Abstract Title:

Naturally occurring Diels-Alder-type adducts from Morus nigra as potent inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase B.

Abstract Source:

Eur J Med Chem. 2018 Jan 20 ;144:277-288. Epub 2017 Dec 7. PMID: 29275228

Abstract Author(s):

Alessandra Mascarello, Angela Camila Orbem Menegatti, Andrea Calcaterra, Priscila Graziela Alves Martins, Louise Domeneghini Chiaradia-Delatorre, Ilaria D'Acquarica, Franco Ferrari, Valentina Pau, Adriana Sanna, Alessandro De Logu, Maurizio Botta, Bruno Botta, Hernán Terenzi, Mattia Mori

Article Affiliation:

Alessandra Mascarello


Mycobacterium tuberculosis (Mtb) protein tyrosine phosphatases A and B (PtpA and PtpB) have been recognized as potential molecular targets for the development of new therapeutic strategies against tuberculosis (TB). In this context, we have recently reported that the naturally occurring Diels-Alder-type adduct Kuwanol E is an inhibitor of PtpB (K = 1.6 ± 0.1 μM). Here, we describe additional Diels-Alder-type adducts isolated from Morus nigra roots bark that inhibit PtpB at sub-micromolar concentrations. The two most potent compounds, namely Kuwanon G and Kuwanon H, showed Kvalues of 0.39 ± 0.27 and 0.20 ± 0.01 μM, respectively, and interacted with the active site of the enzyme as suggested by kinetics and mass spectrometry studies. Molecular docking coupled with intrinsic fluorescence analysis and isothermal titration calorimetry (ITC) further characterized the interactionof these promising PtpB inhibitors. Notably, in an Mtb survival assay inside macrophages, Kuwanon G showed inhibition of Mtb growth by 61.3%. All these results point to the common Diels-Alder-type adduct scaffold, and highlight its relevance for the development of PtpB inhibitors as candidate therapeutics for TB.

Study Type : In Vitro Study

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