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 (Ki = 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 Ki values 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 interaction of 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.

Naturally occurring Diels-Alder-type adducts from Morus nigra as potent inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase B / Mascarello, Alessandra; Orbem Menegatti, Angela Camila; Calcaterra, Andrea; Martins, Priscila Graziela Alves; Chiaradia-Delatorre, Louise Domeneghini; D'Acquarica, Ilaria; Ferrari, Franco; Pau, Valentina; Sanna, Adriana; De Logu, Alessandro; Botta, Maurizio; Botta, Bruno; Terenzi, Hernã¡n; Mori, Mattia. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - ELETTRONICO. - 144:(2018), pp. 277-288. [10.1016/j.ejmech.2017.11.087]

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

Calcaterra, Andrea;D'Acquarica, Ilaria;FERRARI, FRANCO;Botta, Bruno;
2018

Abstract

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 (Ki = 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 Ki values 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 interaction of 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.
diels-alder-type adducts; kuwanones; natural products; PtpB inhibitors; tuberculosis; pharmacology; drug discovery; pharmaceutical science; organic chemistry
01 Pubblicazione su rivista::01a Articolo in rivista
Naturally occurring Diels-Alder-type adducts from Morus nigra as potent inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase B / Mascarello, Alessandra; Orbem Menegatti, Angela Camila; Calcaterra, Andrea; Martins, Priscila Graziela Alves; Chiaradia-Delatorre, Louise Domeneghini; D'Acquarica, Ilaria; Ferrari, Franco; Pau, Valentina; Sanna, Adriana; De Logu, Alessandro; Botta, Maurizio; Botta, Bruno; Terenzi, Hernã¡n; Mori, Mattia. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - ELETTRONICO. - 144:(2018), pp. 277-288. [10.1016/j.ejmech.2017.11.087]
File allegati a questo prodotto
File Dimensione Formato  
Mascarello_Naturally_2018.pdf

solo gestori archivio

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 1.91 MB
Formato Adobe PDF
1.91 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1051243
Citazioni
  • ???jsp.display-item.citation.pmc??? 7
  • Scopus 26
  • ???jsp.display-item.citation.isi??? 22
social impact