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An endosomal toll-like receptor inhibitor drug with therapeutic effects in autoimmune diseases

ABSTRACT: An endosomal toll-like receptor inhibitor drug with therapeutic effects in autoimmune diseases

PROVIDER: PRJNA1076919 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28774084.fastq.gz	Fastqsanger.gz
	SRR28774085.fastq.gz	Fastqsanger.gz
	SRR28774086.fastq.gz	Fastqsanger.gz
	SRR28774087.fastq.gz	Fastqsanger.gz
	SRR28774088.fastq.gz	Fastqsanger.gz

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An endosomal toll-like receptor inhibitor drug with therapeutic effects in autoimmune diseases

Project description:Autoimmune disease is a systemic inflammatory response of immune blood cells caused by self-tolerance dysfunction, due to genetic or environmental factors or a combination thereof. Studies on autoimmune disease regarding the inhibition of toll-like receptor (TLR)7/9-MyD axis or the regulation of plasmacytoid dendritic cells (pDCs) and Th17 comprising an abundance of respective receptors have shown improvements in phenotypes or molecular markers, providing clues to the practicality of the inhibitors of endosomal TLRs. This study discovered several small-molecule compounds in endosomes exerting specific inhibitory effects on SITE1 shared among TLR 3, 7, 8, and 9, named endosomal TLR inhibitors (ETIs). The drug discovery process involved identifying lead compounds optimized to the receptors using a quantitative structure-activity relationship model and subsequent modification of the compounds to improve their binding affinity to target proteins. To propose a method of verifying the drug effects against side or placebo effect arising from false positives, the drug evaluation process converged from cellular response to signaling process to protein binding. Drug values on the inhibition of endosomal TLRs in autoimmune disease were assessed based on the onset of mild-to-life-threatening autoimmune disease including psoriasis, systemic lupus erythematosus, and multiple sclerosis. Complete healing was achieved for psoriasis through direct or indirect association with TLRs. Therapeutic potential of the novel ETIs for psoriasis was verified and is considered an effective drug for other autoimmune diseases associated with the TLR7/9-MyD axis.

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