Development of a light-activated STING agonist.
Development of a light-activated STING agonist.
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光激活 STING 激动剂的开发。
DOI：
10.1039/d3ob01578e
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发表时间：
2024
影响因子：
3.2
通讯作者：
Deiters,Alexander
中科院分区：
文献类型：
--
作者：
Caldwell,StevenE;Janosko,ChasityP;Deiters,Alexander
STING途径对先天免疫至关重要，并且正在作为潜在的治疗靶点进行研究。靶向STING的现有药剂遭受几种不期望的作用，特别是系统性激活的可能性，这增加了自身免疫性疾病的风险。在这项概念验证研究中，我们报告了基于有效化合物SR-717的光激活STING激动剂的开发。我们首先筛选了非笼状激动剂对5种人STING变体的活性，以鉴定最可行的靶标。设计并合成了光笼化激动剂，以阻断配体的羧酸基团与STING蛋白的R238残基之间的必要相互作用。然后，我们研究了用光笼激动剂选择性激活STING，证明了辐射依赖性反应。这种选择性激动剂的开发和表征扩展了条件控制STING激动剂的不断增长的工具箱，以避免系统性免疫激活。
The STING pathway is critical to innate immunity and is being investigated as a potential therapeutic target. Existing agents targeting STING suffer from several undesirable effects, particularly the possibility of systematic activation, which increases the risk of autoimmune disorders. In this proof-of-concept study, we report the development of a light-activated STING agonist, based on the potent compound SR-717. We first screened the activity of the non-caged agonist toward 5 human STING variants to identify the most viable target. A photocaged agonist was designed and synthesized in order to block an essential interaction between the carboxy acid group of the ligand with the R238 residue of the STING protein. We then investigated the selective activation of STING with the photocaged agonist, demonstrating an irradiation-dependent response. The development and characterization of this selective agonist expands the growing toolbox of conditionally controlled STING agonists to avoid systematic immune activation.