Scripps Research scientists have developed a new class of drug compounds that reduce harmful inflammation while leaving the body\u2019s ability to fight infections intact\u2014a long-sought goal in treating autoimmune diseases. The compounds, called ENDOtollins, work by interrupting a \u201cmolecular handshake\u201d between two proteins inside immune cells.<\/p>\n
The research, published in\u00a0Nature Chemical Biology<\/a>\u00a0on April 6, 2026, could lead to more targeted treatments for conditions like lupus, rheumatoid arthritis and juvenile arthritis, which together affect more than 15 million Americans.<\/p>\n \u201cA key component of our approach is to begin by understanding the biological mechanisms at play,\u201d says\u00a0Sergio D. Catz<\/a>, professor at Scripps Research and senior author. \u201cBy accomplishing this first, we can more easily target the pathway driving inflammation without affecting other important processes.\u201d<\/p>\n Current autoimmune disease treatments like hydroxychloroquine work by broadly blocking endosomes, the compartments inside cells where incoming materials are sorted and processed, including molecules that trigger immune responses. While effective, this approach can lead to significant side effects\u2014including gastrointestinal problems and, less commonly, vision damage\u2014causing a significant number of patients to stop treatment.<\/p>\n Catz and his team took a different approach: They focused on two proteins, Munc13-4 and syntaxin 7, that must bind together for immune sensors called Toll-like receptors (TLRs) to activate inside endosomes. This \u201cmolecular handshake\u201d plays a key role in detecting the foreign DNA and RNA from invaders like viruses and bacteria. However, in autoimmune diseases, TLRs become overactive, detecting self-nucleic acids, for example, from neutrophil-extracellular traps, and trigger chronic, damaging inflammation even without a real threat.<\/p>\n In collaboration with co-author\u00a0Hugh Rosen<\/a>, a professor at Scripps Research and the Pearson Family Chair, the team screened roughly 32,000 compounds with the support of the institute\u2019s Molecular Screening Center. The researchers identified molecules that specifically block the Munc13-4\u2013syntaxin 7 interaction without disrupting other cellular functions. Because Munc13-4 is found mainly in immune cells, the compounds offer a targeted way to calm inflammation.<\/p>\n \u201cMost treatments for autoimmune diseases manage symptoms; they don\u2019t change the underlying course of the disease,\u201d says Rosen. \u201cWhat\u2019s 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.\u201d<\/p>\n A key innovation was screening compounds in an intact cellular environment. Unlike many drug screening approaches, which extract proteins from the cell, Catz and his team developed an approach that keeps cellular compartments intact.<\/p>\n \u201cBy maintaining the proteins in their natural environment, we increase the likelihood that compounds we find will actually work in living cells,\u201d says Jennifer Johnson, first author and senior staff scientist at Scripps Research.<\/p>\n The most potent compound, ENDO12, reduced inflammation in animal models that were also given a TLR-activating molecule. Blood levels of inflammatory markers\u2014including immune system activators IL-6 and IFN-\u03b3, and the enzyme myeloperoxidase\u2014dropped significantly in those that were treated.<\/p>\n Crucially, ENDO12 did not impair the animal models\u2019 ability to fight a real viral infection: they showed a normal antiviral immune response when exposed to a virus. This selectivity addresses a major concern with immunosuppressive drugs: that dampening inflammation might leave patients vulnerable to infections.<\/p>\n The team\u2019s next steps include testing ENDOtollins in models that more closely mimic human autoimmune diseases, as well as further optimizing the compounds\u2019 chemistry for potential clinical use.<\/p>\n Beyond autoimmune conditions, the researchers suggest ENDOtollins might help treat cytokine storms\u2014the 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.<\/p>\n 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\u2014including pathways implicated in neurodegeneration and immune dysfunction. Understanding the basis of how these compartments become stressed or dysfunctional could have broad implications for understanding and treating human disease.<\/p>\n Reference:\u00a0Johnson JL, Meneses-Salas E, Shukla A, et al. Munc13-4\u2013STX7 inhibitors impair endosomal TLR activation and systemic inflammation. Nat Chem Biol. 2026. doi:\u00a010.1038\/s41589-026-02181-6<\/a><\/p>\n This article has been republished from the following materials<\/a>. Note: material may have been edited for length and content. For further information, please contact the cited source. 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