Nucleic acid recognition and antiviral activity of 1,4-substituted terphenyl compounds mimicking all faces of the HIV-1 Rev protein positively-charged α-helix

Abstract Small synthetic molecules mimicking the three-dimensional structure of α-helices may find applications as inhibitors of therapeutically relevant protein-protein and protein-nucleic acid interactions. However, the design and use of multi-facial helix mimetics remains in its infancy. Here we...

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Autores principales:	Cristina Medina-Trillo, Daniel M. Sedgwick, Lidia Herrera, Manuela Beltrán, Ángela Moreno, Pablo Barrio, Luis. M. Bedoya, José Alcamí, Santos Fustero, José Gallego
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bc755e05db704dcfa42be8ed46552b46
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spelling	oai:doaj.org-article:bc755e05db704dcfa42be8ed46552b462021-12-02T17:14:58ZNucleic acid recognition and antiviral activity of 1,4-substituted terphenyl compounds mimicking all faces of the HIV-1 Rev protein positively-charged α-helix10.1038/s41598-020-64120-22045-2322https://doaj.org/article/bc755e05db704dcfa42be8ed46552b462020-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-64120-2https://doaj.org/toc/2045-2322Abstract Small synthetic molecules mimicking the three-dimensional structure of α-helices may find applications as inhibitors of therapeutically relevant protein-protein and protein-nucleic acid interactions. However, the design and use of multi-facial helix mimetics remains in its infancy. Here we describe the synthesis and application of novel bilaterally substituted p-terphenyl compounds containing positively-charged aminoalkyl groups in relative 1,4 positions across the aromatic scaffold. These compounds were specifically designed to mimic all faces of the arginine-rich α-helix of the HIV-1 protein Rev, which forms deeply embedded RNA complexes and plays key roles in the virus replication cycle. Two of these molecules recognized the Rev site in the viral RNA and inhibited the formation of the RRE-Rev ribonucleoprotein complex, a currently unexploited target in HIV chemotherapy. Cellular assays revealed that the most active compounds blocked HIV-1 replication with little toxicity, and likely exerted this effect through a multi-target mechanism involving inhibition of viral LTR promoter-dependent transcription and Rev function. Further development of this scaffold may open new avenues for targeting nucleic acids and may complement current HIV therapies, none of which involve inhibitors interfering with the gene regulation processes of the virus.Cristina Medina-TrilloDaniel M. SedgwickLidia HerreraManuela BeltránÁngela MorenoPablo BarrioLuis. M. BedoyaJosé AlcamíSantos FusteroJosé GallegoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-14 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Cristina Medina-Trillo Daniel M. Sedgwick Lidia Herrera Manuela Beltrán Ángela Moreno Pablo Barrio Luis. M. Bedoya José Alcamí Santos Fustero José Gallego Nucleic acid recognition and antiviral activity of 1,4-substituted terphenyl compounds mimicking all faces of the HIV-1 Rev protein positively-charged α-helix
description	Abstract Small synthetic molecules mimicking the three-dimensional structure of α-helices may find applications as inhibitors of therapeutically relevant protein-protein and protein-nucleic acid interactions. However, the design and use of multi-facial helix mimetics remains in its infancy. Here we describe the synthesis and application of novel bilaterally substituted p-terphenyl compounds containing positively-charged aminoalkyl groups in relative 1,4 positions across the aromatic scaffold. These compounds were specifically designed to mimic all faces of the arginine-rich α-helix of the HIV-1 protein Rev, which forms deeply embedded RNA complexes and plays key roles in the virus replication cycle. Two of these molecules recognized the Rev site in the viral RNA and inhibited the formation of the RRE-Rev ribonucleoprotein complex, a currently unexploited target in HIV chemotherapy. Cellular assays revealed that the most active compounds blocked HIV-1 replication with little toxicity, and likely exerted this effect through a multi-target mechanism involving inhibition of viral LTR promoter-dependent transcription and Rev function. Further development of this scaffold may open new avenues for targeting nucleic acids and may complement current HIV therapies, none of which involve inhibitors interfering with the gene regulation processes of the virus.
format	article
author	Cristina Medina-Trillo Daniel M. Sedgwick Lidia Herrera Manuela Beltrán Ángela Moreno Pablo Barrio Luis. M. Bedoya José Alcamí Santos Fustero José Gallego
author_facet	Cristina Medina-Trillo Daniel M. Sedgwick Lidia Herrera Manuela Beltrán Ángela Moreno Pablo Barrio Luis. M. Bedoya José Alcamí Santos Fustero José Gallego
author_sort	Cristina Medina-Trillo
title	Nucleic acid recognition and antiviral activity of 1,4-substituted terphenyl compounds mimicking all faces of the HIV-1 Rev protein positively-charged α-helix
title_short	Nucleic acid recognition and antiviral activity of 1,4-substituted terphenyl compounds mimicking all faces of the HIV-1 Rev protein positively-charged α-helix
title_full	Nucleic acid recognition and antiviral activity of 1,4-substituted terphenyl compounds mimicking all faces of the HIV-1 Rev protein positively-charged α-helix
title_fullStr	Nucleic acid recognition and antiviral activity of 1,4-substituted terphenyl compounds mimicking all faces of the HIV-1 Rev protein positively-charged α-helix
title_full_unstemmed	Nucleic acid recognition and antiviral activity of 1,4-substituted terphenyl compounds mimicking all faces of the HIV-1 Rev protein positively-charged α-helix
title_sort	nucleic acid recognition and antiviral activity of 1,4-substituted terphenyl compounds mimicking all faces of the hiv-1 rev protein positively-charged α-helix
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/bc755e05db704dcfa42be8ed46552b46
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Nucleic acid recognition and antiviral activity of 1,4-substituted terphenyl compounds mimicking all faces of the HIV-1 Rev protein positively-charged α-helix

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