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Results for “oligonucleotide conjugates”

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PubMed1990

The synthesis of polyamide-oligonucleotide conjugate molecules.

We have developed methods for the synthesis of peptide-oligodeoxyribonucleotide conjugate molecules in particular, and polyamide-oligonucleotide conjugates in general. Synthesis is carried out by a solid-phase procedure and involves the assembly of a polyamide on the solid support, conversion of the terminal amino group to a protected primary aliphatic hydroxy group by reaction with alpha, omega-hydroxycarboxylic acid derivatives, and finally oligonucleotide synthesis using phosphoramidite chemistry. The conjugate molecules can be used as DNA probes, with the polyamide component carrying one or more non-radioactive markers. These conjugates also have the potential to be used as anti-sense inhibitors of gene expression, with the peptide segment acting as a targeting moiety.

Amino Acid Sequence↗
PubMed1997

Sequence-specific cleavage of yeast tRNA(Phe) with oligonucleotides conjugated to a diimidazole construct.

Oligonucleotide derivatives conjugated to a chemical construction with two histamine residues imitating the catalytic center of ribonuclease A have been synthesized. In experiments with the conjugates complementary to the 3'-end and to the variable loop and the T loop of yeast tRNA(Phe), it was shown that the compounds can accomplish sequence-specific cleavage of the target RNA in physiologic conditions.

Base Sequence↗
PubMed2004

Oxidative DNA cleavage by free and oligonucleotide-conjugated O-bromobenzoic acid in the presence of copper(II) ions.

o-Bromobenzoic acid was found to promote copper-dependent reactive oxygen species formation from molecular oxygen, resulting in DNA base modification and backbone cleavage. The oligonucleotide conjugate bearing 5-(4'-aminopropyl-sulfomoyl)-2-bromobenzoic acid as a reactive group was synthesized and DNA cleavage activity of this oligonucleotide conjugate was tested on a model deoxyoligonucleotide.

Base Sequence↗
PubMed2006

Diels-Alder cycloadditions in water for the straightforward preparation of peptide-oligonucleotide conjugates.

The Diels-Alder reaction between diene-modified oligonucleotides and maleimide-derivatized peptides afforded peptide-oligonucleotide conjugates with high purity and yield. Synthesis of the reagents was easily accomplished by on-column derivatization of the corresponding peptides and oligonucleotides. The cycloaddition reaction was carried out in mild conditions, in aqueous solution at 37 degrees C. The speed of the reaction was found to vary depending on the size of the reagents, but it can be completed in 8-10 h by reacting the diene-oligonucleotide with a small excess of maleimide-peptide.

Amino Acid Sequence↗
PubMedDate not supplied

Design and simple routes of synthesis of oligonucleotide conjugates for studies of DNA triple helix formation.

A series of oligonucleotides conjugated to intercalators, as well as fluorescent and lipophilic substances, minor groove binders and photoactive molecules were synthesized for studies of their ability to form a stable triple helix. Purine-rich short double stranded DNA fragments from HIV-1 genome and pyrimidine 16-mer oligodeoxyribonucleotide were used as models. A conjugate of a dipyrido[3,2-a:2',3'-c]phenazine-ruthenium (II) complex and a triple helix-forming oligonucleotide was constructed. Upon sequence-specific duplex and triplex formation of the conjugate, the ruthenium complex becomes highly fluorescent. The attached ruthenium complex induces a stabilization of the DNA triple helix and a significant increase of the time of residence of the third strand on the duplex.

DNA↗
PubMed2005

Preparation of a multitopic glycopeptide-oligonucleotide conjugate.

[structure: see text] A novel strategy to prepare glycopeptide-oligonucleotide conjugates bearing a glycocluster is reported. The strategy utilizes a cyclodecapeptide scaffold as a key intermediate to anchor the carbohydrate cluster and the oligonucleotide through sequential oxime bond formation. The oligonucleotide glycocluster retains the binding affinity and recognition specificity for the target sequence. Furthermore, the conjugate shows enhanced binding to the specific lectins due to the cooperative effect produced by the carbohydrate cluster.

Arachis↗
PubMed1995

Evaluation of the specificity of alkaline phosphatase-conjugated oligonucleotide probes for forensic DNA analysis.

