Cargando…
Exploring the Interaction of G-quadruplex Binders with a (3 + 1) Hybrid G-quadruplex Forming Sequence within the PARP1 Gene Promoter Region
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...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9369712/ https://www.ncbi.nlm.nih.gov/pubmed/35897968 http://dx.doi.org/10.3390/molecules27154792 |
_version_ | 1784766553655345152 |
---|---|
author | Mazzini, Stefania Princiotto, Salvatore Artali, Roberto Musso, Loana Aviñó, Anna Eritja, Ramon Gargallo, Raimundo Dallavalle, Sabrina |
author_facet | Mazzini, Stefania Princiotto, Salvatore Artali, Roberto Musso, Loana Aviñó, Anna Eritja, Ramon Gargallo, Raimundo Dallavalle, Sabrina |
author_sort | Mazzini, Stefania |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9369712 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-93697122022-08-12 Exploring the Interaction of G-quadruplex Binders with a (3 + 1) Hybrid G-quadruplex Forming Sequence within the PARP1 Gene Promoter Region Mazzini, Stefania Princiotto, Salvatore Artali, Roberto Musso, Loana Aviñó, Anna Eritja, Ramon Gargallo, Raimundo Dallavalle, Sabrina Molecules Article 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. MDPI 2022-07-26 /pmc/articles/PMC9369712/ /pubmed/35897968 http://dx.doi.org/10.3390/molecules27154792 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Mazzini, Stefania Princiotto, Salvatore Artali, Roberto Musso, Loana Aviñó, Anna Eritja, Ramon Gargallo, Raimundo Dallavalle, Sabrina Exploring the Interaction of G-quadruplex Binders with a (3 + 1) Hybrid G-quadruplex Forming Sequence within the PARP1 Gene Promoter Region |
title | Exploring the Interaction of G-quadruplex Binders with a (3 + 1) Hybrid G-quadruplex Forming Sequence within the PARP1 Gene Promoter Region |
title_full | Exploring the Interaction of G-quadruplex Binders with a (3 + 1) Hybrid G-quadruplex Forming Sequence within the PARP1 Gene Promoter Region |
title_fullStr | Exploring the Interaction of G-quadruplex Binders with a (3 + 1) Hybrid G-quadruplex Forming Sequence within the PARP1 Gene Promoter Region |
title_full_unstemmed | Exploring the Interaction of G-quadruplex Binders with a (3 + 1) Hybrid G-quadruplex Forming Sequence within the PARP1 Gene Promoter Region |
title_short | Exploring the Interaction of G-quadruplex Binders with a (3 + 1) Hybrid G-quadruplex Forming Sequence within the PARP1 Gene Promoter Region |
title_sort | exploring the interaction of g-quadruplex binders with a (3 + 1) hybrid g-quadruplex forming sequence within the parp1 gene promoter region |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9369712/ https://www.ncbi.nlm.nih.gov/pubmed/35897968 http://dx.doi.org/10.3390/molecules27154792 |
work_keys_str_mv | AT mazzinistefania exploringtheinteractionofgquadruplexbinderswitha31hybridgquadruplexformingsequencewithintheparp1genepromoterregion AT princiottosalvatore exploringtheinteractionofgquadruplexbinderswitha31hybridgquadruplexformingsequencewithintheparp1genepromoterregion AT artaliroberto exploringtheinteractionofgquadruplexbinderswitha31hybridgquadruplexformingsequencewithintheparp1genepromoterregion AT mussoloana exploringtheinteractionofgquadruplexbinderswitha31hybridgquadruplexformingsequencewithintheparp1genepromoterregion AT avinoanna exploringtheinteractionofgquadruplexbinderswitha31hybridgquadruplexformingsequencewithintheparp1genepromoterregion AT eritjaramon exploringtheinteractionofgquadruplexbinderswitha31hybridgquadruplexformingsequencewithintheparp1genepromoterregion AT gargalloraimundo exploringtheinteractionofgquadruplexbinderswitha31hybridgquadruplexformingsequencewithintheparp1genepromoterregion AT dallavallesabrina exploringtheinteractionofgquadruplexbinderswitha31hybridgquadruplexformingsequencewithintheparp1genepromoterregion |