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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: Tzu-Yuan Chiu

LAB HEAD: Christopher G. Parker

PROVIDER: PXD045712 | Pride | 2023-11-29

REPOSITORIES: Pride

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			Action	DRS
	15a4tmt7_untargeted_1.raw	Raw
	15a4tmt7_untargeted_2.raw	Raw
	15a4tmt7_untargeted_3.raw	Raw
	15a4tmt7_untargeted_4.raw	Raw
	15a4tmt7_untargeted_5.raw	Raw

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

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