Derivatives of the Fungal Natural Product Illudalic Acid Inhibit the Activity of Protein Histidine Phosphatase PHPT1
Derivatives of the Fungal Natural Product Illudalic Acid Inhibit the Activity of Protein Histidine Phosphatase PHPT1
复制标题
真菌天然产物伊杜达酸的衍生物抑制蛋白组氨酸磷酸酶PHPT1的活性
DOI：
10.1002/cmdc.202300187
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发表时间：
2023
期刊：
影响因子：
3.4
通讯作者：
Barrios, Amy M.
中科院分区：
文献类型：
--
作者：
Wang, Hanfei;Gaston, Jr., Robert;Ahmed, Kh Tanvir;Dudley, Gregory B.;Barrios, Amy M.
PHPT1是一种蛋白质组氨酸磷酸酶，与多种疾病途径有关，但研究该酶的生物学作用和研究其作为治疗靶点的效用所必需的化学工具尚未开发。为此，PHPT1抑制剂的发现是一个值得关注的领域。在这里，我们报道了一项基于苯乙烯酸和苯乙烯酸类似物抑制PHPT1活性的研究。7个类似物中有4个的ic50值低于5 μM，其中最有效的化合物（IA1‐8H2）的ic50值为3.4±0.7 μM。有趣的是，与最近报道的其他PHPT1抑制剂相比，这些化合物似乎是非共价的、非竞争性的PHPT1活性抑制剂。将三个半胱氨酸残基突变为丙氨酸对抑制作用没有影响，这表明半胱氨酸对抑制剂和酶之间的相互作用并不重要。
PHPT1 is a protein histidine phosphatase that has been implicated in several disease pathways, but the chemical tools necessary to study the biological roles of this enzyme and investigate its utility as a therapeutic target have yet to be developed. To this end, the discovery of PHPT1 inhibitors is an area of significant interest. Here, we report an investigation of illudalic acid and illudalic acid analog‐based inhibition of PHPT1 activity. Four of the seven analogs investigated had IC50values below 5 μM, with the most potent compound (IA1‐8H2) exhibiting an IC50value of 3.4±0.7 μM. Interestingly, these compounds appear to be non‐covalent, non‐competitive inhibitors of PHPT1 activity, in contrast to other recently reported PHPT1 inhibitors. Mutating the three cysteine residues to alanine has no effect on inhibition, indicating that cysteine is not critical for interactions between inhibitor and enzyme.