The enzyme PARP1 is an attractive target for cancer therapy, as it is involved in DNA repair processes. Several PARP1 inhibitors have been approved for clinical treatments. However, the rapid outbreak of resistance is seriously threatening the efficacy of these compounds, and alternative strategies are required to selectively regulate PARP1 activity. A noncanonical G-quadruplex-forming sequence within the PARP1 promoter was recently identified. In this study, we explore the interaction of known G-quadruplex binders with the G-quadruplex structure found in the PARP gene promoter region. The results obtained by NMR, CD, and fluorescence titration, also confirmed by molecular modeling studies, demonstrate a variety of different binding modes with small stabilization of the G-quadruplex sequence located at the PARP1 promoter. Surprisingly, only pyridostatin produces a strong stabilization of the G-quadruplex-forming sequence. This evidence makes the identification of a proper (3+1) stabilizing ligand a challenging goal for further investigation.

Exploring the Interaction of G-quadruplex Binders with a (3 + 1) Hybrid G-quadruplex Forming Sequence within the PARP1 Gene Promoter Region / S. Mazzini, S. Princiotto, R. Artali, L. Musso, A. Avinò, R. Eritja, R. Gargallo, S. Dallavalle. - In: MOLECULES. - ISSN 1420-3049. - 27:15(2022 Jul 26), pp. 4792.1-4792.15. [10.3390/molecules27154792]

Exploring the Interaction of G-quadruplex Binders with a (3 + 1) Hybrid G-quadruplex Forming Sequence within the PARP1 Gene Promoter Region

S. Mazzini
Primo
;
S. Princiotto
Secondo
;
R. Artali;L. Musso;S. Dallavalle
Ultimo
2022

Abstract

The enzyme PARP1 is an attractive target for cancer therapy, as it is involved in DNA repair processes. Several PARP1 inhibitors have been approved for clinical treatments. However, the rapid outbreak of resistance is seriously threatening the efficacy of these compounds, and alternative strategies are required to selectively regulate PARP1 activity. A noncanonical G-quadruplex-forming sequence within the PARP1 promoter was recently identified. In this study, we explore the interaction of known G-quadruplex binders with the G-quadruplex structure found in the PARP gene promoter region. The results obtained by NMR, CD, and fluorescence titration, also confirmed by molecular modeling studies, demonstrate a variety of different binding modes with small stabilization of the G-quadruplex sequence located at the PARP1 promoter. Surprisingly, only pyridostatin produces a strong stabilization of the G-quadruplex-forming sequence. This evidence makes the identification of a proper (3+1) stabilizing ligand a challenging goal for further investigation.
G-quadruplex; NMR; PARP1 promoter; circular dichroism; fluorescence; molecular modeling; stabilizing ligand; Circular Dichroism; DNA Repair; Ligands; Promoter Regions, Genetic; G-Quadruplexes
Settore CHIM/06 - Chimica Organica
PRIN201719SDALL_01 - Exploiting synergy in molecular targeted anticancer chemotherapy: synthesis, optimization, mechanism of action determination and biological validation in cellular and animal models of novel molecules targeting convergent metabolic pathways in cancer - DALLAVALLE, SABRINA MARIA DONATELLA - PRIN2017 - PRIN bando 2017 - 2019
PSRL220PCORT_01 - Piano di Sostegno alla Ricerca 2015-2017 - Linea 2 "Dotazione annuale per attività istituzionali" (anno 2020) - CORTESI, PAOLO - PSR_LINEA2_ / Piano di sviluppo di ricerca - Dotazioni dipartimentali - Linea 2 - 2020
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/937427
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