8-Modified-2'-deoxyadenosine analogues induce delayed polymerization arrest during HIV-1 reverse transcription.

The occurrence of resistant viruses to any of the anti-HIV-1 compounds used in the current therapies against AIDS underlies the urge for the development of new drug targets and/or new drugs acting through novel mechanisms. While all anti-HIV-1 nucleoside analogues in clinical use and in clinical tri...

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Autores principales:	Valérie Vivet-Boudou, Catherine Isel, Marwan Sleiman, Redmond Smyth, Nouha Ben Gaied, Patrick Barhoum, Géraldine Laumond, Guillaume Bec, Matthias Götte, Johnson Mak, Anne-Marie Aubertin, Alain Burger, Roland Marquet
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d26822192f44480dba292f5d7d2298a6
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spelling	oai:doaj.org-article:d26822192f44480dba292f5d7d2298a62021-11-18T07:34:48Z8-Modified-2'-deoxyadenosine analogues induce delayed polymerization arrest during HIV-1 reverse transcription.1932-620310.1371/journal.pone.0027456https://doaj.org/article/d26822192f44480dba292f5d7d2298a62011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22087320/?tool=EBIhttps://doaj.org/toc/1932-6203The occurrence of resistant viruses to any of the anti-HIV-1 compounds used in the current therapies against AIDS underlies the urge for the development of new drug targets and/or new drugs acting through novel mechanisms. While all anti-HIV-1 nucleoside analogues in clinical use and in clinical trials rely on ribose modifications for activity, we designed nucleosides with a natural deoxyribose moiety and modifications of position 8 of the adenine base. Such modifications might induce a steric clash with helix αH in the thumb domain of the p66 subunit of HIV-1 RT at a distance from the catalytic site, causing delayed chain termination. Eleven new 2'-deoxyadenosine analogues modified on position 8 of the purine base were synthesized and tested in vitro and in cell-based assays. In this paper we demonstrate for the first time that chemical modifications on position 8 of 2'-deoxyadenosine induce delayed chain termination in vitro, and also inhibit DNA synthesis when incorporated in a DNA template strand. Furthermore, one of them had moderate anti-HIV-1 activity in cell-culture. Our results constitute a proof of concept indicating that modification on the base moiety of nucleosides can induce delayed polymerization arrest and inhibit HIV-1 replication.Valérie Vivet-BoudouCatherine IselMarwan SleimanRedmond SmythNouha Ben GaiedPatrick BarhoumGéraldine LaumondGuillaume BecMatthias GötteJohnson MakAnne-Marie AubertinAlain BurgerRoland MarquetPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 11, p e27456 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Valérie Vivet-Boudou Catherine Isel Marwan Sleiman Redmond Smyth Nouha Ben Gaied Patrick Barhoum Géraldine Laumond Guillaume Bec Matthias Götte Johnson Mak Anne-Marie Aubertin Alain Burger Roland Marquet 8-Modified-2'-deoxyadenosine analogues induce delayed polymerization arrest during HIV-1 reverse transcription.
description	The occurrence of resistant viruses to any of the anti-HIV-1 compounds used in the current therapies against AIDS underlies the urge for the development of new drug targets and/or new drugs acting through novel mechanisms. While all anti-HIV-1 nucleoside analogues in clinical use and in clinical trials rely on ribose modifications for activity, we designed nucleosides with a natural deoxyribose moiety and modifications of position 8 of the adenine base. Such modifications might induce a steric clash with helix αH in the thumb domain of the p66 subunit of HIV-1 RT at a distance from the catalytic site, causing delayed chain termination. Eleven new 2'-deoxyadenosine analogues modified on position 8 of the purine base were synthesized and tested in vitro and in cell-based assays. In this paper we demonstrate for the first time that chemical modifications on position 8 of 2'-deoxyadenosine induce delayed chain termination in vitro, and also inhibit DNA synthesis when incorporated in a DNA template strand. Furthermore, one of them had moderate anti-HIV-1 activity in cell-culture. Our results constitute a proof of concept indicating that modification on the base moiety of nucleosides can induce delayed polymerization arrest and inhibit HIV-1 replication.
format	article
author	Valérie Vivet-Boudou Catherine Isel Marwan Sleiman Redmond Smyth Nouha Ben Gaied Patrick Barhoum Géraldine Laumond Guillaume Bec Matthias Götte Johnson Mak Anne-Marie Aubertin Alain Burger Roland Marquet
author_facet	Valérie Vivet-Boudou Catherine Isel Marwan Sleiman Redmond Smyth Nouha Ben Gaied Patrick Barhoum Géraldine Laumond Guillaume Bec Matthias Götte Johnson Mak Anne-Marie Aubertin Alain Burger Roland Marquet
author_sort	Valérie Vivet-Boudou
title	8-Modified-2'-deoxyadenosine analogues induce delayed polymerization arrest during HIV-1 reverse transcription.
title_short	8-Modified-2'-deoxyadenosine analogues induce delayed polymerization arrest during HIV-1 reverse transcription.
title_full	8-Modified-2'-deoxyadenosine analogues induce delayed polymerization arrest during HIV-1 reverse transcription.
title_fullStr	8-Modified-2'-deoxyadenosine analogues induce delayed polymerization arrest during HIV-1 reverse transcription.
title_full_unstemmed	8-Modified-2'-deoxyadenosine analogues induce delayed polymerization arrest during HIV-1 reverse transcription.
title_sort	8-modified-2'-deoxyadenosine analogues induce delayed polymerization arrest during hiv-1 reverse transcription.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/d26822192f44480dba292f5d7d2298a6
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8-Modified-2'-deoxyadenosine analogues induce delayed polymerization arrest during HIV-1 reverse transcription.

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