G-quadruplex binding properties of a potent PARP-1 inhibitor derived from 7-azaindole-1-carboxamide

Abstract Poly ADP-ribose polymerases (PARP) are key proteins involved in DNA repair, maintenance as well as regulation of programmed cell death. For this reason they are important therapeutic targets for cancer treatment. Recent studies have revealed a close interplay between PARP1 recruitment and G...

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Autores principales:	Sabrina Dallavalle, Loana Musso, Roberto Artali, Anna Aviñó, Leonardo Scaglioni, Ramon Eritja, Raimundo Gargallo, Stefania Mazzini
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f7228d4c577546f6824be235df0c9bc6
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spelling	oai:doaj.org-article:f7228d4c577546f6824be235df0c9bc62021-12-02T12:11:12ZG-quadruplex binding properties of a potent PARP-1 inhibitor derived from 7-azaindole-1-carboxamide10.1038/s41598-021-83474-92045-2322https://doaj.org/article/f7228d4c577546f6824be235df0c9bc62021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83474-9https://doaj.org/toc/2045-2322Abstract Poly ADP-ribose polymerases (PARP) are key proteins involved in DNA repair, maintenance as well as regulation of programmed cell death. For this reason they are important therapeutic targets for cancer treatment. Recent studies have revealed a close interplay between PARP1 recruitment and G-quadruplex stabilization, showing that PARP enzymes are activated upon treatment with a G4 ligand. In this work the DNA binding properties of a PARP-1 inhibitor derived from 7-azaindole-1-carboxamide, (2-[6-(4-pyrrolidin-1-ylmethyl-phenyl)-pyrrolo[2,3-b]pyridin-1-yl]-acetamide, compound 1) with model duplex and quadruplex DNA oligomers were studied by NMR, CD, fluorescence and molecular modelling. We provide evidence that compound 1 is a strong G-quadruplex binder. In addition we provide molecular details of the interaction of compound 1 with two model G-quadruplex structures: the single repeat of human telomeres, d(TTAGGGT)4, and the c-MYC promoter Pu22 sequence. The formation of defined and strong complexes with G-quadruplex models suggests a dual G4 stabilization/PARP inhibition mechanism of action for compound 1 and provides the molecular bases of its therapeutic potential.Sabrina DallavalleLoana MussoRoberto ArtaliAnna AviñóLeonardo ScaglioniRamon EritjaRaimundo GargalloStefania MazziniNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sabrina Dallavalle Loana Musso Roberto Artali Anna Aviñó Leonardo Scaglioni Ramon Eritja Raimundo Gargallo Stefania Mazzini G-quadruplex binding properties of a potent PARP-1 inhibitor derived from 7-azaindole-1-carboxamide
description	Abstract Poly ADP-ribose polymerases (PARP) are key proteins involved in DNA repair, maintenance as well as regulation of programmed cell death. For this reason they are important therapeutic targets for cancer treatment. Recent studies have revealed a close interplay between PARP1 recruitment and G-quadruplex stabilization, showing that PARP enzymes are activated upon treatment with a G4 ligand. In this work the DNA binding properties of a PARP-1 inhibitor derived from 7-azaindole-1-carboxamide, (2-[6-(4-pyrrolidin-1-ylmethyl-phenyl)-pyrrolo[2,3-b]pyridin-1-yl]-acetamide, compound 1) with model duplex and quadruplex DNA oligomers were studied by NMR, CD, fluorescence and molecular modelling. We provide evidence that compound 1 is a strong G-quadruplex binder. In addition we provide molecular details of the interaction of compound 1 with two model G-quadruplex structures: the single repeat of human telomeres, d(TTAGGGT)4, and the c-MYC promoter Pu22 sequence. The formation of defined and strong complexes with G-quadruplex models suggests a dual G4 stabilization/PARP inhibition mechanism of action for compound 1 and provides the molecular bases of its therapeutic potential.
format	article
author	Sabrina Dallavalle Loana Musso Roberto Artali Anna Aviñó Leonardo Scaglioni Ramon Eritja Raimundo Gargallo Stefania Mazzini
author_facet	Sabrina Dallavalle Loana Musso Roberto Artali Anna Aviñó Leonardo Scaglioni Ramon Eritja Raimundo Gargallo Stefania Mazzini
author_sort	Sabrina Dallavalle
title	G-quadruplex binding properties of a potent PARP-1 inhibitor derived from 7-azaindole-1-carboxamide
title_short	G-quadruplex binding properties of a potent PARP-1 inhibitor derived from 7-azaindole-1-carboxamide
title_full	G-quadruplex binding properties of a potent PARP-1 inhibitor derived from 7-azaindole-1-carboxamide
title_fullStr	G-quadruplex binding properties of a potent PARP-1 inhibitor derived from 7-azaindole-1-carboxamide
title_full_unstemmed	G-quadruplex binding properties of a potent PARP-1 inhibitor derived from 7-azaindole-1-carboxamide
title_sort	g-quadruplex binding properties of a potent parp-1 inhibitor derived from 7-azaindole-1-carboxamide
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f7228d4c577546f6824be235df0c9bc6
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G-quadruplex binding properties of a potent PARP-1 inhibitor derived from 7-azaindole-1-carboxamide

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