Piezo1, a mechano-activated ion channel, has wide-ranging physiological and therapeutic implications, with the ongoing development of specific agonists unveiling cellular responses to mechanical stimuli. In our study, we systematically analyzed the chemical subunits in Piezo1 protein agonist Yoda1 to comprehend the structure–activity relationship and push forward next-generation agonist development. Preliminary screening assays for Piezo1 agonism were performed using the Piezo1-mCherry-transfected HEK293A cell line, keeping Yoda1 as a positive control. We introduce a novel Piezo1 agonist Yaddle1 (34, 0.40 μM), featuring a trifluoromethyl group, with further exploration through in vitro studies and density functional theory calculations, emphasizing its tetrel interactions, to act as an ambidextrous wedge between the domains of Piezo1. In contrast to the poor solubility of the established agonist Yoda1, our results showed that the kinetic solubility of Yaddle1 (26.72 ± 1.8 μM at pH 7.4) is 10-fold better than that of Yoda1 (1.22 ± 0.11 μM at pH 7.4). Yaddle1 (34) induces Ca²⁺ influx in human CD4⁺ T cell, suggesting its potential as a vaccine adjuvant for enhanced T cell activation.

中文翻译：

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探索 Yoda1 的结构属性，以开发新一代 Piezo1 激动剂 Yaddle1 作为针对最佳 T 细胞激活的疫苗佐剂


Piezo1 是一种机械激活的离子通道，具有广泛的生理和治疗意义，随着特定激动剂的不断开发，揭示了细胞对机械刺激的反应。在我们的研究中，我们系统地分析了Piezo1蛋白激动剂Yoda1中的化学亚基，以了解其构效关系并推动下一代激动剂的开发。使用 Piezo1-mCherry 转染的 HEK293A 细胞系进行 Piezo1 激动作用的初步筛选测定，保留 Yoda1 作为阳性对照。我们引入了一种新型 Piezo1 激动剂 Yaddle1（34，0.40 μM），具有三氟甲基基团，通过体外研究和密度泛函理论计算进行了进一步探索，强调其 tetrel 相互作用，作为 Piezo1 域之间的灵巧楔子。与已建立的激动剂 Yoda1 的溶解度差相反，我们的结果表明，Yaddle1 的动力学溶解度（pH 7.4 时为 26.72 ± 1.8 μM）比 Yoda1（pH 7.4 时为 1.22 ± 0.11 μM）好 10 倍。 Yaddle1 (34) 诱导人 CD4 ⁺ T 细胞中 Ca ²⁺ 流入，表明其作为增强 T 细胞活化的疫苗佐剂的潜力。