Current methods of forensic DNA profiling by restriction fragment length polymorphism analysis rely on radioactive detection of DNA. The use of radioactive isotopes is complicated, expensive and requires elaborate safety precautions. Recently, non-radioactive detection methods involving the use of alkaline phosphatase-conjugated oligonucleotide probes have become available. These probes differ from most 32P-labeled probes in that they are synthetic oligonucleotides, whereas the 32P-labeled probes are purified plasmid inserts from cloned VNTR regions. Because of this difference, it is possible that the specificity of the non-isotopic probe will differ from that of the 32P-labeled probe. This study compares the specificity of the two types of probes by parallel analysis of a set of DNA samples, including a subset of relatively small alleles, at the loci D1S7, D2S44, D4S139, D10S28, and D17S26. We found that although the alkaline phosphatase detection method is slightly less sensitive than 32P detection, the AP-conjugated oligonucleotide probes tested have specificity comparable to, and are appropriate and suitable substitutes for, 32P-labeled plasmid inserts.

Alkaline Phosphatase↗
PubMed2026

Dual recognition drives site-directed G-quadruplex stabilization: Oligonucleotide design in G4 ligand-oligonucleotide conjugates.

G-quadruplex (G4) DNA structures are increasingly recognized for their roles in transcriptional regulation and genome stability, making them attractive therapeutic targets. Selective recognition of individual G4s remains challenging due to the high structural similarity among G4 motifs. G4 Ligand-Oligonucleotides conjugates (GL-Os) address this challenge by combining small-molecule G4 ligands with the sequence specificity of oligonucleotides, targeting sequences flanking the intended G4 target. Here, we systematically investigate how oligonucleotide length, backbone composition, and sequence complementarity govern GL-O binding, selectivity, and G4 stabilization. We show that effective G4 recognition depends on the interdependence between oligonucleotide hybridization and G4 ligand binding, such that both elements cooperatively reinforce complex stability and site specificity. Longer oligonucleotides promote more stable complexes and stronger G4 stabilization, whereas central mismatches disrupt this dual-recognition mechanism. Replacement of DNA with peptide nucleic acids (PNAs) enhances binding strength, thermal stability, and metabolic stability. Importantly, ligand conjugation redirects PNA oligonucleotides from nonspecific polymerase stalling toward selective G4 stabilization. Finally, we demonstrate receptor-mediated cellular uptake of modified GL-Os, supporting the feasibility of cellular delivery while highlighting remaining delivery barriers. Together, these findings show the molecular design principles governing GL-O behavior and provide a foundation for the future development and evaluation of selective G4-targeting therapeutics.

G-quadruplex DNA↗
PubMed1992

Sequence-specific cleavage of single-stranded DNA by oligonucleotides conjugated to bleomycin.

Cleavage of a single-stranded DNA fragment by complementary oligonucleotides conjugated to bleomycin A5 has been investigated. The conjugates efficiently cleave the DNA at the GT sequences near the oligonucleotide binding site. The temperature dependence of the reaction and the composition of the degradation products indicate that the oligonucleotide-linked bleomycin attacks the available double-stranded DNA regions within the oligonucleotide-DNA duplex and in the hairpin DNA region in the vicinity of the carrier oligonucleotide binding site.

Antibiotics, Antineoplastic↗
PubMed2001

Synthesis of peptide-oligonucleotide conjugates: application to basic peptides.

Efficient methods of synthesis of peptide-oligonucleotide conjugates are badly needed for studies of uptake into cells in culture. We describe improvements to the procedures involved in "native ligation" conjugation in solution to extend the method to basic peptides. Further, we describe progress in development of a total solid-phase synthesis approach that makes use of a L-homoserine linker as the key reagent for growing of oligonucleotide and peptide chains on a single solid support.

Amino Acid Sequence↗
PubMed2003

Spatial organization of topoisomerase I-mediated DNA cleavage induced by camptothecin-oligonucleotide conjugates.

Triple helix-forming oligonucleotides covalently linked to topoisomerase I inhibitors, in particular the antitumor agent camptothecin, trigger topoisomerase I-mediated DNA cleavage selectively in the proximity of the binding site of the oligonucleotide vector. In the present study, we have performed a systematic analysis of the DNA cleavage efficiency as a function of the positioning of the camptothecin derivative, either on the 3' or the 5' side of the triplex, and the location of the cleavage site. A previously identified cleavage site was inserted at different positions within two triplex site-containing 59 bp duplexes. Sequence-specific DNA cleavage by topoisomerase I occurs only with triplex conjugates bearing the inhibitor at the 3'-end of the oligonucleotide and on the oligopyrimidine strand of the duplex. The lack of targeted cleavage on the 5' side is attributed to the structural differences of the 3' and 5' duplex-triplex DNA junctions. The changes induced in the double helix by the triple-helical structure interfere with the action of the enzyme according to a preferred spatial organization. Camptothecin conjugates of oligonucleotides provide efficient tools to probe the organization of the topoisomerase I-DNA complex and will be useful to understand the functioning of topoisomerase I in living cells.

