Highly Potent and Selective N-Aryl Oxamic Acid-Based Inhibitors for Mycobacterium tuberculosis Protein Tyrosine Phosphatase B.
Highly Potent and Selective N-Aryl Oxamic Acid-Based Inhibitors for Mycobacterium tuberculosis Protein Tyrosine Phosphatase B.
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DOI：
10.1021/acs.jmedchem.0c00302
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发表时间：
2020-09-10
影响因子：
7.3
通讯作者：
Zhang ZY
中科院分区：
文献类型：
--
作者：
Ruddraraju KV;Aggarwal D;Niu C;Baker EA;Zhang RY;Wu L;Zhang ZY
结核病是一种由结核分枝杆菌（Mtb）引起的传染病。结核分枝杆菌蛋白酪氨酸磷酸酶B （mPTPB）是结核分枝杆菌在宿主巨噬细胞中存活所需的毒力因子。因此，mPTPB代表了一个令人兴奋的结核病治疗靶点。在这里，我们发现n -苯基肟酸是一种高效的选择性单酸基磷酸酪氨酸模拟物，可抑制mPTPB。对初始靶点化合物4 （IC50 = 257 nM）的SAR研究发现，mPTPB的几种IC50值低于20 nM的高效抑制剂。其中，化合物4t对mPTPB的Ki值为2.7 nM，优于25种哺乳动物PTPs的4500倍以上。动力学、分子对接和定点诱变分析证实了这些化合物是mPTPB的活性定点可逆抑制剂。这些抑制剂可以逆转细菌磷酸酶诱导的宿主细胞免疫反应的改变。此外，抑制剂的分子量<400 Da，对数D7.4 < 2.5，拓扑极性表面积< 75，配体效率>.43，良好的水溶性和代谢稳定性，从而为进一步的治疗开发提供了良好的起点。
Tuberculosis is an infectious disease caused by the bacterium Mycobacterium tuberculosis (Mtb). Mtb protein tyrosine phosphatase B (mPTPB) is a virulence factor required for Mtb survival in host macrophages. Consequently, mPTPB represents an exciting target for tuberculosis treatment. Here, we identified N-phenyl oxamic acid as a highly potent and selective monoacid-based phosphotyrosine mimetic for mPTPB inhibition. SAR studies on the initial hit, compound 4 (IC50 = 257 nM), resulted in several highly potent inhibitors with IC50 values lower than 20 nM for mPTPB. Among them, compound 4t showed a Ki of 2.7 nM for mPTPB with over 4500-fold preference over 25 mammalian PTPs. Kinetic, molecular docking, and site-directed mutagenesis analyses confirmed these compounds as active site-directed reversible inhibitors of mPTPB. These inhibitors can reverse the altered host cell immune responses induced by the bacterial phosphatase. Furthermore, the inhibitors possess molecular weights <400 Da, log D7.4 < 2.5, topological polar surface area < 75, ligand efficiency > 0.43, and good aqueous solubility and metabolic stability, thus offering excellent starting points for further therapeutic development.
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影响因子：
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