Synthesis of Peptide−Oligonucleotide Conjugates with Single and Multiple Peptides Attached to 2‘-Aldehydes through Thiazolidine, Oxime, and Hydrazine Linkages

Zatsepin, Timofei S.; Stetsenko, Dmitry A.; Arzumanov, Andrey A.; Романова, Е. А.; Gait, Michael J.; Oretskaya, Tatiana S.

doi:10.1021/bc020016+

Cited by 119 publications

(84 citation statements)

References 51 publications

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“…4b) rather than the gen eralized scheme of conservative contacts between NF κB dimer and the κB site 5′ GGGAMWTTCC 3′ is more applicable for further interpretation of affinity modifica tion data. Affinity modification of ε amino groups of Lys residues in a NF κB p50 homodimer was performed using modified DNAs, namely oligonucleotide duplexes containing aldehyde group in 2′ position of the sugar moiety [18,19,27]. The reaction product is a Schiff base which needs to be reduced into the secondary amine with NaBH 3 CN (Fig.…”

Section: Resultsmentioning

confidence: 99%

Analysis of DNA-Protein Interactions in Complexes of Transcription Factor NF-κB with DNA

Romanenkov

Ustyugov

Zatsepin

et al. 2005

Biochemistry (Moscow)

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We have applied bioinformatic analysis of X-ray 3D structures of complexes of transcription factor NF-kappaB with DNAs. We determined the number of possible Van der Waals contacts and hydrogen bonds between amino acid residues and nucleotides. Conservative contacts in the NF-kappaB dimer-DNA complex composed of p50 and/or p65 NF-kappaB subunit and DNA sequences like 5 -GGGAMWTTCC-3 were revealed. Based on these results, we propose a novel scheme for interactions between NF-kappaB p50 homodimer and the kappaB region of the immunoglobulin light chain gene enhancer (Ig-kappaB). We applied a chemical cross-linking technique to study the proximity of some Lys and Cys residues of NF-kappaB p50 subunit with certain reactive nucleotides into its recognition site. In all cases, the experimentally determined protein-DNA contacts were in good agreement with the predicted ones.

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Section: Resultsmentioning

confidence: 99%

Analysis of DNA-Protein Interactions in Complexes of Transcription Factor NF-κB with DNA

Romanenkov

Ustyugov

Zatsepin

et al. 2005

Biochemistry (Moscow)

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“…The reactiv ity of the aldehyde group in the arabinonucleoside is virtually identical to that of the aldehyde group in the ribonucleoside. 45 Duplexes based on modified oligo nucleotides can be used for affinity modification of DNA binding proteins because the introduction of 2´ O (2 oxoethyl)arabinouridine into the oligomer chain causes no essential changes in local structures of nucleic acids.…”

Section: Resultsmentioning

confidence: 99%

“…The peptide N aminooxyacetyl DPGYIGSR amide was synthesized according to a known procedure. 45 Thin layer chromatography was carried out on Kieselgel 60 F 254 plates (Merck, Germany). Column chromatography was performed on silica gel 33-70 (BDH, UK).…”

Section: Methodsmentioning

confidence: 99%

Synthesis and properties of oligodeoxyribonucleotides containing 2’-O-(2,3-dihydroxypropyl)- and 2’-O-(2-oxoethyl)arabinouridine residues

