Synthesis and Characterization of Cell-Permeable Oligonucleotides Bearing Reduction-Activated Protecting Groups on the Internucleotide Linkages

Saneyoshi, Hisao; Iketani, Koichi; Kondo, Kenji; Saneyoshi, Takeo; Okamoto, Isaku; Ono, Akira

doi:10.1021/acs.bioconjchem.6b00368

Cited by 20 publications

(12 citation statements)

References 51 publications

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“…35) However, the solubility of oligonucleotides decreased as the numbers of protecting groups increased. The balance between solubility and cellular membrane permeability may be important in the development of effective oligonucleotide drugs.…”

Section: Discussionmentioning

confidence: 99%

“…The protecting groups were deprotected to give native oligonucleotides. 35) Conversely, the non-cleavable substrate (ODN 3) was completely stable under the same condition.…”

Section: Oligonucleotide Prodrugs Bearing Reductionactivated Protectimentioning

confidence: 99%

“…ODNs 6-8 were labeled with fluorescein at their 5′-ends. 35) HeLa cells were treated with solutions containing the different ODNs (10 µM) for 1 h. The fixed cells were observed by confocal microscopy. The fluorescence intensity of the labeled ODNs in HeLa cells increased as the number of protecting groups increased.…”

Section: Oligonucleotide Prodrugs Bearing Reductionactivated Protectimentioning

confidence: 99%

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Development of Protecting Groups for Prodrug-Type Oligonucleotide Medicines

Saneyoshi

Ono

2018

CHEMICAL & PHARMACEUTICAL BULLETIN

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In recent years, nucleic acid-based drug therapeutics have gained considerable attention for their potential in the treatment of various diseases. However, their therapeutic value is greatly hindered by the challenge of delivering them into cells. One possible strategy to improve cellular uptake is the use of "prodrug-type oligonucleotide medicine" in which negatively charged phosphodiester moieties are masked by bio-labile protecting groups. In this review, we describe our recent studies related to bio-labile protecting groups for phosphodiester moieties in the development of prodrug-type oligonucleotide medicines.

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Section: Discussionmentioning

confidence: 99%

“…The protecting groups were deprotected to give native oligonucleotides. 35) Conversely, the non-cleavable substrate (ODN 3) was completely stable under the same condition.…”

Section: Oligonucleotide Prodrugs Bearing Reductionactivated Protectimentioning

confidence: 99%

Section: Oligonucleotide Prodrugs Bearing Reductionactivated Protectimentioning

confidence: 99%

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Development of Protecting Groups for Prodrug-Type Oligonucleotide Medicines

Saneyoshi

Ono

2018

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Hypoxic conditions that are characteristic of solid tumors represent a remarkable stimulus to convert non-active prodrugs into active drugs under reductase action. Three examples of hypoxia-activated ONs have been reported thus far, with a hypoxia-labile modification either in the phosphate backbone to mask the negative charge and provide better tumor selectivity [ 25 – 26 ] or at the nucleobase to modulate the hybridization properties with the target [ 27 ]. In all cases, a nitro-derivative-modified thymidine phosphoramidite was prepared and incorporated into oligothymidylates (dT) n or heterosequences at different sites.…”

Section: Reviewmentioning

confidence: 99%

“…Furthermore, such nitrofuryl and nitrothienyl modifications improved nuclease resistance and cellular uptake of ONs in proportion to the number of lipophilic groups. In another study, a series of ONs with mixed sequences bearing some nitrophenylpropyl modifications were synthesized and exhibited good resistance toward nucleases and stability in human serum ( Scheme 5 ) [ 26 ]. Their cellular uptake in HeLa cells was greater than that of the naked ON and increased with the number of labile groups masking the phosphates.…”

Section: Reviewmentioning

confidence: 99%

Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing

Debart¹,

Dupouy²,

Vasseur³

2018

Beilstein J. Org. Chem.

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Oligonucleotides (ONs) have been envisaged for therapeutic applications for more than thirty years. However, their broad use requires overcoming several hurdles such as instability in biological fluids, low cell penetration, limited tissue distribution, and off-target effects. With this aim, many chemical modifications have been introduced into ONs definitively as a means of modifying and better improving their properties as gene silencing agents and some of them have been successful. Moreover, in the search for an alternative way to make efficient ON-based drugs, the general concept of prodrugs was applied to the oligonucleotide field. A prodrug is defined as a compound that undergoes transformations in vivo to yield the parent active drug under different stimuli. The interest in stimuli-responsive ONs for gene silencing functions has been notable in recent years. The ON prodrug strategies usually help to overcome limitations of natural ONs due to their low metabolic stability and poor delivery. Nevertheless, compared to permanent ON modifications, transient modifications in prodrugs offer the opportunity to regulate ON activity as a function of stimuli acting as switches. Generally, the ON prodrug is not active until it is triggered to release an unmodified ON. However, as it will be described in some examples, the opposite effect can be sought.This review examines ON modifications in response to various stimuli. These stimuli may be internal or external to the cell, chemical (glutathione), biochemical (enzymes), or physical (heat, light). For each stimulus, the discussion has been separated into sections corresponding to the site of the modification in the nucleotide: the internucleosidic phosphate, the nucleobase, the sugar or the extremities of ONs. Moreover, the review provides a current and detailed account of stimuli-responsive ONs with the main goal of gene silencing. However, for some stimuli-responsive ONs reported in this review, no application for controlling gene expression has been shown, but a certain potential in this field could be demonstrated. Additionally, other applications in different domains have been mentioned to extend the interest in such molecules.

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Prodrug‐Type Phosphotriester Oligonucleotides with Linear Disulfide Promoieties Responsive to Reducing Environment

Sugimoto,

Hayashi,

Funaki

et al. 2023

ChemBioChem

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Various chemical modifications have been developed to create new antisense oligonucleotides (AONs) for clinical applications. Our previously designed prodrug‐type phosphotriester‐modified oligonucleotide with cyclic disulfides (cyclic SS PTE ON) can be converted into unmodified ON in an intracellular‐mimetic reducing environment. However, the conversion rate of the cyclic SS PTE ON was very low, and the AON with cyclic SS PTE modifications showed much weaker antisense activity than corresponding the fully phosphorothioate‐modified AON. In this study, we synthesized several types of PTE ONs containing linear disulfides (linear SS PTE ONs) and evaluated their conversion rates under reducing conditions. From the results, the structural requirements for the conversion of the synthesized linear SS PTE ONs were elucidated. Linear SS PTE ON with promising promoieties showed a nuclease resistance up to 4.8‐fold compared to unmodified ON and a cellular uptake by endocytosis without any transfection reagent. In addition, although the knockdown activity of the linear SS PTE gapmer AON is weaker than that of the fully phosphorothioate‐modified gapmer AON, the knockdown activity is slightly stronger than that of the cyclic SS PTE gapmer AON. These results suggest that the conversion rates may be related to the expression of the antisense activity.

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Synthesis and Characterization of Cell-Permeable Oligonucleotides Bearing Reduction-Activated Protecting Groups on the Internucleotide Linkages

Cited by 20 publications

References 51 publications

Development of Protecting Groups for Prodrug-Type Oligonucleotide Medicines

Development of Protecting Groups for Prodrug-Type Oligonucleotide Medicines

Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing

Prodrug‐Type Phosphotriester Oligonucleotides with Linear Disulfide Promoieties Responsive to Reducing Environment

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