期刊
JOURNAL OF PHYSICAL CHEMISTRY B
卷 126, 期 12, 页码 2394-2406出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jpcb.2c00341
关键词
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资金
- National Institute of Health [R01HL141432]
- University of Tennessee Health Science Center
Cytokine signaling mediated by cytokine receptors plays a crucial role in immune regulation and diseases. This study demonstrates the inhibition of ST2 and IL33 binding by small molecules containing an aromatic ring and a charged group, suggesting a potential mechanism for modulating extracellular cytokine receptors and cytokine interaction.
Cytokine signaling initiated by the binding of the cytokine receptors to cytokines plays important roles in immune regulation and diseases. Structurally, cytokine receptors interact with cytokines via an extensive, rugged interface that represents a challenge in inhibitor development. Our computational analysis has previously indicated that butyric acid, mimicking acidic residues, preferentially binds to sites in ST2 (Stimulation-2) that interact with acidic residues of IL33, the endogenous cytokine for ST2. To investigate if a charged group in small molecules facilitates ligand binding to ST2, we developed a biochemical homogeneous time resolved fluorescence assay to determine the inhibition of ST2/IL33 binding by five molecules containing an aromatic ring and a charged group. Three molecules, including niacin, salicylic acid, and benzamidine, exhibit inhibition activities at millimolar concentrations. We further employed the computational cosolvent mapping analysis to identify a shared mode of interaction between niacin, salicylic acid, and ST2. The mode of interaction was further confirmed by four analogous compounds that exhibited similar or improved activities. Our study provided the evidence of inhibition of ST2 and IL33 binding by salicylic acid and analogs. The results suggest that biological activity of salicylic acid may be partly mediated through modulating extracellular cytokine receptors and cytokine interaction.
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