title: Cefsulodin Inspired Potent and Selective Inhibitors of mPTPB, a Virulent Phosphatase from Mycobacterium tuberculosis.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology and Chemical Genomics Core Facility, Indiana University School of Medicine , 635 Barnhill Drive, Indianapolis, Indiana 46202, United States.
authors.forename: Rongjun
authors.initials: R
authors.lastname: He
authors.affiliation: Department of Biochemistry and Molecular Biology and Chemical Genomics Core Facility, Indiana University School of Medicine , 635 Barnhill Drive, Indianapolis, Indiana 46202, United States.
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Yu
authors.affiliation: Department of Biochemistry and Molecular Biology and Chemical Genomics Core Facility, Indiana University School of Medicine , 635 Barnhill Drive, Indianapolis, Indiana 46202, United States.
authors.forename: Ruo-Yu
authors.initials: RY
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology and Chemical Genomics Core Facility, Indiana University School of Medicine , 635 Barnhill Drive, Indianapolis, Indiana 46202, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology and Chemical Genomics Core Facility, Indiana University School of Medicine , 635 Barnhill Drive, Indianapolis, Indiana 46202, United States.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Gunawan
authors.affiliation: Department of Biochemistry and Molecular Biology and Chemical Genomics Core Facility, Indiana University School of Medicine , 635 Barnhill Drive, Indianapolis, Indiana 46202, United States.
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
keywords: Protein tyrosine phosphatase; antituberculosis; mPTPB inhibitor; pTyr mimetics