期刊
MOLECULES
卷 28, 期 5, 页码 -出版社
MDPI
DOI: 10.3390/molecules28052287
关键词
IL-15; IL-15R alpha; small-molecule IL-15R alpha inhibitor; benzoic acid
Chronic overproduction of IL-15 is involved in various inflammatory and autoimmune disorders. Inhibiting IL-15 signaling by targeting its specific high affinity subunit alpha of the IL-15 receptor (IL-15R alpha) shows potential as a therapeutic approach to alleviate IL-15-related diseases. This study explored the structure-activity relationship of known IL-15R alpha inhibitors and identified new molecules that efficiently reduced IL-15-dependent cell proliferation and cytokine secretion. The rational design of IL-15 inhibitors holds promise in the development of safe and effective therapeutic agents.
Chronic overproduction of IL-15 contributes to the pathogenesis of numerous inflammatory and autoimmune disorders. Experimental methods used to reduce the cytokine activity show promise as potential therapeutic approaches to modify IL-15 signaling and alleviate the development and progression of IL-15-related diseases. We previously demonstrated that an efficient reduction of IL-15 activity can be obtained by selective blocking of the specific, high affinity subunit alpha of the IL-15 receptor (IL-15R alpha) with small-molecule inhibitors. In this study, we determined the structure-activity relationship of currently known IL-15R alpha inhibitors in order to define the critical structural features required for their activity. To validate our predictions, we designed, analyzed in silico, and assessed in vitro function of 16 new potential IL-15R alpha inhibitors. All newly synthesized molecules were benzoic acid derivatives with favorable ADME properties and they efficiently reduced IL-15 dependent peripheral blood mononuclear cells (PBMCs) proliferation, as well as TNF-alpha and IL-17 secretion. The rational design of IL-15 inhibitors may propel the identification of potential lead molecules for the development of safe and effective therapeutic agents.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据