Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-786
Maga, G; Amacker, M; Hübscher, U; Gosselin, G; Imbach, J L; Mathé, C; Faraj, A; Sommadossi, J P; Spadari, S (1999). Molecular basis for the enantioselectivity of HIV-1 reverse transcriptase: role of the 3'-hydroxyl group of the L-(beta)-ribose in chiral discrimination between D- and L-enantiomers of deoxy- and dideoxy-nucleoside triphosphate analogs. Nucleic Acids Research, 27(4):972-978.
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In order to identify the basis for the relaxed enantio-selectivity of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) and to evaluate possible cross-resistance patterns between L-nucleoside-, D-nucleoside- and non-nucleoside RT inhibitors, to be utilised in anti-HIV-1 combination therapy, we applied an in vitro approach based on the utilisation of six recom-binant HIV-1 RT mutants containing single amino acid substitutions known to confer Nevirapine resistance in treated patients. The mutants were compared on different RNA/DNA and DNA/DNA substrates to the wild type (wt) enzyme for their sensitivity towards inhibition by the D- and L-enantiomers of 2'-deoxy- and 2',3'-dideoxynucleoside triphosphate analogs. The results showed that the 3'-hydroxyl group of the L-(beta)-2'-deoxyribose moiety caused an unfavourable steric hindrance with critic residues in the HIV-1 RT active site and this steric barrier was increased by the Y181I mutation. Elimination of the 3'-hydroxyl group removed this hindrance and significantly improved binding to the HIV-1 RT wt and to the mutants. These results demonstrate the critical role of both the tyrosine 181 of RT and the 3'-position of the sugar ring, in chiral discrimination between D- and L-nucleoside triphosphates. Moreover, they provide an important rationale for the combination of D- and L-(beta)-dideoxynucleoside analogs with non-nucleoside RT inhibitors in anti-HIV chemotherapy, since non-nucleosideinhibitors resistance mutations did not confer cross-resistance to dideoxynucleoside analogs.
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|Item Type:||Journal Article, refereed|
|Communities & Collections:||05 Vetsuisse Faculty > Institute of Veterinary Biochemistry and Molecular Biology|
|Dewey Decimal Classification:||570 Life sciences; biology|
|Date:||15 February 1999|
|Deposited On:||11 Feb 2008 12:18|
|Last Modified:||05 Apr 2016 12:15|
|Publisher:||Oxford University Press|
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