Our immune system has evolved a defensive armamentarium to combat pathogens; critically including mechanisms that detect and respond to pathogen derived nucleic acids. However, immune sensing of nucleic acids constitutes a double-edged sword: While prompt detection of pathogens is key to our survival, aberrant activation or an excessive response to the body’s own DNA or RNA underpins the pathophysiology of a range of autoimmune diseases. This is exemplified by the pathology of systemic lupus erythematosus (SLE) which involve nucleic acid sensing endosomal Toll-like receptors (TLRs). Several large-scale human genetic association studies have implicated multiple components of endosomal TLR-mediated pathways in SLE development. Further support comes from animal studies, as well as from mechanistic in vitro and ex vivo experiments. Endosomal TLR signalling components are therefore potential intervention points towards developing novel drugs for the treatment of SLE.

An exciting target protein is the endolysosomal solute carrier, SLC15A4, whose key role common to all endosomal TLR was initially discovered in mice in a forward genetic screen for genes involved in the type-I interferon response. A loss of function mutation in the SLC15A4 locus abrogated the TLR7/9 -induced type-I response in the plasmacytoid dendritic cells¹. The mouse strain bearing this mutation (named feeble)was also protected from developing of lupus features ² . Further support for the importance of this gene in lupus comes from independent GWAS studies which identified several SLC15A4 SNPs as risk factors for SLE. A seminal study in 2018, elucidated the exact role of SLC15A4 in this pathway, showing that it forms a complex with TASL – a protein encoded by another SLE-associated gene, previously known as CXorf21³ . The SLC15A4-TASL complex acts as an immune adapter required for the activation of IRF5 and the associated type-I interferon response downstream of the endolysosmal TLRs. Together, these data indicate that a small-molecule inhibitor of SLC15A4/TASL could hold significant therapeutic benefit for treating SLE and potentially other interferonopathies. Two recent publications described the discovery of SLC15A4 inhibitors^{4 5}. The authors took different approaches; Chiu et al. applied a chemoproteomic approach to identify a functional SLC15A4-interacting compound, whereas Boeszoermenyi and colleagues used a phenotypic screen to discover a molecule that binds to SLC15A4 and induces TASL degradation through disruption of the complex. At OMass Therapeutics, we have used our mass-spec-based platform to discover compounds that directly interact with the purified solute carrier. We have also demonstrated that these compounds can suppress the endolysosomal TLR response in a SLC15A4-dependent manner in different cell types including primary human PBMCs.

Taken together, these data clearly demonstrate that the SLC15A4/TASL node is amenable to pharmacological intervention by small molecules. Of course, the challenge is to develop a safe orally bioavailable drug — a path that we are pursuing at OMass. The robust activity and properties of our chemical series give us cause for optimism to be able to deliver a preclinical candidate in the course of next year.

(1) Blasius, A. L.; Arnold, C. N.; Georgel, P.; Rutschmann, S.; Xia, Y.; Lin, P.; Ross, C.; Li, X.; Smart, N. G.; Beutler, B. Slc15a4, AP-3, and Hermansky-Pudlak Syndrome Proteins Are Required for Toll-like Receptor Signaling in Plasmacytoid Dendritic Cells. Proc Natl Acad Sci U S A 2010, No. 46, 19973–19978. https://doi.org/10.1073/pnas.1014051107.

(2) Katewa, A.; Suto, E.; Hui, J.; Heredia, J.; Liang, J.; Hackney, J.; Anderson, K.; Alcantar, T. M.; Bacarro, N.; Dunlap, D.; Eastham, J.; Paler-Martinez, A.; Rairdan, X. Y.; Modrusan, Z.; Lee, W. P.; Austin, C. D.; Lafkas, D.; Ghilardi, N. The Peptide Symporter SLC15a4 Is Essential for the Development of Systemic Lupus Erythematosus in Murine Models. PLoS One 2021, No. 1, e0244439. https://doi.org/10.1371/journal.pone.0244439.

(3) Heinz, L. X.; Lee, J.; Kapoor, U.; Kartnig, F.; Sedlyarov, V.; Papakostas, K.; César-Razquin, A.; Essletzbichler, P.; Goldmann, U.; Stefanovic, A.; Bigenzahn, J. W.; Scorzoni, S.; Pizzagalli, M. D.; Bensimon, A.; Müller, A. C.; King, F. J.; Li, J.; Girardi, E.; Mbow, M. L.; Whitehurst, C. E.; Rebsamen, M.; Superti-Furga, G. TASL Is the SLC15A4-Associated Adaptor for IRF5 Activation by TLR7–9. Nature 2020, No. 7808, 316–322. https://doi.org/10.1038/s41586-020-2282-0.

(4) Chiu, T.-Y.; Lazar, D. C.; Wang, W. W.; Wozniak, J. M.; Jadhav, A. M.; Li, W.; Gazaniga, N.; Theofilopoulos, A. N.; Teijaro, J. R.; Parker, C. G. Chemoproteomic Development of SLC15A4 Inhibitors with Anti-Inflammatory Activity. Nat Chem Biol 2024. https://doi.org/10.1038/s41589-023-01527-8.

(5) Boeszoermenyi, A.; Bernaleau, L.; Chen, X.; Kartnig, F.; Xie, M.; Zhang, H.; Zhang, S.; Delacrétaz, M.; Koren, A.; Hopp, A.-K.; Dvorak, V.; Kubicek, S.; Aletaha, D.; Yang, M.; Rebsamen, M.; Heinz, L. X.; Superti-Furga, G. A Conformation-Locking Inhibitor of SLC15A4 with TASL Proteostatic Anti-Inflammatory Activity. Nat Commun 2023, No. 1. https://doi.org/10.1038/s41467-023-42070-3.