Synthesis and enzymatic incorporation of morpholino thymidine-5′-triphosphate in DNA fragments

Marciacq, Florence; Sauvaigo, Sylvie; Issartel, Jean-Paul; Mouret, Jean-François; Molko, D.

doi:10.1016/s0040-4039(99)00842-4

Cited by 20 publications

(10 citation statements)

References 13 publications

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“…DNA/RNA polymerases incorporate their natural substrates with high specificity and fidelity; however, different research groups have shown that polymerases can also accept a range of sugarmodified nucleotides as substrates. [10][11][12][13][14][15][16][17][18][19][20][21] Although LNA monomers structurally mimic RNA, they mediate high-affinity recognition of complementary RNA and DNA as constituents of either RNA or DNA strands. We therefore decided to study the enzymatic incorporation of LNA monomers into both RNA (transcription experiments) and DNA (primer extension assays) strands by using a variety of DNA/RNA polymerases.…”

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confidence: 99%

Enzymatic Incorporation of LNA Nucleotides into DNA Strands

2007

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confidence: 99%

Enzymatic Incorporation of LNA Nucleotides into DNA Strands

2007

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“…It was ear lier shown that the morpholinothymidine triphosphate derivative is a terminating substrate of the thermophilic Taq DNA polymerase and is specifically incorporated into positions complementary to adenine. This was asso ciated with termination of the further synthesis of the chain, i.e., this analog seemed to be a suitable substrate for creating a DNA sequencing set [13].…”

Section: Resultsmentioning

confidence: 99%

Analysis of interactions of DNA polymerase ? and reverse transcriptases of human immunodeficiency and mouse leukemia viruses with dNTP analogs containing a modified sugar residue

Лебедева

Seredina

Silnikov

et al. 2005

Biochemistry (Moscow)

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Substrate properties of various morpholinonucleoside triphosphates in the reaction of DNA elongation catalyzed by DNA polymerase beta, reverse transcriptase of human immunodeficiency virus (HIV-1 RT), and reverse transcriptase of Moloney murine leukemia virus (M-MuLV RT) were compared. Morpholinonucleoside triphosphates were utilized by DNA polymerase beta and HIV-1 reverse transcriptase as substrates, which terminated further synthesis of DNA, but were virtually not utilized by M-MuLV reverse transcriptase. The kinetic parameters of morpholinoderivatives of cytosine (MorC) and uridine (MorU) were determined in the reaction of primer elongation catalyzed by DNA polymerase beta and HIV-1 reverse transcriptase. MorC was a more effective substrate of HIV-1 reverse transcriptase and significantly less effective substrate of DNA polymerase beta than MorU. The possible use of morpholinonucleoside triphosphates as selective inhibitors of HIV-1 reverse transcriptase is discussed.

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“…Morpholino nucleosides are widely used for the synthesis of oligonucleotide mimetics [48]. However, there are only few examples of the utilization of morpholino nucleoside monomers or their phosphorylated derivatives for the goal of molecular biology and biochemistry [49,50]. In the present study we describe the synthesis, inhibition activity and the molecular modeling of the novel conjugates combining from ADP and morpholino nucleosides (morpholino nucleoside adenine dinucleotides, MorXppA), where morpholino nucleosides mimic the nicotinamide riboside fragment of the NAD+ molecule ( Figure 2).…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Molecular Modeling Study of Conjugates of ADP and Morpholino Nucleosides as A Novel Class of Inhibitors of PARP-1, PARP-2 and PARP-3

Sherstyuk

Ivanisenko

Zakharenko

et al. 2019

IJMS

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We report on the design, synthesis and molecular modeling study of conjugates of adenosine diphosphate (ADP) and morpholino nucleosides as potential selective inhibitors of poly(ADP-ribose)polymerases-1, 2 and 3. Sixteen dinucleoside pyrophosphates containing natural heterocyclic bases as well as 5-haloganeted pyrimidines, and mimicking a main substrate of these enzymes, nicotinamide adenine dinucleotide (NAD+)-molecule, have been synthesized in a high yield. Morpholino nucleosides have been tethered to the β-phosphate of ADP via a phosphoester or phosphoramide bond. Screening of the inhibiting properties of these derivatives on the autopoly(ADP-ribosyl)ation of PARP-1 and PARP-2 has shown that the effect depends upon the type of nucleobase as well as on the linkage between ADP and morpholino nucleoside. The 5-iodination of uracil and the introduction of the P–N bond in NAD+-mimetics have shown to increase inhibition properties. Structural modeling suggested that the P–N bond can stabilize the pyrophosphate group in active conformation due to the formation of an intramolecular hydrogen bond. The most active NAD+ analog against PARP-1 contained 5-iodouracil 2ʹ-aminomethylmorpholino nucleoside with IC50 126 ± 6 μM, while in the case of PARP-2 it was adenine 2ʹ-aminomethylmorpholino nucleoside (IC50 63 ± 10 μM). In silico analysis revealed that thymine and uracil-based NAD+ analogs were recognized as the NAD+-analog that targets the nicotinamide binding site. On the contrary, the adenine 2ʹ-aminomethylmorpholino nucleoside-based NAD+ analogs were predicted to identify as PAR-analogs that target the acceptor binding site of PARP-2, representing a novel molecular mechanism for selective PARP inhibition. This discovery opens a new avenue for the rational design of PARP-1/2 specific inhibitors.

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Synthesis and enzymatic incorporation of morpholino thymidine-5′-triphosphate in DNA fragments

Cited by 20 publications

References 13 publications

Enzymatic Incorporation of LNA Nucleotides into DNA Strands

Enzymatic Incorporation of LNA Nucleotides into DNA Strands

Analysis of interactions of DNA polymerase ? and reverse transcriptases of human immunodeficiency and mouse leukemia viruses with dNTP analogs containing a modified sugar residue

Design, Synthesis and Molecular Modeling Study of Conjugates of ADP and Morpholino Nucleosides as A Novel Class of Inhibitors of PARP-1, PARP-2 and PARP-3

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