Development of Protecting Groups for Prodrug-Type Oligonucleotide Medicines

Saneyoshi, Hisao; Ono, Akira

doi:10.1248/cpb.c17-00696

Cited by 8 publications

(4 citation statements)

References 56 publications

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“…A question has been raised as to whether conjugated ONs should be classified as prodrugs. Clearly, some, such as those using protective groups along the backbone [ 64 ], require cleavage of the conjugated moiety(s) for activity and, therefore, meet the definition. However, others may not, depending on the mechanism of action.…”

Section: Metabolismmentioning

confidence: 99%

OSWG Recommended Approaches to the Nonclinical Pharmacokinetic (ADME) Characterization of Therapeutic Oligonucleotides

Berman,

Antonsson,

Batkai

et al. 2023

Nucleic Acid Therapeutics

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This white paper summarizes the recommendations of the absorption, distribution, metabolism, and excretion (ADME) Subcommittee of the Oligonucleotide Safety Working Group for the characterization of absorption, distribution, metabolism, and excretion of oligonucleotide (ON) therapeutics in nonclinical studies. In general, the recommended approach is similar to that for small molecule drugs. However, some differences in timing and/or scope may be warranted due to the greater consistency of results across ON classes as compared with the diversity among small molecule classes. For some types of studies, a platform-based approach may be appropriate; once sufficient data are available for the platform, presentation of these data should be sufficient to support development of additional ONs of the same platform. These recommendations can serve as a starting point for nonclinical study design and foundation for discussions with regulatory agencies.

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Section: Metabolismmentioning

confidence: 99%

OSWG Recommended Approaches to the Nonclinical Pharmacokinetic (ADME) Characterization of Therapeutic Oligonucleotides

Berman,

Antonsson,

Batkai

et al. 2023

Nucleic Acid Therapeutics

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“… [26] The introduced NF and NT groups can be removed using enzymatic reduction. Such a reduction responsive conversion from uncharged phosphotriester groups to the corresponding charged phosphodiester groups can improve cellular uptake of therapeutic oligonucleotides through prodrug‐type approach [20b] . In contrast, to install the nitrobenzyl (NB) group into the terminal phosphate group of oligonucleotides through a postmodification approach instead of phosphoramidite chemistry, NB‐diazo was designed, as shown in Figure 9 [27a] .…”

Section: Nucleic Acidsmentioning

confidence: 99%

Installing Reduction Responsiveness into Biomolecules by Introducing Nitroaryl Groups

Higashi

Shintani

Ikeda

2022

Chemistry A European J

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Artificially synthesized stimuli‐responsive biomolecules are attractive as molecular tools for monitoring and modulating biological systems. In biological systems, redox stimuli are common, and their dysregulation is typically linked to various abnormal or disease states. In this Concept article, the molecular design of reduction‐responsive biomolecules, such as peptides, nucleic acids, and saccharides, which are produced by introducing nitroaryl groups into them, is reviewed with a special emphasis on simple 4‐nitrobenzene‐based motifs.

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“…Early examples include the introduction of labile protecting groups onto prodrug oligonucleotides, which could be cleaved by nitroreductase for therapeutic applications. [ 60 ] A reduction‐responsive protecting group, tert ‐butyldithiomethyl, has also been developed for RNA, offering the potential for selective activation in the presence of high glutathione concentrations within cells. [ 61 ] Ikeda and coworkers recently incorporated a 4‐nitrobenzyl moiety at the O6 position of guanosine (G NB ) as a reduction‐responsive group that can be removed in response to both chemical (sodium hydrosulfite) and enzymatic (nitroreductase in the presence of NADH) stimuli.…”

Section: Chemically Induced Switchingmentioning

confidence: 99%

Engineering Aptamer Switches for Multifunctional Stimulus‐Responsive Nanosystems

et al. 2020

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specific and strong recognition of molecular targets (i.e., aptamers), catalyze biochemical reactions (i.e., ribozymes), or form sophisticated and dynamic "smart materials" or even 3D constructs (i.e., DNA origami). [2] There is particular interest in the use of nucleic acids for the construction of molecular switches, which undergo a function-altering structural change in response to an external stimulus. [3] Many such examples exist in nature, where switches enable organisms to sense physiological changes and selectively control biological functions in response. For example, riboswitches exist naturally as domains within messenger RNA (mRNA) transcripts that can bind to specific metabolites with high specificity in order to stabilize a secondary structure that prevents subsequent translation. [4] Synthetic, engineered molecular switches based on nucleic acids can achieve even greater diversity of function. Such designs make use of aptamersnucleic acid-based affinity reagents isolated via an in vitro process of systematic evolution by exponential enrichment (SELEX), in which DNA or RNA sequences with specific ligand binding are isolated from a large pool of random sequences. [5] Aptamers have proven to be robust recognition elements due to their thermal stability, ease of synthesis, and capacity to undergo ready modification with a broad array of functional groups. Importantly, traditional selection methods can be expanded upon by innovative engineering techniques to enable the incorporation of additional functions that further extend the utility of aptamers. Aptamers can adopt various 2-and 3-D structures such as duplexes, hairpins, and G-quadruplexes, and the inducible formation and disruption of these configurations can be exploited to enable complex functions besides simple biosensing. Consequently, aptamers have been incorporated into many intricate configurations, such as logic gates and dynamic nanomachines. Various research groups have also described aptamer-based switches that undergo conformational changes in response to triggers such as shifts in pH, stimulation with light, or the presence of a specific ligand. [6] Although still a relatively young area of research, these efforts could prove highly useful for materials research-conferring even greater and more selective control over devices based on functionalized nucleic acids. Aptamers are becoming increasingly integrated with various organic and inorganic molecules in order to control the assembly and operation of novel functional Although RNA and DNA are best known for their capacity to encode biological information, it has become increasingly clear over the past few decades that these biomolecules are also capable of performing other complex functions, such as molecular recognition (e.g., aptamers) and catalysis (e.g., ribozymes). Building on these foundations, researchers have begun to exploit the predictable base-pairing properties of RNA and DNA in order to utilize nucleic acids as functional materials that can undergo a molecular "switching" ...

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Development of Protecting Groups for Prodrug-Type Oligonucleotide Medicines

Cited by 8 publications

References 56 publications

OSWG Recommended Approaches to the Nonclinical Pharmacokinetic (ADME) Characterization of Therapeutic Oligonucleotides

OSWG Recommended Approaches to the Nonclinical Pharmacokinetic (ADME) Characterization of Therapeutic Oligonucleotides

Installing Reduction Responsiveness into Biomolecules by Introducing Nitroaryl Groups

Engineering Aptamer Switches for Multifunctional Stimulus‐Responsive Nanosystems

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