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

ABSTRACT: SLC15A4 is an endolysosome-resident transporter intimately linked with autoinflammation and autoimmunity. Specifically, SLC15A4 is critical for Toll-like receptor (TLR) 7-9 as well as the nucleotide-binding oligomerization domain-containing protein (NOD) 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 chemical probes 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 described herein suppress endolysosomal TLR and NOD functions in a variety of human and mouse immune cells, furnish evidence of their ability to suppress inflammation in vivo and in clinical settings, and provide insights into their mechanism of action. Our findings establish SLC15A4 as a druggable target for the treatment of autoimmune/autoinflammatory conditions.

INSTRUMENT(S): Orbitrap Fusion Lumos, Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Weichao Li

LAB HEAD: Christopher Parker

PROVIDER: PXD045715 | Pride | 2023-11-29

REPOSITORIES: Pride

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			Action	DRS
	011121_WL_SLC15A4_FFF_Set1.msf	Msf
	011121_WL_SLC15A4_FFF_Set1_1.raw	Raw
	011121_WL_SLC15A4_FFF_Set1_1_2.raw	Raw
	011121_WL_SLC15A4_FFF_Set1_2.raw	Raw
	011121_WL_SLC15A4_FFF_Set1_2_2.raw	Raw

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Project description:Dialkyldiazirines have emerged as a photoaffinity probe of choice for interactome mapping in live cell experiments. Upon irradiation, ‘linear’ dialkyldiazirines produce dialkylcarbenes, which are susceptible to both intramolecular reactions and unimolecular elimination processes, as well as diazoalkanes, which also participate in intermolecular labeling. Cyclobutylidene has a nonclassical bonding structure and is stable enough to be captured in bimolecular reactions. Cyclobutanediazirines have more recently been studied as photoaffinity probes based on cyclobutylidene, but the mechanism, especially with respect to the role of putative diazo intermediates, was not fully understood. Here, we show that photolysis (365 nm) of cyclobutanediazirines can produce cyclobutylidene intermediates as evidenced by formation of their expected bimolecular and unimolecular products, including methylenecyclopropane derivatives. Unlike linear diazirines, cyclobutanediazirine photolysis in the presence of tetramethylethylene produces a [2+1] cycloaddition adduct. By contrast, linear diazirines produce diazo compounds upon low temperature photolysis in THF, whereas diazo compounds are not detected in similar photolyses of cyclobutanediazirines. Diazocyclobutane, prepared by independent synthesis, is labile, reactive toward water, and capable of protein alkylation. The rate of diazocyclobutane decomposition is not affected by 365 nm light, suggesting that the photochemical conversion of diazocyclobutane to cyclobutylidene is not an important pathway. Finally, chemical proteomic studies revealed that a likely consequence of this primary conversion to a highly reactive carbene is a marked decrease in labeling by cyclobutanediazirine-based probes relative to linear diazirine counterparts both at the individual protein and proteome-wide levels. Collectively, these observations are consistent with a mechanistic picture for cyclobutanediazirine photolysis that involves carbene chemistry with minimal formation of diazo intermediates, and contrasts with the photolyses of linear diazirines where alkylation by diazo intermediates plays a more significant role.

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

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