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

Project description: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.

2023-11-29 | PXD045712 | Pride

Portimine profiling in Human and mouse cells

Project description:practipractical 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 NMD3cal 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

2023-07-12 | PXD041911 | Pride

Transcriptional effects of the IWR1 deletion

Project description:Analysis of the genome-wide transcrptional effects caused by the deletion of the IWR1 gene by comparing the transcriptional profile of a iwr1 mutant strain with the isogenic wild type strain when cells were exponentially grown in YPD medium. Three independent cultures for the wt and the iwr1 mutant were used for the whole genome transcription analysis and they were grown in YPD at the early exponential phase. Total RNA was isolated and cDNA synthesis and labeling, filter hybridization and quantification/normalization of hybridization signals were performed as described in Garcia-Martinez, J., Aranda, A. and Perez-Ortin, J.E. (2004) Mol Cell 15(2),303-313.

2009-10-13 | E-GEOD-17303 | biostudies-arrayexpress

Profiling nuclear cysteine ligandability and effects on nuclear localization using proximity labeling-coupled chemoproteomics

Project description:The nucleus controls cell growth and reproduction by well-orchestrated interactions between nuclear proteins and chromatin. Mutations that result in the dysregulation of these chromatin-associated proteins are known to lead to the onset of numerous diseases. Many of these nuclear proteins have remained recalcitrant to traditional non-covalent small-molecule ligand discovery. Covalent ligands can provide a promising approach for targeting proteins such as transcription factors that lack ordered small-molecule binding pockets. Here, we present a chemoproteomic platform that couples proximity labeling (PL) using a Histone-TurboID (His-TID) construct with competitive isoTOP-ABPP to identify ligandable nuclear cysteines. Application of covalent scout fragments, KB02 and KB05, revealed ligandable cysteine sites on diverse proteins involved in transcriptional regulation, spindle assembly, and DNA repair. To identify functional liganding events that alter target-protein association with chromatin, we monitor the effects of KB02 and KB05 on the chromatin-associated proteome. Importantly, we identify proteins that show both increased and decreased association with chromatin in the presence of the covalent fragments. Notably, the Parkinson disease protein 7 (PARK7) showed increased nuclear localization and association with chromatin upon covalent liganding at Cys106 by KB02. Together, our PL-assisted nuclear-focused chemoproteomic platform provides us insights into nuclear cysteine ligandability and the functional effects of ligand binding on chromatin association, thereby furthering our understanding of the potentially druggability of the nuclear proteome.

2024-01-24 | PXD043732 | Pride

Methanosaeta thermophila ammonia stress

Project description:Effects of high concentration of ammonia were assessed by using mid-log phase cultures of Methanosaeta thermophila.

2013-04-01 | E-MEXP-3849 | biostudies-arrayexpress

Expression of Cell Cycle related genes in developing mouse cerebellum

Project description:The goal of the study was to analize expression of cell cycle related genes during postnatal development of Ts65Dn (Down syndrome mouse model) and control mice cerebellum. Keywords: Gene expression study in mouse model of disease RNA from 3 controls and 3 Ts65Dn postnatal day 2 cerebellum were analized on separate arrays.

2008-05-18 | E-GEOD-9216 | biostudies-arrayexpress

Transcription profiling of Methanothermobacter thermautotrophicus to identify transcriptome responses to contact with the flagellar filament protein (FliC) and flagellar cap protein (FliD) of P. thermopropionicum

Project description:In the syntrophic interaction between fermentative bacteria (Pelotomaculum thermopropionicum) and methanogenic archaea (methanogens: Methanothemobacter thermautotrophicus), reducing equivalents (e.g., H2) produced by fermentative bacteria should efficiently be consumed by methanogens in order for the fermentation of volatile fatty acids (VFA, e.g., butyrate, propionate, and acetate) to be thermodynamically feasible. It has been known that physical approximation (e.g., coaggregation) between VFA-fermenting syntrophic bacteria (syntrophs) and hydrogenotrophic methanogens is necessary for efficient H2 transfer between them. Our previous study has shown that, at an early exponential growth phase of syntrophic coculture, cells of Pelotomaculum thermopropionicum (syntroph) were connected to cells of Methanothermobacter thermautotrophicus (methanogen) via unidentified extracellular filamentous appendages, after which they started to coaggregate, suggesting that the filamentous appendages may have been important for their syntrophic interaction. The filamentous appendages seemed to specifically connect these syntrophic partners, since such pairwise connection has been observed neither in single-species cultures (monocultures) nor in mixtures with other microbes. <br> We found that P. thermopropionicum has putative gene clusters for flagellum and pilus, while no extracellular filament gene was identified in the M. thermautotrophicus genome. So we examined transcriptome responses of M. thermautotrophicus to the contact with flagellar filament protein (FliC) and flagellar cap protein (FliD) of P. thermopropionicum.

2008-01-31 | E-MEXP-1362 | biostudies-arrayexpress

Evaluation of fully functionalized diazirine tags for chemical proteomic applications

Project description:The use of photo-affinity labeling (PAL) reagents for the mapping of noncovalent small molecule-protein interactions has become widespread. Recently, several ‘fully-functionalized’ (FF) chemical tags have been developed wherein a photoactivatable capture group, an enrichment handle, and a functional group for synthetic conjugation to a molecule of interest are integrated into a single modular tag. Diazirine-based FF tags in particular are increasingly employed in chemical proteomic investigations, however, despite routine usage, their relative utility has not been established. Here, we systematically evaluate several diazirine-containing FF tags, including a terminal diazirine analog developed herein, for chemical proteomic investigations. Specifically, we compared the general reactivity of five diazirine tags and assessed their impact on the profiles of various small molecules, including fragments and known inhibitors revealing that such tags can have profound effects on the proteomic profiles of chemical probes. Our findings should be informative for chemical probe design, PAL-reagent development, and chemical proteomic investigations.

2021-05-18 | PXD025652 | Pride

Heat shock: genomic run-on (GRO) analysis

Project description:This SuperSeries is composed of the following subset Series: GSE24483: TR heat-shock GSE24484: RA heat-shock Refer to individual Series

2011-04-19 | E-GEOD-24488 | biostudies-arrayexpress

Xanthocillin X Effectively Kills A.Baumannii via Dysregulation of Heme Biosynthesis

Project description:Isonitrile natural products exhibit promising antibacterial activities, however, their mode of action (MoA) remains largely unknown. Based on the nanomolar potency of xanthocillin X (Xan) against diverse difficult-to-treat Gram-negative bacteria, including the critical priority pathogen Acinetobacter baumannii, we performed in-depth studies to decipher its MoA. While neither metal binding nor cellular protein targets were relevant for Xan´s antibiotic effects, sequencing of resistant strains revealed a conserved mutation in the heme biosynthesis enzyme porphobilinogen synthase (PbgS). This mutation caused impaired enzymatic efficiency indicative of reduced heme production. This discovery led to the validation of an untapped mechanism by which direct heme sequestration of Xan prevents its binding into cognate enzyme pockets resulting in uncontrolled cofactor biosynthesis, accumulation of porphyrins and corresponding stress with deleterious effects for bacterial viability. Thus, Xan represents a promising antibiotic displaying activity even against multidrug resistant strains while exhibiting low toxicity to human cells.

2021-09-09 | PXD021400 | Pride

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