title: Phosphodiester substrates for incorporation of nucleotides in DNA using HIV-1 reverse transcriptase.
abstract: In previous research we demonstrated that some amino acid derivatives of deoxyadenosine 5'-O-monophosphate act as substrates for incorporation into DNA by HIV-1 reverse transcriptase while retaining the canonical base-pair selectivity for all natural bases. Thus, some amino acids mimic the pyrophosphate group in the polymerization process with this enzyme. Herein we extended this study to the evaluation of a range of potential new leaving groups with aromatic and aliphatic structures carrying one or two carboxylic acid functions. Out of this series, the isophthalic acid derivative of deoxyadenosine 5'-O-monophosphate gave single-nucleotide incorporation results similar to those obtained with the L-aspartic acid phosphoramidate of deoxyadenosine monophosphate. The glycolic acid analogue is a better substrate than the glycine congener, supporting the good leaving group properties of a phosphodiester linkage. These investigations provide new insight into the structural requirements for leaving groups that can mimic the pyrophosphate moiety of nucleoside triphosphates.
authors.affiliation: Catholic University Leuven, Faculty of Pharmaceutical Sciences, Rega Institute, Laboratory of Medicinal Chemistry, Minderbroederstraat 10, 3000 Leuven, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Giraut
authors.forename: Natalia
authors.initials: N
authors.lastname: Dyubankova
authors.forename: Xiao-ping
authors.initials: XP
authors.lastname: Song
authors.forename: Piet
authors.initials: P
authors.lastname: Herdewijn
mesh_terms: D000577:Amides / Q000737:chemistry / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D003838:Deoxyadenine Nucleotides / Q000737:chemistry / Q000378:metabolism; D054303:HIV Reverse Transcriptase / Q000378:metabolism*; D006801:Humans; D009711:Nucleotides / Q000378:metabolism*; D010756:Phosphoric Acids / Q000737:chemistry / Q000378:metabolism
chemical_list: D000577:Amides; D003838:Deoxyadenine Nucleotides; D009711:Nucleotides; D010756:Phosphoric Acids; C012873:2'-deoxy-5'-adenosine monophosphate; D004247:DNA; C011067:phosphoramidic acid; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase