8-modified-2'-deoxyadenosine analogues induce delayed polymerization arrest during HIV-1 reverse transcription
Data(s) |
07/11/2011
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Resumo |
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.<br /> |
Identificador | |
Idioma(s) |
eng |
Publicador |
Public Library of Science |
Relação |
http://dro.deakin.edu.au/eserv/DU:30047592/mak-8modified-2011.pdf http://dx.doi.org/10.1371/journal.pone.0027456 |
Direitos |
2011, Public Library of Science |
Palavras-Chave | #cell line #deoxyadenosines #drug design #HIV reverse transcriptase #HIV-1 #humans #structure-activity relationship #virus replication |
Tipo |
Journal Article |