further studies are needed before AJ2-30 or related compounds can be tested clinically. The team plans to design new and improved versions of the drug for continued research.
This breakthrough not only provides a potential new therapy for lupus but also opens doors for studying and treating other autoimmune diseases. The researchers at Scripps Research are optimistic that their findings could lead to significant advancements in the field of immunology and the development of targeted therapies for various autoimmune conditions.
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