DNA repair inhibitors are one of the latest additions to cancer chemotherapy. In general, chemotherapy produces DNA damage but tumoral cells may become resistant if enzymes involved in DNA repair are overexpressed and are able to reverse DNA damage. One of the most successful drugs based on modulating DNA repair are the poly(ADP-ribose) polymerase 1 (PARP1) inhibitors. Several PARP1 inhibitors have been recently developed and approved for clinical treatments. We envisaged that PARP inhibition could be potentiated by simultaneously modulating the expression of PARP 1 and the enzyme activity, by a two-pronged strategy. A noncanonical G-quadruplex-forming sequence within the PARP1 promoter has been recently identified. In this study, we explored the potential binding of clinically approved PARP1 inhibitors to the G-quadruplex structure found at the gene promoter region. The results obtained by NMR, CD, and fluorescence titration confirmed by molecular modeling demonstrated that two out the four PARP1 inhibitors studied are capable of forming defined complexes with the PARP1 G-quadruplex. These results open the possibility of exploring the development of better G-quadruplex binders that, in turn, may also inhibit the enzyme.

Investigation of the complexes formed between parp1 inhibitors and parp1 g-quadruplex at the gene promoter region / S. Dallavalle, S. Princiotto, L.M. Mattio, R. Artali, L. Musso, A. Avino, R. Eritja, C. Pisano, R. Gargallo, S. Mazzini. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1661-6596. - 22:16(2021 Aug 14), pp. 8737.1-8737.13. [10.3390/ijms22168737]

Investigation of the complexes formed between parp1 inhibitors and parp1 g-quadruplex at the gene promoter region

Dallavalle S.;Princiotto S.;Mattio L. M.;Artali R.;Musso L.;Avino A.;Mazzini S.
2021-08-14

Abstract

DNA repair inhibitors are one of the latest additions to cancer chemotherapy. In general, chemotherapy produces DNA damage but tumoral cells may become resistant if enzymes involved in DNA repair are overexpressed and are able to reverse DNA damage. One of the most successful drugs based on modulating DNA repair are the poly(ADP-ribose) polymerase 1 (PARP1) inhibitors. Several PARP1 inhibitors have been recently developed and approved for clinical treatments. We envisaged that PARP inhibition could be potentiated by simultaneously modulating the expression of PARP 1 and the enzyme activity, by a two-pronged strategy. A noncanonical G-quadruplex-forming sequence within the PARP1 promoter has been recently identified. In this study, we explored the potential binding of clinically approved PARP1 inhibitors to the G-quadruplex structure found at the gene promoter region. The results obtained by NMR, CD, and fluorescence titration confirmed by molecular modeling demonstrated that two out the four PARP1 inhibitors studied are capable of forming defined complexes with the PARP1 G-quadruplex. These results open the possibility of exploring the development of better G-quadruplex binders that, in turn, may also inhibit the enzyme.
CD; Dual-targeting; Fluorescence titration; G-quadruplex; Molecular modeling; NMR spectroscopy; PARP1 inhibitors; PARP1 promoter;
Settore CHIM/06 - Chimica Organica
PSR2015-1716MPORR_M - PIANO DI SOSTEGNO ALLA RICERCA 2015-2017 - LINEA 2 "DOTAZIONE ANNUALE PER ATTIVITA' ISTITUZIONALE" - PORRINI, MARISA - PSR2015-17 - Piano di sviluppo di ricerca 2015-17 - 2016
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/865382
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