New compound targeting the immune system shows promise in treating lupus

Scientists at 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 “unusable” because most researchers have long struggled to isolate it, determine its structure, or even pin down its exact function within immune cells. – so far.

The research, published in Nature Chemical Biology, shows that the compound successfully reduced inflammation in mouse models of inflammation, as well as in isolated cells from people diagnosed with lupus. This provides scientists with a new tool to study the role of SLC15A4 in autoimmunity, as well as a potential new treatment to progress toward additional preclinical trials.

“This is an example of a protein that has been correlated with disease in many ways, including human genetics and various disease models, but no one has been able to develop small molecules to target it,” says lead author Christopher Parker, Ph.D., associate professor in the Department of Chemistry at Scripps Research. “We not only created such a compound, but we also validated that it could have therapeutic effects.”

SLC15A4 was first characterized in 2010 by Bruce Beutler, MD, who at the time was chair of genetics at Scripps Research (he is 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 protein are associated with inflammation. Beutler, along with Ari Theofilopoulos, MD, now professor emeritus in the Department of Immunology and Microbiology, also showed that deleting the SLC15A4 gene in mice with lupus improved their disease.

Other studies have since shown that SLC15A4 is present at higher levels in some patients with lupus and Crohn’s disease, and that some people with SLC15A4 mutations make them less likely to develop these diseases. However, researchers have had difficulty studying the protein.

“This is an incredibly complex protein embedded in very specific membranes of immune cells,” says John Teijaro, Ph.D., 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 that environment, which makes it incredibly difficult to perform most typical drug tests or screenings.”

Parker’s lab, however, has developed methods to introduce chemical probes into living cells and determine which probes bind to a protein of interest, such as SLC15A4, without ever removing the protein from its environment in the cell. In the new study, they used this approach to discover nine different molecular fragments that could all bind to SLC15A4 proteins inside human immune cells. They conducted various experiments to prove that one of these fragments, FFF-21, physically bound to SLC15A4 and hindered its inflammation-promoting function.

“This not only advances research on SLC15A4, but also validates our overall approach,” says Parker. “This general strategy can be applied to many other challenging drug targets.”

The researchers then created dozens of modified versions of FFF-21, studying whether any had stronger effects. A variant, called the AJ2-30, worked particularly well. In several cell types, including healthy human immune cells and cells from people with lupus, AJ2-30 blocked SLC15A4 function and stopped inflammation. When the cells lacked the SLC15A4 gene, the drug no longer worked, indicating that its interactions with SLC15A4 were essential. Additional experiments revealed that AJ2-30 not only blocked SLC15A4 but also caused its degradation by cells.

“We didn’t know until now whether pharmaceutical blocking of SLC15A4 could attenuate certain cellular signs of lupus, but in this paper we showed that this is the case,” says Teijaro. “We don’t have data on other diseases yet, but we think there are a number of other autoimmune diseases where a molecule like this could be effective.”

Additional studies are needed before AJ2-30 or related compounds can be tested clinically, but researchers say the ability to block SLC15A4 opens new doors for both study and possibly treatment of diseases. autoimmune. The team plans to design new, improved versions of the drug for further study.

In addition to Parker and Teijaro, the study’s authors include co-first authors Tzu-Yuan Chiu Daniel C. Lazar and Wesley W. Wang, as well as Jacob M. Wozniak, Appaso M. Jadhav, Weichao Li, Nathalia Gazaniga and Argyrios N. Theofilopoulos of Scripps Research.