Cefsulodin Inspired Potent and Selective Inhibitors of mPTPB, a Virulent Phosphatase from Mycobacterium tuberculosis
dc.contributor.author | He, Rongjun | |
dc.contributor.author | Yu, Zhi-Hong | |
dc.contributor.author | Zhang, Ruo-Yu | |
dc.contributor.author | Wu, Li | |
dc.contributor.author | Gunawan, Andrea M. | |
dc.contributor.author | Zhang, Zhong-Yin | |
dc.contributor.department | Department of Biochemistry & Molecular Biology, IU School of Medicine | en_US |
dc.date.accessioned | 2017-06-13T19:12:44Z | |
dc.date.available | 2017-06-13T19:12:44Z | |
dc.date.issued | 2015-12-10 | |
dc.description.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. | en_US |
dc.identifier.citation | He, 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.5b00373 | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/12997 | |
dc.language.iso | en_US | en_US |
dc.publisher | ACS Publications | en_US |
dc.relation.isversionof | 10.1021/acsmedchemlett.5b00373 | en_US |
dc.relation.journal | ACS Medicinal Chemistry Letters | en_US |
dc.rights | Publisher Policy | en_US |
dc.source | PMC | en_US |
dc.subject | Protein tyrosine phosphatase | en_US |
dc.subject | Antituberculosis | en_US |
dc.subject | mPTPB inhibitor | en_US |
dc.subject | pTyr mimetics | en_US |
dc.title | Cefsulodin Inspired Potent and Selective Inhibitors of mPTPB, a Virulent Phosphatase from Mycobacterium tuberculosis | en_US |
dc.type | Article | en_US |
ul.alternative.fulltext | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677373/ | en_US |
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