Journal Article

Molecular basis for the enantioselectivity of HIV-1 reverse transcriptase: Role of the 3′-hydroxyl group of the L-(β)-ribose in chiral discrimination between D- and L-enantiomers of deoxy- and dideoxy-nucleoside triphosphate analogs

Giovanni Maga, Silvio Spadari, Mario Amacker, Ulrich Hübscher, Gilles Gosselin, Jean-Luis Imbach, Christophe Mathé, Abdesslem Faraj and Jean-Pierre Sommadossi

in Nucleic Acids Research

Volume 27, issue 4, pages 972-978
Published in print February 1999 | ISSN: 0305-1048
Published online February 1999 | e-ISSN: 1362-4962 | DOI: https://dx.doi.org/10.1093/nar/27.4.972
Molecular basis for the enantioselectivity of HIV-1 reverse transcriptase: Role of the 3′-hydroxyl group of the L-(β)-ribose in chiral discrimination between D- and L-enantiomers of deoxy- and dideoxy-nucleoside triphosphate analogs

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In order to identify the basis for the relaxed enantioselectivity 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 recombinant 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-(β)-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-(β)-dideoxynucleoside analogs with non-nucleoside RT inhibitors in anti-HIV chemotherapy, since non-nucleoside inhibitors resistance mutations did not confer crossresistance to dideoxynucleoside analogs.

Journal Article.  3918 words.  Illustrated.

Subjects: Chemistry ; Biochemistry ; Bioinformatics and Computational Biology ; Genetics and Genomics ; Molecular and Cell Biology

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