Oligonucleotide‐peptide conjugates as potential antisense agents

Zubin, E. M.; Романова, Е. А.; Волков, Е. М.; Tashlitsky, Vadim N.; Коршунова, Г. А.; Shabarova, Zoe A.; Oretskaya, Tatiana S.

doi:10.1016/s0014-5793(99)00921-7

Cited by 29 publications

(20 citation statements)

References 20 publications

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“…The resulting oligonucleotides were purified by electrophoresis in a denaturing polyacrylamide gel. Oligonucleotides containing 2′‐(3‐aminopropionyl)amino‐2‐deoxyarabinoadenosine were prepared as described by Zubin and coworkers [14]. Oligonucleotides containing 2′‐amino‐2′‐deoxyuridine were synthesized according to [15].…”

Section: Oligonucleotide Synthesismentioning

confidence: 99%

HIV‐1 integrase can process a 3′‐end crosslinked substrate

Agapkina

Smolov

Zubin

et al. 2003

European Journal of Biochemistry

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Integrase of the human immunodeficiency virus type-1 (HIV-1) recognizes specific sequences located in the U3 and U5 regions at the ends of viral DNA. We synthesized DNA duplexes mimicking the U5 region and containing either 2¢-aminonucleosides or non-nucleoside 1,3-propanediol insertions at the third and terminal positions and studied their interactions with HIV-1 integrase. Both modifications introduced a local structural distortion in the DNA double helix. Replacement of the terminal nucleosides by corresponding 2¢-aminonucleosides had no significant effect on integrase activity. We used an integrase substrate bearing terminal 2¢-aminonucleosides in both strands to synthesize a duplex with cross-linked strands. This duplex was then used to determine whether terminal base pair disruption is an obligatory step of retroviral DNA 3¢-processing. Processing of the cross-linked analog of the integrase substrate yielded a product of the same length as 3¢-processing of the wild-type substrate but the reaction efficiency was lower. Replacement of the third adenosine in the processed strand by a corresponding 2¢-aminonucleoside did not affect integrase activity, whereas, its replacement by 1,3-propanediol completely inhibited 3¢-processing. Both modifications of the complementary thymidine in the nonprocessed strand increased the initial rate of 3¢-processing. The same effect was observed when both nucleosides, at the third position, were replaced by corresponding 2¢-aminonucleosides. This indicates that the local duplex distortion facilitated the cleavage of the phosphodiester bond. Thus, a localized destabilization of the third A-T base pair is necessary for efficient 3¢-processing, whereas 3¢-end-fraying is important but not absolutely required.Keywords: integrase; 2¢-aminonucleoside; interstrand crosslinking; DNA modification.Human immunodeficiency virus type-1 (HIV-1) integrase is the retroviral enzyme that mediates the integration of viral DNA into the host DNA. This process is the key step in retroviral replication. Integrase catalyzes two successive reactions: the first is the cleavage of GT dinucleotides from each 3¢-end of the viral DNA; this reaction is called 3¢-processing. The second reaction, named strand transfer, involves the attack of internucleotide phosphates in the host DNA by the 3¢-hydroxyl groups generated during 3¢-processing; it results in the integration of viral DNA by the transesterification mechanism. Integrase is currently the least studied HIV-1 enzyme, and this fact considerably delays the preparation of efficient integrase inhibitors.Integrase consists of three domains: the N-terminal, catalytic and C-terminal domains. The structures of each domain and of two-domain fragments have been determined by X-ray crystallography or NMR-spectroscopy [1][2][3][4], but the structures of the whole enzyme and of the integrase-viral DNA complex have not yet been determined. The protein-DNA interactions through which integrase mediates the formation of a stable, catalytically active complex with the vir...

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Section: Oligonucleotide Synthesismentioning

confidence: 99%

HIV‐1 integrase can process a 3′‐end crosslinked substrate

Agapkina

Smolov

Zubin

et al. 2003

European Journal of Biochemistry

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“…In contrast to antisense oligonucleotides, however, aptamers are in general longer (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) vs. 10-20 nucleotides), possess different types of chemical modifications (sugar, e.g., 2Ј-F, 2Ј-O-Me, 2Ј-NH 2 , vs. backbone modifications), and assume complex tertiary structures that are, in many respects, more similar to the three-dimensional forms of globular proteins than to nucleic acids. Given these considerable differences, the in vivo disposition of aptamers is not readily predictable from antisense results.…”

Section: Introductionmentioning

confidence: 99%

“…Given these considerable differences, the in vivo disposition of aptamers is not readily predictable from antisense results. Earlier studies involving antisense oligonucleotides have explored the effects of various conjugation chemistries on pharmacokinetics and biodistribution, with the ultimate goal of increasing delivery of antisense molecules to their sites of action inside cells or within certain tissue types in vivo (29)(30)(31)(32)(33). For example, conjugation with cholesterol has been reported to increase the circulation half-life of antisense oligonucleotides, most likely through association with plasma lipoproteins, and to promote hepatic uptake (34).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and Biodistribution of Novel Aptamer Compositions

et al. 2004

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“…To overcome this problem a solid-phase fragment coupling strategy can be used both for OPC [44][45][46][47] and for PPC synthesis [48] (Fig. (5)).…”

Section: Synthetic Methodologiesmentioning

confidence: 99%

Conjugates of Oligonucleotides and Analogues with Cell Penetrating Peptides as Gene Silencing Agents

Zatsepin¹,

Turner²,

Oretskaya³

et al. 2005

CPD

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The review describes key aspects of the synthesis and biological activities of conjugates of oligonucleotides and their analogues with synthetic peptides, in particular aimed towards gene silencing applications. The common methods of synthesis of oligonucleotide-peptide conjugates (OPCs) and PNA-peptide conjugates (PPCs) are described, which include both total solid-phase and fragment coupling approaches. In addition, various applications of conjugates as gene silencing agents are outlined. These include antisense and steric block applications in mammalian cells of OPCs, PPCs and phosphorodiamidate morpholinooligonucleotide (PMO)-peptide conjugates, gene silencing in bacteria, various DNA targeting applications, and recent reports of gene silencing activities of siRNA-peptide conjugates. A table listing all peptides used as oligonucleotide conjugates for gene silencing applications is also included.

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Oligonucleotide‐peptide conjugates as potential antisense agents

Cited by 29 publications

References 20 publications

HIV‐1 integrase can process a 3′‐end crosslinked substrate

HIV‐1 integrase can process a 3′‐end crosslinked substrate

Pharmacokinetics and Biodistribution of Novel Aptamer Compositions

Conjugates of Oligonucleotides and Analogues with Cell Penetrating Peptides as Gene Silencing Agents

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