et al. 2005

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2´ O (2,3 Dihydroxypropyl)arabinouridine containing oligodeoxyribonucleotides were synthesized starting from a new modified nucleoside, viz., 2´ O (2,3 dihydroxypropyl)arabino uridine, and the corresponding 3´ phosphoramidite. Oxidation of these oligodeoxyribo nucleotides with sodium periodate afforded oligonucleotides containing 2´ O (2 oxo ethyl)arabinouridine residues. Subsequent modification of the aldehyde containing oligonucle otides involved the reactions with 9 hydrazinoacridine and N aminooxyacetyl peptide and reductive amination by 4 (1 pyrenyl)butyrohydrazide and biotin hydrazide. Thermal stabilities of duplexes of modified oligodeoxyribonucleotides with complementary oligodeoxyribo nucleotides are slightly lower than those of natural duplexes. Duplexes with complementary oligoribonucleotides are substantially destabilized.Oligonucleotides including modified oligonucleotides find wide application in various fields of molecular biol ogy. They are used as primers for DNA sequencing and amplification, for the determination of DNA primary structures by hybridization, and also as potential thera peutics. 2,3 In particular, modified oligonucleotides are employed for the preparation of conjugates with various compounds, such as peptides, oligosaccharides, and fluo rescent dyes for studying the behavior of nucleic acids in vitro or in vivo. Affinity modification of DNA binding proteins is used to study the structures and functioning of the active sites of the latter. 4,5Conjugation of fluorophores or electrochemically ac tive compounds to oligonucleotides enables the use of such derivatives in the design of DNA detection systems by hybridization. 6-8 Marker groups substantially increase sensitivity of DNA detection. Many conjugates of oligo nucleotides with peptides, carbohydrates, and lipophilic compounds more easily penetrate cell membranes than native nucleic acids, and this fact can be used in antisense and antigene biotechnology. 9-11Covalent attachment of proteins to nucleic acids is the method of choice for solving a series of problems. First and foremost, it allows identification of the amino acids interacting with particular regions of nucleic acids in nucleic acid-protein complexes. In studies of multi protein complexes formed during the replication, transla tion, etc., one can determine a protein component inter acting with a region of nucleic acid recognition 12 and examine cell extracts with the aim of revealing proteins that selectively interact with particular nucleotide se quences. This approach is also applicable in the SELEX technology for the design of nucleic acid aptamers that irreversibly bind to proteins. 13,14 In recent years, consid erable progress has been achieved in crystallization of covalent nucleic acid-protein complexes and elucida tion of their structures by X ray diffraction. 15 Earlier, we have demonstrated that 2´ O (2 oxo ethyl)uridine containing DNA duplexes can successfully be used for the affinity modification of DNA binding proteins, such as transcription factor NF κB 1...

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“…8 To form a polymeric prodrug of P18, the N-terminal amino acid of the cathepsin B-sensitive linker was in turn amidated with a Fmocprotected amino-PEG-acid, modified, after deprotection, by successive reactions with S-benzyl-thiosuccinic acid and hydrazine, to reverse the direction of the peptide chain and form a acyl hydrazone linker, respectively. 13,14 This pegylated peptide was then released from the resin as a fully deprotected sequence which was finally conjugated to doxorubicin in solution by hydrazone ligation. The latter bond is generally stable physiologically, only undergoing hydrolysis at pHs lower than 5.…”

Section: Preparation Of a Dual-release Prodrug Candidatementioning

confidence: 99%

Polymeric prodrug combination to exploit the therapeutic potential of antimicrobial peptides against cancer cells

et al. 2016

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Antimicrobial Peptides (AMPs) have unique anticancer properties, but their clinical application is currently limited by an inadequate margin of safety. A prodrug strategy associated with a combination therapy approach could address this limitation by increasing their therapeutic index and their efficacy. Accordingly, the first targeted anticancer polymeric prodrug candidates of AMPs, intended for combination therapy with another polymeric prodrug of an approved antineoplastic agent (doxorubicin), were synthesized as either a PEG-based dual-release prodrug or two individual pegylated prodrugs. The latter are based on a cathepsin B-labile peptide linker and an acid-sensitive acyl hydrazone bond for the AMP and doxorubicin prodrugs, respectively. Anticancer activities and toxicity differentials achieved with the free peptide and its polymer conjugates against ovarian, cancer and non-malignant, cells, indicate that protease-dependent reversible pegylation could be implemented to increase the therapeutic indices of AMPs in cancer therapy. The results obtained also show that this approach can be developed if the releasable PEG linker can be optimised to conciliate the attributes and restrictions of pegylation against proteases. In addition, combination of the polymeric prodrugs of the AMP and of doxorubicin provides additive antitumor effects which could be exploited to enhance the efficacy of the AMP candidate.

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Synthesis of Peptide−Oligonucleotide Conjugates with Single and Multiple Peptides Attached to 2‘-Aldehydes through Thiazolidine, Oxime, and Hydrazine Linkages

Cited by 119 publications

References 51 publications

Analysis of DNA-Protein Interactions in Complexes of Transcription Factor NF-κB with DNA

Analysis of DNA-Protein Interactions in Complexes of Transcription Factor NF-κB with DNA

Synthesis and properties of oligodeoxyribonucleotides containing 2’-O-(2,3-dihydroxypropyl)- and 2’-O-(2-oxoethyl)arabinouridine residues

Polymeric prodrug combination to exploit the therapeutic potential of antimicrobial peptides against cancer cells

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