Improvement of the activity of the anti-HIV-1 integrase aptamer T30175 by introducing a modified thymidine into the loops

Abstract In this paper, we report our investigations on analogues of the anti-human immunodeficiency virus type 1 (HIV-1) integrase (IN) aptamer T30175 in which the individual thymidines forming the loops were replaced by 5-hydroxymethyl-2′-deoxyuridine residues (H). Circular dichroism, nuclear magn...

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Autores principales:	Antonella Virgilio, Teresa Amato, Luigi Petraccone, Francesca Esposito, Nicole Grandi, Enzo Tramontano, Raquel Romero, Shozeb Haider, Isabel Gomez-Monterrey, Ettore Novellino, Luciano Mayol, Veronica Esposito, Aldo Galeone
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a75cacdbf3dd4a539019f5c9a75a4920
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spelling	oai:doaj.org-article:a75cacdbf3dd4a539019f5c9a75a49202021-12-02T15:09:06ZImprovement of the activity of the anti-HIV-1 integrase aptamer T30175 by introducing a modified thymidine into the loops10.1038/s41598-018-25720-12045-2322https://doaj.org/article/a75cacdbf3dd4a539019f5c9a75a49202018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25720-1https://doaj.org/toc/2045-2322Abstract In this paper, we report our investigations on analogues of the anti-human immunodeficiency virus type 1 (HIV-1) integrase (IN) aptamer T30175 in which the individual thymidines forming the loops were replaced by 5-hydroxymethyl-2′-deoxyuridine residues (H). Circular dichroism, nuclear magnetic resonance and gel electrophoresis investigations clearly indicated that all the modified aptamers preserve the ability to form the original 5′-5′ end-stacked head-to-head dimeric G-quadruplex structure, in which each G-quadruplex adopts a parallel arrangement and is characterized by three G-tetrads, three propeller loops and one bulge-loop. All the modified aptamers were tested in an IN inhibition LEDGF-independent assay. While the modified aptamers INTB-H13 and INTB-H17 showed IC50 values comparable with that of the parent aptamer (INTB-nat), analogues INTB-H2, INTB-H5 and, to a lesser extent, INTB-H9 showed a higher ability to inhibit the HIV IN than the unmodified aptamer. Molecular modelling studies evaluating the aptamer/HIV IN interaction highlighted the ability of the modified thymidines to establish several contacts with the target protein. All the data point to the importance of loops in the aptamer/target interaction and suggest that the site-specific replacement of loop residues with commercially available analogues can be considered a straightforward strategy to improve the biological activities of several G-quadruplex aptamers.Antonella VirgilioTeresa AmatoLuigi PetracconeFrancesca EspositoNicole GrandiEnzo TramontanoRaquel RomeroShozeb HaiderIsabel Gomez-MonterreyEttore NovellinoLuciano MayolVeronica EspositoAldo GaleoneNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-9 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Antonella Virgilio Teresa Amato Luigi Petraccone Francesca Esposito Nicole Grandi Enzo Tramontano Raquel Romero Shozeb Haider Isabel Gomez-Monterrey Ettore Novellino Luciano Mayol Veronica Esposito Aldo Galeone Improvement of the activity of the anti-HIV-1 integrase aptamer T30175 by introducing a modified thymidine into the loops
description	Abstract In this paper, we report our investigations on analogues of the anti-human immunodeficiency virus type 1 (HIV-1) integrase (IN) aptamer T30175 in which the individual thymidines forming the loops were replaced by 5-hydroxymethyl-2′-deoxyuridine residues (H). Circular dichroism, nuclear magnetic resonance and gel electrophoresis investigations clearly indicated that all the modified aptamers preserve the ability to form the original 5′-5′ end-stacked head-to-head dimeric G-quadruplex structure, in which each G-quadruplex adopts a parallel arrangement and is characterized by three G-tetrads, three propeller loops and one bulge-loop. All the modified aptamers were tested in an IN inhibition LEDGF-independent assay. While the modified aptamers INTB-H13 and INTB-H17 showed IC50 values comparable with that of the parent aptamer (INTB-nat), analogues INTB-H2, INTB-H5 and, to a lesser extent, INTB-H9 showed a higher ability to inhibit the HIV IN than the unmodified aptamer. Molecular modelling studies evaluating the aptamer/HIV IN interaction highlighted the ability of the modified thymidines to establish several contacts with the target protein. All the data point to the importance of loops in the aptamer/target interaction and suggest that the site-specific replacement of loop residues with commercially available analogues can be considered a straightforward strategy to improve the biological activities of several G-quadruplex aptamers.
format	article
author	Antonella Virgilio Teresa Amato Luigi Petraccone Francesca Esposito Nicole Grandi Enzo Tramontano Raquel Romero Shozeb Haider Isabel Gomez-Monterrey Ettore Novellino Luciano Mayol Veronica Esposito Aldo Galeone
author_facet	Antonella Virgilio Teresa Amato Luigi Petraccone Francesca Esposito Nicole Grandi Enzo Tramontano Raquel Romero Shozeb Haider Isabel Gomez-Monterrey Ettore Novellino Luciano Mayol Veronica Esposito Aldo Galeone
author_sort	Antonella Virgilio
title	Improvement of the activity of the anti-HIV-1 integrase aptamer T30175 by introducing a modified thymidine into the loops
title_short	Improvement of the activity of the anti-HIV-1 integrase aptamer T30175 by introducing a modified thymidine into the loops
title_full	Improvement of the activity of the anti-HIV-1 integrase aptamer T30175 by introducing a modified thymidine into the loops
title_fullStr	Improvement of the activity of the anti-HIV-1 integrase aptamer T30175 by introducing a modified thymidine into the loops
title_full_unstemmed	Improvement of the activity of the anti-HIV-1 integrase aptamer T30175 by introducing a modified thymidine into the loops
title_sort	improvement of the activity of the anti-hiv-1 integrase aptamer t30175 by introducing a modified thymidine into the loops
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/a75cacdbf3dd4a539019f5c9a75a4920
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Improvement of the activity of the anti-HIV-1 integrase aptamer T30175 by introducing a modified thymidine into the loops

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