Abstract：
:Rational design of drug-like small-molecule ligands based on structural information of proteins remains a significant challenge in chemical biology. In particular, designs targeting protein-protein interfaces have met little success given the dynamic nature of the protein surfaces. Herein, we utilized the structure of a small-molecule ligand in complex with Toll-like receptor 8 (TLR8) as a model system due to TLR8's clinical relevance. Overactivation of TLR8 has been suggested to play a prominent role in the pathogenesis of various autoimmune diseases; however, there are still few small-molecule antagonists available, and our rational designs led to the discovery of six exceptionally potent compounds with ∼picomolar IC50 values. Two X-ray crystallographic structures validated the contacts within the binding pocket. A variety of biological evaluations in cultured cell lines, human peripheral blood mononuclear cells, and splenocytes from human TLR8-transgenic mice further demonstrated these TLR8 inhibitors' high efficacy, suggesting strong therapeutic potential against autoimmune disorders.
journal_name
Cell Chem Bioljournal_title
Cell chemical biologyauthors
Hu Z,Tanji H,Jiang S,Zhang S,Koo K,Chan J,Sakaniwa K,Ohto U,Candia A,Shimizu T,Yin Hdoi
10.1016/j.chembiol.2018.07.004subject
Has Abstractpub_date
2018-10-18 00:00:00pages
1286-1291.e3issue
10eissn
2451-9456issn
2451-9448pii
S2451-9456(18)30231-9journal_volume
25pub_type
杂志文章abstract：:USP2a is a deubiquitinase responsible for stabilization of cyclin D1, a crucial regulator of cell-cycle progression and a proto-oncoprotein overexpressed in numerous cancer types. Here we report that lithocholic acid (LCA) derivatives are inhibitors of USP proteins, including USP2a. The most potent LCA derivative, LCA...
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abstract：:The cysteine prodrug N-acetyl cysteine (NAC) is widely used as a pharmacological antioxidant and cytoprotectant. It has been reported to lower endogenous oxidant levels and to protect cells against a wide range of pro-oxidative insults. As NAC itself is a poor scavenger of oxidants, the molecular mechanisms behind the...
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journal_title：Cell chemical biology
pub_type： 杂志文章
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pub_type： 杂志文章
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journal_title：Cell chemical biology
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journal_title：Cell chemical biology
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journal_title：Cell chemical biology
pub_type： 杂志文章
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pub_type： 杂志文章
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journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2018.07.009
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journal_title：Cell chemical biology
pub_type： 杂志文章
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journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2016.09.005
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journal_title：Cell chemical biology
pub_type： 评论,杂志文章
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journal_title：Cell chemical biology
pub_type： 杂志文章,评审
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pub_type： 杂志文章,评审
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journal_title：Cell chemical biology
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journal_title：Cell chemical biology
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journal_title：Cell chemical biology
pub_type： 杂志文章
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journal_title：Cell chemical biology
pub_type： 杂志文章
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journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2018.12.007
更新日期：2018-12-20 00:00:00
abstract：:Host cell metabolism regulates viral infection. In this issue of Cell Chemical Biology, Kulkarni et al. (2017) reveal the importance of oxygen concentrations and glycolysis in the reactivation of human T cell leukemia virus (HTLV-1). Identifying the host metabolic networks that regulate infection will foster our under...
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
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journal_title：Cell chemical biology
pub_type： 评论,杂志文章
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journal_title：Cell chemical biology
pub_type： 杂志文章
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更新日期：2018-10-18 00:00:00
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journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2019.08.003
更新日期：2019-10-17 00:00:00
abstract：:Interferon-induced transmembrane protein 3 (IFITM3) is a key interferon effector that broadly prevents infection by diverse viruses. However, the cellular factors that control IFITM3 homeostasis and antiviral activity have not been fully elucidated. Using site-specific photo-crosslinking and quantitative proteomic ana...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2020.03.004
更新日期：2020-05-21 00:00:00
