Future directions for medicinal chemistry in the field of oligonucleotide therapeutics

Hall, Jonathan

doi:10.1261/rna.079511.122

Cited by 13 publications

(12 citation statements)

References 98 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One of the most convenient approaches for obtaining phosphate-modified oligonucleotides is based on the alternative oxidation step in the protocol of the standard solid-phase phosphoramidite method of synthesis. For example, phosphorothioate modifications, which can be obtained by this approach, are widely used in creating various NA constructions, including complex oligonucleotide structures with combinations of different modifications [ 1 , 2 , 4 , 7 , 45 ]. Previously, we developed another way of carrying out the alternative oxidation step, based on the application of the Staudinger reaction involving electron-deficient azides.…”

Section: Discussionmentioning

confidence: 99%

“…At present, modified oligonucleotides are finding new applications in a wide range of scientific and technological fields, including the creation of unique therapeutics and diagnostics [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. For example, 18 drugs based on therapeutic nucleic acids (NAs) have already been officially approved for use in the treatment of various human diseases, and all of them contain chemical modifications [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Influence of Combinations of Lipophilic and Phosphate Backbone Modifications on Cellular Uptake of Modified Oligonucleotides

Zharkov,

Markov,

Zhukov

et al. 2024

Molecules

View full text Add to dashboard Cite

Numerous types of oligonucleotide modifications have been developed since automated synthesis of DNA/RNA became a common instrument in the creation of synthetic oligonucleotides. Despite the growing number of types of oligonucleotide modifications under development, only a few of them and, moreover, their combinations have been studied widely enough in terms of their influence on the properties of corresponding NA constructions. In the present study, a number of oligonucleotides with combinations of 3′-end lipophilic (a single cholesteryl or a pair of dodecyl residues) and phosphate backbone modifications were synthesized. The influence of the combination of used lipophilic groups with phosphate modifications of various natures and different positions on the efficiency of cell penetration was evaluated. The obtained results indicate that even a couple of phosphate modifications are able to affect a set of oligonucleotide properties in a complex manner and can remarkably change cellular uptake. These data clearly show that the strategy of using different patterns of modification combinations has great potential for the rational design of oligonucleotide structures with desired predefined properties.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Influence of Combinations of Lipophilic and Phosphate Backbone Modifications on Cellular Uptake of Modified Oligonucleotides

Zharkov,

Markov,

Zhukov

et al. 2024

Molecules

View full text Add to dashboard Cite

show abstract

“…Several ASO drugs based on diverse nucleotide modalities including DNA-PTO, RNA-MOE, RNA-OMe, RNA-F and PMO have been approved for the treatment of human diseases (22,(61)(62)(63). In terms of pharmacokinetics, pharmacodynamics and bioavailability in the human body each modality has different properties (64).…”

Section: Aso Chemistry and Binding Affinitymentioning

confidence: 99%

A side-by-side comparison of peptide-delivered antisense antibiotics employing different nucleotide mimics

Ghosh

Popella²,

Dhamodharan

et al. 2023

Preprint

View full text Add to dashboard Cite

Antisense oligomer (ASO)-based antibiotics that target mRNAs of essential bacterial genes have great potential for counteracting antimicrobial resistance and for precision microbiome editing. To date, the development of such antisense antibiotics has primarily focused on using phosphorodiamidate morpholino (PMO) and peptide nucleic acid (PNA) backbones, largely ignoring the growing number of chemical modalities that have spurred the success of ASO-based human therapy. Here, we directly compare the activities of seven chemically distinct 10mer ASOs, all designed to target the essential gene acpP upon delivery with a KFF-peptide carrier into Salmonella. Our systematic analysis of PNA, PMO, phosphorothioate-modified DNA (PTO), 2′-methylated RNA (RNA-OMe), 2′-methoxyethylated RNA (RNA-MOE), 2′-fluorinated RNA (RNA-F) and 2′-4′-locked RNA (LNA) is based on a variety of in vitro and in vivo methods to evaluate ASO uptake, target pairing and inhibition of bacterial growth. Our data show that only PNA and PMO are efficiently delivered by the KFF peptide into Salmonella to inhibit bacterial growth. Nevertheless, the strong target binding affinity and in vitro translational repression activity of LNA and RNA-MOE make them promising modalities for antisense antibiotics that will require the identification of an effective carrier.

show abstract

“…Since the pioneer work published by M. L. Stephenson and P. C. Zamecnik in 1978 [ 18 ], tremendous progress has been achieved in the field of gene targeting, resulting in recent years in the development of the first antisense oligonucleotide (mipomersen, 2013, Kynamro), and the first small interfering RNA (patisiran, 2018, Onpattro) has been approved by the FDA (United States Food and Drug Administration) for clinical application. After that, several DNA- and RNA-based products have successfully passed through clinical trials and been approved for clinical use with a number of others being at different stages of preclinical and clinical investigations [ 19 , 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Extracellular Vesicles for Therapeutic Nucleic Acid Delivery: Loading Strategies and Challenges

Oshchepkova

Zenkova

Vlassov

2023

IJMS

View full text Add to dashboard Cite

Extracellular vesicles (EVs) are membrane vesicles released into the extracellular milieu by cells of various origins. They contain different biological cargoes, protecting them from degradation by environmental factors. There is an opinion that EVs have a number of advantages over synthetic carriers, creating new opportunities for drug delivery. In this review, we discuss the ability of EVs to function as carriers for therapeutic nucleic acids (tNAs), challenges associated with the use of such carriers in vivo, and various strategies for tNA loading into EVs.

show abstract

Future directions for medicinal chemistry in the field of oligonucleotide therapeutics

Cited by 13 publications

References 98 publications

Influence of Combinations of Lipophilic and Phosphate Backbone Modifications on Cellular Uptake of Modified Oligonucleotides

Influence of Combinations of Lipophilic and Phosphate Backbone Modifications on Cellular Uptake of Modified Oligonucleotides

A side-by-side comparison of peptide-delivered antisense antibiotics employing different nucleotide mimics

Extracellular Vesicles for Therapeutic Nucleic Acid Delivery: Loading Strategies and Challenges

Contact Info

Product

Resources

About