Chemoproteomics-guided development of SLC15A4 inhibitors with anti-inflammatory activity

Abstract SLC15A4 is an endolysosome-resident transporter that is intimately linked with autoinflammation and autoimmunity. Specifically, SLC15A4 is critical for Toll-like receptor (TLR) 7, 8, and 9 as well as the nucleotide-binding oligomerization domain-containing protein (NOD) 2 signaling in several immune cell subsets. Notably, SLC15A4 is essential for the development of systemic lupus erythematosus in murine models and is associated with autoimmune conditions in humans. Despite its therapeutic potential, to our knowledge no pharmacological tools have been developed that target SLC15A4. Here, we use an integrated chemical proteomics approach to develop a suite of chemical tools, including first-in-class functional inhibitors, for SLC15A4. We demonstrate SLC15A4 inhibitors suppress endosomal TLR and NOD functions in a variety of human and mouse immune cells and provide early evidence of their ability to suppress inflammation in vivo and in clinical settings. Our findings establish SLC15A4 as a druggable target for the treatment of autoimmune/autoinflammatory conditions. One-Sentence Summary Discovery and characterization of SLC15A4 inhibitors with anti-inflammatory activity.