title: Discovery of Mycobacterium tuberculosis protein tyrosine phosphatase B (PtpB) inhibitors from natural products.
abstract: Protein tyrosine phosphatase B (PtpB) is one of the virulence factors secreted into the host cell by Mycobacterium tuberculosis. PtpB attenuates host immune defenses by interfering with signal transduction pathways in macrophages and, therefore, it is considered a promising target for the development of novel anti-tuberculosis drugs. Here we report the discovery of natural compound inhibitors of PtpB among an in house library of more than 800 natural substances by means of a multidisciplinary approach, mixing in silico screening with enzymatic and kinetics studies and MS assays. Six natural compounds proved to inhibit PtpB at low micromolar concentrations (< 30 µM) with Kuwanol E being the most potent with K i = 1.6 ± 0.1 µM. To the best of our knowledge, Kuwanol E is the most potent natural compound PtpB inhibitor reported so far, as well as it is the first non-peptidic PtpB inhibitor discovered from natural sources. Compounds herein identified may inspire the design of novel specific PtpB inhibitors.
authors.affiliation: Laboratório Estrutura e Atividade, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mascarello
authors.forename: Mattia
authors.initials: M
authors.lastname: Mori
authors.forename: Louise Domeneghini
authors.initials: LD
authors.lastname: Chiaradia-Delatorre
authors.forename: Angela Camila Orbem
authors.initials: AC
authors.lastname: Menegatti
authors.forename: Franco
authors.initials: F
authors.lastname: Delle Monache
authors.forename: Franco
authors.initials: F
authors.lastname: Ferrari
authors.forename: Rosendo Augusto
authors.initials: RA
authors.lastname: Yunes
authors.forename: Ricardo José
authors.initials: RJ
authors.lastname: Nunes
authors.forename: Hernán
authors.initials: H
authors.lastname: Terenzi
authors.forename: Bruno
authors.initials: B
authors.lastname: Botta
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D010449:Peptide Mapping; D011485:Protein Binding / Q000187:drug effects; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D059748:Proteolysis
chemical_list: D001426:Bacterial Proteins; D001688:Biological Products; D004791:Enzyme Inhibitors; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases