Scientists from Scripps Research have developed a small molecule that blocks the activity of a protein linked to autoimmune diseases, including systemic lupus erythematosus (SLE) and Crohn’s disease. This protein, known as SLC15A4, has been considered largely “undruggable,” as most researchers had long struggled to isolate the protein, determine its structure, or even pin down its exact function within immune cells—until now.
The research, published in Nature Chemical Biology on January 8, 2024, shows that the compound successfully reduced inflammation in mouse models of inflammation and in isolated cells from people diagnosed with lupus. This provides scientists with a new tool to study the role of SLC15A4 in autoimmunity and a potential new therapy to move toward additional preclinical trials.
“This is an example of a protein that had been correlated with disease in a number of ways, including human genetics and various disease models, but no one had been able to develop small molecules to target it,” says senior author Christopher Parker, PhD, associate professor in the Department of Chemistry at Scripps Research. “We not only created such a compound but validated that it can have therapeutic effects.”
SLC15A4 was first characterized in 2010 by Bruce Beutler, MD, the Chair of Genetics at Scripps Research (now at the University of Texas Southwestern Medical Center). His work established that SLC15A4 proteins play a key role in controlling immune responses and that higher levels of the proteins are associated with inflammation. Beutler and Ari Theofilopoulos, MD, now professor emeritus in the Department of Immunology and Microbiology, also showed that removing the SLC15A4 gene from mice with lupus ameliorated their disease.
Other studies have since found that SLC15A4 is present at higher levels in some patients with lupus and Crohn’s disease and that certain people with SLC15A4 mutations make them less likely to develop these diseases. However, researchers have struggled to study the protein.
“It is an incredibly complicated protein embedded in very specific membranes within immune cells,” says John Teijaro, PhD, professor in the Department of Immunology and Microbiology and co-senior author of the new work. “It doesn’t behave very well when you remove it from this environment, which makes it incredibly difficult to carry out most typical assays or drug screens.”
Parker’s lab, however, has pioneered methods to introduce chemical probes to living cells and screen which probes bind to a protein of interest—like SLC15A4—without ever removing the protein from its environment in the cell. The new study used this approach to discover nine different molecular fragments that could bind to SLC15A4 proteins inside human immune cells. They carried out various experiments to prove that one of these fragments, FFF-21, was physically attaching to SLC15A4 and impeding its function in promoting inflammation.
“This not only helps move forward research on SLC15A4 but also validates our overall approach,” says Parker. “This general strategy can be applied to many other challenging drug targets.”