He Rongjun, Yu Zhi-Hong, Zhang Ruo-Yu, Wu Li, Gunawan Andrea M, Zhang Zhong-Yin
Department of Biochemistry and Molecular Biology and Chemical Genomics Core Facility, Indiana University School of Medicine , 635 Barnhill Drive, Indianapolis, Indiana 46202, United States.
ACS Med Chem Lett. 2015 Nov 3;6(12):1231-5. doi: 10.1021/acsmedchemlett.5b00373. eCollection 2015 Dec 10.
mPTPB is a virulent phosphatase from Mycobacterium tuberculosis and a promising therapeutic target for tuberculosis. To facilitate mPTPB-based drug discovery, we identified α-sulfophenylacetic amide (SPAA) from cefsulodin, a third generation β-lactam cephalosporin antibiotic, as a novel pTyr pharmacophore for mPTPB. Structure-guided and fragment-based optimization of SPAA led to the most potent and selective mPTPB inhibitor 9, with a K i of 7.9 nM and more than 10,000-fold preference for mPTPB over a large panel of 25 phosphatases. Compound 9 also exhibited excellent cellular activity and specificity in blocking mPTPB function in macrophage. Given its novel structure, modest molecular mass, and extremely high ligand efficiency (0.46), compound 9 represents an outstanding lead compound for anti-TB drug discovery targeting mPTPB.
mPTPB是一种来自结核分枝杆菌的毒性磷酸酶，是结核病一个很有前景的治疗靶点。为了促进基于mPTPB的药物发现，我们从第三代β-内酰胺类头孢菌素抗生素头孢磺啶中鉴定出α-磺基苯乙酰胺（SPAA），作为mPTPB的一种新型磷酸化酪氨酸药效团。基于结构和片段的SPAA优化产生了最有效和最具选择性的mPTPB抑制剂9，其抑制常数（K i）为7.9 nM，对mPTPB的选择性比对25种磷酸酶组成的大样本库中的其他磷酸酶高10000倍以上。化合物9在巨噬细胞中阻断mPTPB功能时还表现出优异的细胞活性和特异性。鉴于其新颖的结构、适中的分子量和极高的配体效率（0.46），化合物9是针对mPTPB的抗结核药物发现的一种优秀先导化合物。