Base Sequence↗
PubMed1996

Structure/nuclease activity relationships of DNA cleavers based on cationic metalloporphyrin-oligonucleotide conjugates.

The covalent attachment of a managanese-tris(methylpyridiniumyl)porphyrin entity to an antisense oligonucleotide allowed sequence-selective oxidative cleavage of DNA when the metalloporphyrin was activated by potassium monopersulfate (KHSO5). We prepared several structurally modified metallo-porphyrin-oligonucleotide conjugates in order to find out the most efficient compound for in vitro DNA cleavage. The nature and the length of the tether were modulated, the metalloporphyrin entity was modified (metal, ligand), and different ways of activation of the metalloporphyrin were assayed. We noticed that the location of the peptidic bond within the linker could greatly affect the cleavage efficiency of the different conjugates. We showed that the most efficient conjugate for oxidative DNA cleavage was a manganese tetracationic porphyrin-oligonucleotide compound. When the metalloporphyrin moiety was activated by a reducing agent in the presence of molecular oxygen, DNA cleavage was efficient at suitable concentrations of the reducing agent, in order to avoid the reduction of the activated DNA cleaver, a putative high-valent metal-oxo species, by the excess of reducing agent.

Base Sequence↗
PubMed1997

Influence of the nature of the porphyrin ligand on the nuclease activity of metalloporphyrin-oligonucleotide conjugates designed with cationic, hydrophobic or anionic metalloporphyrins.

The synthesis of metalloporphyrin-oligonucleotide conjugates with different metalloporphyrin moieties are described as well as the comparison of their in vitro nuclease efficiency toward a single-stranded DNA target. Between cationic, anionic and hydrophobic manganese porphyrins covalently linked to the oligonucleotide, the best nuclease activity was obtained with the cationic ones, suggesting that the affinity of the cleaver to the DNA target is a key factor.

Anions↗
PubMed2004

New strategy for the synthesis of 3',5'-bifunctionalized oligonucleotide conjugates through sequential formation of chemoselective oxime bonds.

A convenient strategy for the synthesis of bifunctionalized oligonucleotide conjugates bearing two different reporters at the 3' and 5' ends of the oligonucleotide is presented. The method involves the preparation of oligonucleotides bearing an aldehyde and/or aminooxy functionality at each end, followed by reaction to form oxime bonds with appropriately functionalized reporters. The conjugation reactions are carried out under mild aqueous conditions with good reaction yield.

Aldehydes↗
PubMed1993

Inhibition of HIV proliferation in MT-4 cells by antisense oligonucleotide conjugated to lipophilic groups.

Anti-HIV activity of antisense oligonucleotide derivatives conjugated to lipophilic groups has been investigated. Aliphatic linear structures and cholesterol were coupled to the 5'-terminal phosphate of oligonucleotides via glycine or propylene diamine spacers. The oligonucleotides were targeted to a conserved sequence of the viral gene env, to a sequence in the negative sense viral RNA, to the 5'-terminus of the gene rev and to poly(A) sequences. The conjugation with lipophilic groups stimulated binding of oligonucleotides to cells and protected the oligonucleotides against cellular nucleases. The lipophilic derivatives of oligonucleotides containing an ester bond in the linker structure were cleaved by cellular esterases yielding oligonucleotides protected from 5'-nuclease degradation by the glycine residue. Antiviral activity of the derivatives exceeded that of the corresponding unmodified oligonucleotides. The virus suppression was sequence-specific and most pronounced in the case of the cholesteryl conjugated oligonucleotides.

Base Sequence↗
PubMedDate not supplied

A new "native ligation" procedure for peptide-oligonucleotide conjugation.

"Native ligation", a powerful method of joining peptide fragments, has been applied successfully to peptide-oligonucleotide conjugation. Novel reagents are described for the solid-phase synthesis of peptide N-terminal thioesters and 5'-cysteinyl oligonucleotides suitable for ligation reactions.

Cysteine↗