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.

Marine derived cyclic imine toxins, portimine A and B, have attracted extensive attention owing to their intriguing chemical structure and promising anti-cancer therapeutic potential. However, access to large quantities is currently unfeasible and the molecular mechanism behind their potent activity is unknown. To address this, a scalable 15-step total synthesis of portimines is presented, which benefits from the logic used in two-phase terpenoid synthesis along with unique tactics such as exploiting ring-chain tautomerization and skeletal reorganization to minimize protecting group chemistry through “self-protection”. Critically, this total synthesis enabled a structural reassignment of portimine B and an in-depth functional evaluation of portimine A, revealing that it induces apoptosis selectively in human cancer cell lines with high potency. Finally, practical access to the portimines and analogs thereof simplified the development of photoaffinity analogs, which were used in chemical proteomic experiments to identify a primary target of portimine A as the 60S ribosomal export protein NMD3.