Selective inhibition of Human Immunodeficiency Virus type 1 (HIV-1) by a novel family of tricyclic nucleosides

Nucleoside 1, with an unusual tricyclic carbohydrate moiety, specifically inhibits HIV-1 replication while being inactive against HIV-2 or other (retro) viruses. In an attempt to increase the inhibitory efficacy against HIV-1, and to further explore the structural features required for anti-HIV-1 ac...

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Authors: Bonache, María-Cruz, Cordeiro, Alessandra, Quesada, Ernesto, Vanstreels, Els, Daelemans, Dirk, Camarasa Rius, María José, Balzarini, Jan, San-Félix, Ana
Format: article
Status:Versión aceptada para publicación
Publication Date:2011
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/97083
Online Access:http://hdl.handle.net/10261/97083
Access Level:Open access
Keyword:Antiviral agents
AIDS
HIV-1 reverse transcriptase inhibitors
Nucleosides
Carbohydrates
Glycosylation
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spelling Selective inhibition of Human Immunodeficiency Virus type 1 (HIV-1) by a novel family of tricyclic nucleosidesBonache, María-CruzCordeiro, AlessandraQuesada, ErnestoVanstreels, ElsDaelemans, DirkCamarasa Rius, María JoséBalzarini, JanSan-Félix, AnaAntiviral agentsAIDSHIV-1 reverse transcriptase inhibitorsNucleosidesCarbohydratesGlycosylationNucleoside 1, with an unusual tricyclic carbohydrate moiety, specifically inhibits HIV-1 replication while being inactive against HIV-2 or other (retro) viruses. In an attempt to increase the inhibitory efficacy against HIV-1, and to further explore the structural features required for anti-HIV-1 activity, different types of modifications have been carried out on this prototype compound. These include substitution of the ethoxy group at the C-400 position by alkoxy groups of different length, branching, conformational freedom or functionalization. In addition, the 400-ethoxy group has been removed or substituted by other functional groups. The role of the tert-butyldimethylsilyl (TBDMS) group at the 20 position has also been studied by preparing the corresponding 20-deprotected derivative or by replacing it by other silyl (terthexyldimethylsilyl) or acyl (acetyl) moieties. Finally, the thymine of the prototype compound has been replaced by N-3-methylthymine, uracil or thiophenyl. Some of these compounds were endowed with a 6- to 7-fold higher selectivity than the prototype 1. The tricyclic nucleosides here described represent a novel type of selective anti HIV-1 inhibitors, targeted at the HIV-1-encoded reverse transcriptase.We thank Susana Ruiz, Ann Absillis and Leen Ingels for excellent technical assistance. The Spanish MEC/MCINN (Project SAF 2009- 13914-C02-01), the Spanish CSIC (Project PIF 08-019-2) and the Concerted Research Actions of the K.U. Leuven (GOA 10/014) are also acknowledged for financial support. The Spanish CSIC (JAEDoc Program) and European Science Foundation (ESF) are also acknowledged for a JAE-Doc contract to M.-C. Bonache.Peer reviewedElsevierMinisterio de Ciencia e Innovación (España)University of LeuvenConsejo Superior de Investigaciones Científicas (España)European Science Foundation2011info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Postprintinfo:eu-repo/semantics/acceptedVersionhttp://hdl.handle.net/10261/97083reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.1016/j.antiviral.2011.05.002info:eu-repo/semantics/openAccessoai:digital.csic.es:10261/970832026-05-22T06:33:51Z
dc.title.none.fl_str_mv Selective inhibition of Human Immunodeficiency Virus type 1 (HIV-1) by a novel family of tricyclic nucleosides
title Selective inhibition of Human Immunodeficiency Virus type 1 (HIV-1) by a novel family of tricyclic nucleosides
spellingShingle Selective inhibition of Human Immunodeficiency Virus type 1 (HIV-1) by a novel family of tricyclic nucleosides
Bonache, María-Cruz
Antiviral agents
AIDS
HIV-1 reverse transcriptase inhibitors
Nucleosides
Carbohydrates
Glycosylation
title_short Selective inhibition of Human Immunodeficiency Virus type 1 (HIV-1) by a novel family of tricyclic nucleosides
title_full Selective inhibition of Human Immunodeficiency Virus type 1 (HIV-1) by a novel family of tricyclic nucleosides
title_fullStr Selective inhibition of Human Immunodeficiency Virus type 1 (HIV-1) by a novel family of tricyclic nucleosides
title_full_unstemmed Selective inhibition of Human Immunodeficiency Virus type 1 (HIV-1) by a novel family of tricyclic nucleosides
title_sort Selective inhibition of Human Immunodeficiency Virus type 1 (HIV-1) by a novel family of tricyclic nucleosides
dc.creator.none.fl_str_mv Bonache, María-Cruz
Cordeiro, Alessandra
Quesada, Ernesto
Vanstreels, Els
Daelemans, Dirk
Camarasa Rius, María José
Balzarini, Jan
San-Félix, Ana
author Bonache, María-Cruz
author_facet Bonache, María-Cruz
Cordeiro, Alessandra
Quesada, Ernesto
Vanstreels, Els
Daelemans, Dirk
Camarasa Rius, María José
Balzarini, Jan
San-Félix, Ana
author_role author
author2 Cordeiro, Alessandra
Quesada, Ernesto
Vanstreels, Els
Daelemans, Dirk
Camarasa Rius, María José
Balzarini, Jan
San-Félix, Ana
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia e Innovación (España)
University of Leuven
Consejo Superior de Investigaciones Científicas (España)
European Science Foundation
dc.subject.none.fl_str_mv Antiviral agents
AIDS
HIV-1 reverse transcriptase inhibitors
Nucleosides
Carbohydrates
Glycosylation
topic Antiviral agents
AIDS
HIV-1 reverse transcriptase inhibitors
Nucleosides
Carbohydrates
Glycosylation
description Nucleoside 1, with an unusual tricyclic carbohydrate moiety, specifically inhibits HIV-1 replication while being inactive against HIV-2 or other (retro) viruses. In an attempt to increase the inhibitory efficacy against HIV-1, and to further explore the structural features required for anti-HIV-1 activity, different types of modifications have been carried out on this prototype compound. These include substitution of the ethoxy group at the C-400 position by alkoxy groups of different length, branching, conformational freedom or functionalization. In addition, the 400-ethoxy group has been removed or substituted by other functional groups. The role of the tert-butyldimethylsilyl (TBDMS) group at the 20 position has also been studied by preparing the corresponding 20-deprotected derivative or by replacing it by other silyl (terthexyldimethylsilyl) or acyl (acetyl) moieties. Finally, the thymine of the prototype compound has been replaced by N-3-methylthymine, uracil or thiophenyl. Some of these compounds were endowed with a 6- to 7-fold higher selectivity than the prototype 1. The tricyclic nucleosides here described represent a novel type of selective anti HIV-1 inhibitors, targeted at the HIV-1-encoded reverse transcriptase.
publishDate 2011
dc.date.none.fl_str_mv 2011
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Postprint
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/97083
url http://hdl.handle.net/10261/97083
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.1016/j.antiviral.2011.05.002
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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