University of Piemonte Orientale - Department of Sciences and Technological Innovation; University of Piemonte Orientale, Department of Sciences and Technological Innovation, ISALIT
The thienopyrimidine TP053 is an antitubercular prodrug active against both replicating and non-replicating Mycobacterium tuberculosis cells. Its mechanism of activation involves the reduction of a NO2 group by the mycothiol-dependent reductase Mrx2, which has been hypothesized to be responsible for the toxic effects in M. tuberculosis cells. Similar mechanisms of action have been described for other antitubercular prodrugs containing a NO2 group, such as the nitroimidazoles. By a multidisciplinary approach, it has been demonstrated that the activation of TP053 is responsible for a global perturbation in the mycobacterial cells through the release of nitric oxide. Moreover, an active TP053 metabolite was isolated and characterized. This peculiar mechanism makes TP053 a very interesting prodrug for tuberculosis drug discovery also against non-replicating bacilli.
Keywords: thienopyrimidine, prodrug, Mycobacterium tuberculosis, nitric oxide, Mrx2, active metabolite
Chiarelli, Laurent R. and Manfredi, Marcello and Salina, Elena and Silvia Orena, Beatrice and Mori, Giorgio and Azhikina, Tatyana and Riabova, Olga and Lepioshkin, Alexander and Grigorov, Artyom and Forbak, Martin and Madacki, Jan and Gosetti, Fabio and Buzzi, Arianna and Degiacomi, Giulia and Mikušová, Katarína and Korduláková, Jana and Marengo, Emilio and Riccardi, Giovanna and Makarov, Vadim and Pasca, Maria Rosalia, The Thienopyrimidine TP053 Prodrug Kills Mycobacterium Tuberculosis Cells by Nitric Oxide Release (November 6, 2018). Available at SSRN: https://ssrn.com/abstract=3279413 or http://dx.doi.org/10.2139/ssrn.3279413
This version of the paper has not been formally peer reviewed.
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