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The Thienopyrimidine TP053 Prodrug Kills Mycobacterium Tuberculosis Cells by Nitric Oxide Release

43 Pages Posted: 7 Nov 2018 Publication Status: Review Complete

See all articles by Laurent R. Chiarelli

Laurent R. Chiarelli

University of Pavia - Department of Biology and Biotechnology

Marcello Manfredi

University of Piemonte Orientale - Department of Sciences and Technological Innovation; University of Piemonte Orientale, Department of Sciences and Technological Innovation, ISALIT

Elena Salina

Russian Academy of Sciences (RAS), Research Center of Biotechnology, Bach Institute of Biochemistry

Beatrice Silvia Orena

University of Pavia - Department of Biology and Biotechnology

Giorgio Mori

University of Pavia - Department of Biology and Biotechnology

Tatyana Azhikina

Russian Academy of Sciences (RAS) - Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry

Olga Riabova

Russian Academy of Sciences (RAS), Research Center of Biotechnology, Bach Institute of Biochemistry

Alexander Lepioshkin

Russian Academy of Sciences (RAS), Research Center of Biotechnology, Bach Institute of Biochemistry

Artyom Grigorov

Lomonosov Moscow State University

Martin Forbak

Comenius University - Department of Biochemistry

Jan Madacki

Comenius University - Department of Biochemistry

Fabio Gosetti

University of Piemonte Orientale - Department of Sciences and Technological Innovation

Arianna Buzzi

University of Piemonte Orientale - Department of Sciences and Technological Innovation

Giulia Degiacomi

University of Pavia - Department of Biology and Biotechnology

Katarína Mikušová

Comenius University - Department of Biochemistry

Jana Korduláková

Comenius University - Department of Biochemistry

Emilio Marengo

University of Piemonte Orientale - Department of Sciences and Technological Innovation

Giovanna Riccardi

University of Pavia - Department of Biology and Biotechnology

Vadim Makarov

Russian Academy of Sciences (RAS), Research Center of Biotechnology, Bach Institute of Biochemistry

Maria Rosalia Pasca

University of Pavia - Department of Biology and Biotechnology

More...

Abstract

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

Suggested Citation

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.

Laurent R. Chiarelli

University of Pavia - Department of Biology and Biotechnology

Corso Str. Nuova, 65, 27100
Pavia
Italy

Marcello Manfredi

University of Piemonte Orientale - Department of Sciences and Technological Innovation

Via del Duomo, 6
Vercelli
Italy

University of Piemonte Orientale, Department of Sciences and Technological Innovation, ISALIT

Novara
Italy

Elena Salina

Russian Academy of Sciences (RAS), Research Center of Biotechnology, Bach Institute of Biochemistry

Leninsky Ave, 14
Moscow
Russia

Beatrice Silvia Orena

University of Pavia - Department of Biology and Biotechnology

Corso Str. Nuova, 65, 27100
Pavia
Italy

Giorgio Mori

University of Pavia - Department of Biology and Biotechnology

Corso Str. Nuova, 65, 27100
Pavia
Italy

Tatyana Azhikina

Russian Academy of Sciences (RAS) - Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry

Moscow, 117997
Russia

Olga Riabova

Russian Academy of Sciences (RAS), Research Center of Biotechnology, Bach Institute of Biochemistry

Leninsky Ave, 14
Moscow
Russia

Alexander Lepioshkin

Russian Academy of Sciences (RAS), Research Center of Biotechnology, Bach Institute of Biochemistry

Leninsky Ave, 14
Moscow
Russia

Artyom Grigorov

Lomonosov Moscow State University

SP-1, Leninskie Gory
Moscow, 119991
Russia

Martin Forbak

Comenius University - Department of Biochemistry

SK-84215 Bratislava
Slovakia

Jan Madacki

Comenius University - Department of Biochemistry

SK-84215 Bratislava
Slovakia

Fabio Gosetti

University of Piemonte Orientale - Department of Sciences and Technological Innovation

Via del Duomo, 6
Vercelli
Italy

Arianna Buzzi

University of Piemonte Orientale - Department of Sciences and Technological Innovation

Via del Duomo, 6
Vercelli
Italy

Giulia Degiacomi

University of Pavia - Department of Biology and Biotechnology

Corso Str. Nuova, 65, 27100
Pavia
Italy

Katarína Mikušová

Comenius University - Department of Biochemistry

SK-84215 Bratislava
Slovakia

Jana Korduláková

Comenius University - Department of Biochemistry

SK-84215 Bratislava
Slovakia

Emilio Marengo

University of Piemonte Orientale - Department of Sciences and Technological Innovation

Via del Duomo, 6
Vercelli
Italy

Giovanna Riccardi

University of Pavia - Department of Biology and Biotechnology

Corso Str. Nuova, 65, 27100
Pavia
Italy

Vadim Makarov (Contact Author)

Russian Academy of Sciences (RAS), Research Center of Biotechnology, Bach Institute of Biochemistry ( email )

Leninsky Ave, 14
Moscow
Russia

Maria Rosalia Pasca

University of Pavia - Department of Biology and Biotechnology ( email )

Corso Str. Nuova, 65, 27100
Pavia
Italy

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