title: Iminodipropionic acid as the leaving group for DNA polymerization by HIV-1 reverse transcriptase.
abstract: Previous studies have demonstrated that some selected amino monoacids and amino diacids can function as leaving groups in the polymerase-catalyzed incorporation of deoxynucleotides into DNA. Among these, the iminodiacetic acid phosphoramidate of deoxyadenosine monophosphate (IDA-dAMP) represents an interesting example, as it could overcome some of the problems observed when using L-aspartic acid as the leaving group, that is, poor chain elongation. We have now synthesized and evaluated a series of IDA-dAMP analogues that bear either an extended aliphatic chain in the amino acid function, or a phosphonic acid moiety (substituting for the carboxylic acid function). Among these compounds, the nucleotide with an iminodipropionic acid leaving group (IDP-dAMP) was identified as the best substrate; the excellent single incorporation (91 % conversion to a P+1 strand at 50 μM) was at a substrate concentration ten times lower than that used for IDA-dAMP). This nucleotide also presented improved kinetics and elongation capability compared to IDA-dAMP. The analogues with T, G, and C base moieties were also investigated for their incorporation ability with HIV-1 RT. The incorporation efficiency was found to decrease in the order A>T>G>C. The properties of the iminodipropionic acid as the leaving group surpass those of previously evaluated leaving groups; this acid will be a prime candidate for in vivo testing.
authors.affiliation: Rega Institute, Laboratory of Medicinal Chemistry, Katholieke Universiteit Leuven, Minderbroederstraat 10, 3000 Leuven, Belgium.
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Song
authors.forename: Camille
authors.initials: C
authors.lastname: Bouillon
authors.forename: Eveline
authors.initials: E
authors.lastname: Lescrinier
authors.forename: Piet
authors.initials: P
authors.lastname: Herdewijn
mesh_terms: D000249:Adenosine Monophosphate / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D002474:Cell-Free System; D002855:Chromatography, Thin Layer; D004247:DNA / Q000737:chemistry; D017931:DNA Primers; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D015195:Drug Design; D005998:Glycine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007098:Imino Acids / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D018716:Molecular Mimicry / Q000235:genetics; D019384:Nucleic Acid Synthesis Inhibitors; D009711:Nucleotides / Q000138:chemical synthesis* / Q000494:pharmacology; D010756:Phosphoric Acids / Q000737:chemistry / Q000378:metabolism; D058105:Polymerization / Q000187:drug effects*; D011422:Propionates / Q000737:chemistry* / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D017931:DNA Primers; D007098:Imino Acids; D019384:Nucleic Acid Synthesis Inhibitors; D009711:Nucleotides; D010756:Phosphoric Acids; D011422:Propionates; D018894:Reverse Transcriptase Inhibitors; C549539:deoxyadenosine monophosphate iminodiacetic acid phosphoramidate; D000249:Adenosine Monophosphate; D004247:DNA; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D004259:DNA-Directed DNA Polymerase; C029658:propionic acid; D005998:Glycine