The synthesis of peptide-oligonucleotide conjugates by a fragment coupling approach

Peyrottes, Suzanne; Mestre, Béatrice; Burlina, Fabienne; Gait, Michael J.

doi:10.1016/s0040-4020(98)00731-5

Cited by 40 publications

(36 citation statements)

References 34 publications

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“…anchoring the 2Ј-deoxyguanosine moiety on the solid support and then coupling a 9 15 equiv. Aa ϩ 15 equiv.…”

Section: Resultsmentioning

confidence: 99%

“…[28] For amino acid or peptide couplings to H 2 N-linker-oligonucleotide-resins, some authors have reported low or nonreproducible yields. [9] Other authors have not described any particular problems in relation to the stepwise elongation of a peptide on an oligonucleotideϪresin using Fmoc-amino acids, [3] whereas others have encountered more difficulties in the coupling of the first Fmoc-amino acid than in the subsequent couplings. [7] The latter result [7] would confirm the hypothesis that coupling yields to phosphate-unprotected oligonucleotide-resins may be superior to those of couplings to phosphate-protected oligonucleotide-resins, [9] but we have always had less difficulties in the first amino acid incorporation than in the subsequent ones.…”

Section: Resultsmentioning

confidence: 99%

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Alternative Procedures for the Synthesis of Methionine-Containing Peptide−Oligonucleotide Hybrids

et al. 2000

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The synthesis of methionine-containing peptide−oligonucleotide hybrids has been found to be best accomplished by a stepwise solid-phase approach in which peptide assembly using the sulfoxide derivative of methionine is followed by elongation of the oligonucleotide chain using the phosphite triester methodology, ammonia deprotection, and reduction of the sulfoxide to thioether by reaction with N-

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“…anchoring the 2Ј-deoxyguanosine moiety on the solid support and then coupling a 9 15 equiv. Aa ϩ 15 equiv.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Alternative Procedures for the Synthesis of Methionine-Containing Peptide−Oligonucleotide Hybrids

et al. 2000

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“…40 Other groups also prefer coupling reactions using deprotected phosphodiesters for related oligonucleotides. 41 The phosphodiester anions are kinetically more stable towards attack by nucleophiles than their phosphotriester precursors.…”

Section: Common Side Reactionsmentioning

confidence: 99%

Synthesis and Properties of Oligonucleotides with Acylamido Substituents

Richert¹,

Grünefeld²

2007

Synlett

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This account recounts how a project, initially designed to generate folded peptidyl-DNA motifs for cellular delivery, led to the discovery of acylamido substituents that increase affinity for target strands and improve mismatch discrimination of hybridization probes. Our syntheses of oligonucleotides with acylamido groups involve phosphoramidites of aminodideoxynucleosides as intermediates and amide-forming reactions on solid support, performed after assembly of the DNA chain. The richly functionalized intermediates invite a host of side reactions. Strategies to suppress these side reactions are discussed. In our quest for oligonucleotides with improved biophysical and biological properties we used late, onsupport combinatorial couplings to generate small chemical libraries subjected to mass-spectrometrically monitored selection experiments. The combinatorial approach was used to identify acylamido substituents at the termini that act as caps for DNA duplexes. Though truly bioavailable DNA derivatives were not found, oligonucleotides with a short dendrimer at the 5¢-terminus and a blocked 3¢-terminus were shown to possess improved enzymatic stability, while retaining high affinity for target strands. The on-support synthesis of acylamido DNA gives access to structurally diverse molecules with potential in biomedical applications, including the use in high-fidelity DNA microarrays. 1 Introduction 2 Synthesis of Acylamido-DNA and the Stability of Its Duplexes 2.1 Design and General Synthetic Aspects 2.2 Common Side Reactions 2.3 Combinatorial Syntheses 2.4 Oligodeoxynucleotide-Peptide Hybrids 2.5 Dendrimer-DNA Hybrids with Increased Nuclease Resistance 3 Oligonucleotides with Improved Duplex-Forming Properties 3.1 General Considerations 3.2 Oligodeoxynucleotides with Directly Linked Acylamido Substituents 3.3 Acylamido Caps with Linkers that Can Be Introduced as Phosphoramidites 3.4

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“…Commonly used nucleophilic groups include primary amines and thiols [7 ± 11]. For example, we reported a few years ago the solid-phase conjugation of small peptides to oligonucleotides that had been functionalized with an amino linker [12] [13]. Electrophilic groups have been introduced into synthetic oligonucleotides relatively rarely, for example, at the 2'-position [14] [15].…”

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confidence: 99%

“…Further conjugations of 5'-carboxylic acid-modified oligonucleotides I and II were carried out on solid phase in organic solvent. The choice of amine was influenced by the expected application for the conjugate; for example, affinity labelling (biotin-PEGamine (16)), fluorescent labelling (dansylcadaverine (15) and 1-pyrenemethylamine (18)), introduction of positive charge or nucleophile (spermine (12) and histamine (14)), addition of hydrophobicity (octadecylamine (13)) or chemical ligation [15] [16] (3-aminopropane-1,2-diol (17)). To obtain a high yield of structurally diverse types of conjugates ( Table 2), we used pre-activation of polymer-bound carboxylic oligonucleotide with HBTU/HOBT 1 : 1 at 358 in dry DMF for 35 min, followed by addition of the amine or short peptide solution in DMF and incubation for a further 1 h. An equimolar amount of Et 3 N was included also if the amine was present as its salt.…”

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confidence: 99%

A New and Efficient Method for Synthesis of 5′-Conjugates of Oligonucleotides through Amide-Bond Formation on Solid Phase

Kachalova

Stetsenko

Романова

et al. 2002

HCA

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Dedicated to Prof. Dr. Wolfgang Pfleiderer on the occasion of his 75th birthday An efficient method for synthesis of oligonucleotide 5'-conjugates through amide-bond formation on solid phase is described. Protected oligonucleotides containing a 5'-carboxylic acid function were obtained by use of a novel non-nucleosidic phosphoramidite building block, where the carboxylic acid moiety was protected by a 2-chlorotrityl group. The protecting group is stable to the phosphoramidite coupling conditions used in solid-phase oligonucleotide assembly, but is easily deprotected by mild acidic treatment. The protecting group may be removed also by ammonolysis. 5'-Carboxylate-modified oligonucleotides were efficiently conjugated on solid support under normal peptide-coupling conditions to various amines or to the N-termini of small peptides to yield products of high purity. The method is well-suited in principle for the synthesis of peptide-oligonucleotide conjugates containing an amide linkage between the 5'-end of an oligonucleotide and the N-terminus of a peptide.

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The synthesis of peptide-oligonucleotide conjugates by a fragment coupling approach

Cited by 40 publications

References 34 publications

Alternative Procedures for the Synthesis of Methionine-Containing Peptide−Oligonucleotide Hybrids

Alternative Procedures for the Synthesis of Methionine-Containing Peptide−Oligonucleotide Hybrids

Synthesis and Properties of Oligonucleotides with Acylamido Substituents

A New and Efficient Method for Synthesis of 5′-Conjugates of Oligonucleotides through Amide-Bond Formation on Solid Phase

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