A new study published in Nature Chemical Biology titled, “Munc13-4–STX7 inhibitors impair endosomal TLR activation and systemic inflammation,” scientists from Scripps Research have developed a new class of drug compounds, called ENDOtollins, that reduce harmful inflammation while maintaining the body’s ability to fight infections. The results offer new directions to treat autoimmune diseases, such as lupus, and rheumatoid and juvenile arthritis, which together affect more than 15 million Americans. 

“A key component of our approach is to begin by understanding the biological mechanisms at play,” said Sergio Catz, PhD, professor at Scripps Research and corresponding author of the study. “By accomplishing this first, we can more easily target the pathway driving inflammation without affecting other important processes.” 

Current autoimmune disease treatments, such as hydroxychloroquine, function by broadly blocking endosomes. While effective, this approach can lead to significant side effects, including gastrointestinal problems and, less commonly, vision damage, that cause patients to stop treatment. 

The authors focused on two proteins, Munc13-4 and syntaxin 7, that bind together to activate Toll-like receptors (TLRs), immune sensors that activate endosomes. This mechanism plays a key role in detecting foreign DNA and RNA from viruses and bacteria. In autoimmune diseases, TLRs become overactive and trigger chronic, damaging inflammation in the absence of a threat. 

The team screened roughly 32,000 compounds and identified molecules that specifically block the Munc13-4–syntaxin 7 interaction without disrupting other cellular functions. Given that Munc13-4 is found mainly in immune cells, the compounds offer a targeted approach to reduce inflammation. 

“Most treatments for autoimmune diseases manage symptoms; they don’t change the underlying course of the disease,” said Hugh Rosen, MD, PhD, professor at Scripps Research and co-author of the study. “What’s exciting about this approach is its potential to be disease-modifying: targeting the specific molecular machinery that drives inflammation, rather than broadly suppressing the immune system.” 

Notably, the study screened compounds in an intact cellular environment which contrasts from many drug screening approaches, which extract proteins from the cell. 

“By maintaining the proteins in their natural environment, we increase the likelihood that compounds we find will actually work in living cells,” said Jennifer Johnson, PhD, first author and senior staff scientist at Scripps Research. 

The most potent compound, ENDO12, reduced inflammation in animal models that were also given a TLR-activating molecule. Blood levels of inflammatory markers, including immune system activators IL-6 and IFN-γ, and the enzyme myeloperoxidase, dropped significantly in animals that were treated. 

ENDO12 treated animals demonstrated normal antiviral immune response when exposed to a virus. This selectivity addresses the concern that dampening inflammation with immunosuppressive drugs may leave patients vulnerable to infections. 

Looking ahead, the team will test ENDOtollins in models that more closely mimic human autoimmune diseases and evaluate the compounds’ chemistry for potential clinical use. 

Beyond autoimmune conditions, the researchers suggest ENDOtollins might help treat cytokine storms, the dangerous immune overreactions seen in patients with severe COVID-19 and as a side effect of CAR T cancer therapy. Both involve excessive IL-6 and runaway inflammation. 

While translating these findings into treatments for patients remains a long-term goal, Catz emphasizes that the mechanistic insights are valuable in their own right. ENDOtollins can serve as precision tools to probe other cellular processes regulated by endosomes and lysosomes, including pathways implicated in neurodegeneration and immune dysfunction.  

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