He, RongjunYu, Zhi-HongZhang, Ruo-YuWu, LiGunawan, Andrea M.Zhang, Zhong-Yin2017-06-132017-06-132015-12-10He, R., Yu, Z.-H., Zhang, R.-Y., Wu, L., Gunawan, A. M., & Zhang, Z.-Y. (2015). Cefsulodin Inspired Potent and Selective Inhibitors of mPTPB, a Virulent Phosphatase from Mycobacterium tuberculosis. ACS Medicinal Chemistry Letters, 6(12), 1231–1235. http://doi.org/10.1021/acsmedchemlett.5b00373https://hdl.handle.net/1805/12997mPTPB 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.en-USPublisher PolicyProtein tyrosine phosphataseAntituberculosismPTPB inhibitorpTyr mimeticsArticle