Prolyl Hydroxylase Domain Protein Inhibitor Not Harboring a 2-Oxoglutarate Scaffold Protects against Hypoxic Stress
Prolyl Hydroxylase Domain Protein Inhibitor Not Harboring a 2-Oxoglutarate Scaffold Protects against Hypoxic Stress
复制标题
不带有 2-氧戊二酸支架的脯氨酰羟化酶结构域蛋白抑制剂可防止缺氧应激
DOI：
10.1021/acsptsci.2c00002
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发表时间：
2022
影响因子：
6
通讯作者：
and Tadayuki Tsujita*
中科院分区：
文献类型：
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作者：
Kento Sonoda ;Sudarma Bogahawatta;Akito Katayama;Saki Ujike;Sae Kuroki;Naho Kitagawa;Kohichi Hirotsuru;Norio Suzuki;Toshio Miyata;Shin-ichi Kawaguchi;and Tadayuki Tsujita*
缺氧诱导因子-α (HIF-α) 激活在治疗缺血（如中风、心肌梗塞和慢性肾病）方面显示出良好的效果。已经开发出许多 HIF-α 激活剂来改善这些疾病的症状。许多具有 2-酮戊二酸 (2-OG) 支架，可与含有脯氨酰羟化酶结构域的蛋白质 (PHD) 的活性中心相互作用，取代辅酶 2-OG。这可以稳定 HIF-α。因此，2-OG类似物的特异性不高。在这里，我们从 10000 多种化合物中鉴定出 5-(1-乙酰基-5-苯基吡唑烷-3-亚基)-1,3-二甲基巴比妥酸 (PyrzA) 是一种不含 2-OG 支架的新型 HIF 激活剂。在培养细胞中，PyrzA 增强了 HIF-α 的稳定性并上调了 HIF 靶基因的表达。有趣的是，PyrzA 降低了 HIF-1α 脯氨酰羟基化，表明 PyrzA 可能激活 HIF 以防止 HIF-α 降解。这些结果表明 PyrzA 通过一种新机制稳定 HIF，并且可能是潜在的 HIF 激活剂候选者。
Hypoxia-inducible factor-α (HIF-α) activation has shown promising results in the treatment of ischemia, such as stroke, myocardial infarction, and chronic kidney disease. A number of HIF-α activators have been developed to improve the symptoms of these diseases. Many feature 2-oxoglutarate (2-OG) scaffolds that interact with the active centers of prolyl hydroxylase domain-containing proteins (PHDs), displacing the coenzyme 2-OG. This stabilizes HIF-α. Therefore, the specificity of the 2-OG analogs is not high. Here, we identified 5-(1-acetyl-5-phenylpyrazolidin-3-ylidene)-1,3-dimethylbarbituric acid (PyrzA) among over 10 000 compounds as a novel HIF activator that does not contain a 2-OG scaffold. In cultured cells, PyrzA enhanced HIF-α stability and upregulated the expression of HIF target genes. Interestingly, PyrzA decreased HIF-1α prolyl hydroxylation, suggesting that PyrzA may activate HIF to prevent the degradation of HIF-α. These results indicate that PyrzA stabilizes HIF via a novel mechanism and could be a potential HIF activator candidate.