Improved RE31 Analogues Containing Modified Nucleic Acid Monomers: Thermodynamic, Structural, and Biological Effects

Kotkowiak, Weronika; Wengel, Jesper; Scotton, Chris J.; Pasternak, Anna

doi:10.1021/acs.jmedchem.8b01806

Cited by 27 publications

(25 citation statements)

References 43 publications

(129 reference statements)

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“…The aptamers modified simultaneously with UNA and LNAs possess a two-fold higher anticoagulant effect. RE31 variants modified with nucleosides in UNA, LNA, or β-L-RNA series exhibited prolongation of aptamer stability in human serum [95].…”

Section: Locked and Unlocked Nucleic Acidmentioning

confidence: 99%

Aptamers Chemistry: Chemical Modifications and Conjugation Strategies

et al. 2019

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Soon after they were first described in 1990, aptamers were largely recognized as a new class of biological ligands that can rival antibodies in various analytical, diagnostic, and therapeutic applications. Aptamers are short single-stranded RNA or DNA oligonucleotides capable of folding into complex 3D structures, enabling them to bind to a large variety of targets ranging from small ions to an entire organism. Their high binding specificity and affinity make them comparable to antibodies, but they are superior regarding a longer shelf life, simple production and chemical modification, in addition to low toxicity and immunogenicity. In the past three decades, aptamers have been used in a plethora of therapeutics and drug delivery systems that involve innovative delivery mechanisms and carrying various types of drug cargos. However, the successful translation of aptamer research from bench to bedside has been challenged by several limitations that slow down the realization of promising aptamer applications as therapeutics at the clinical level. The main limitations include the susceptibility to degradation by nucleases, fast renal clearance, low thermal stability, and the limited functional group diversity. The solution to overcome such limitations lies in the chemistry of aptamers. The current review will focus on the recent arts of aptamer chemistry that have been evolved to refine the pharmacological properties of aptamers. Moreover, this review will analyze the advantages and disadvantages of such chemical modifications and how they impact the pharmacological properties of aptamers. Finally, this review will summarize the conjugation strategies of aptamers to nanocarriers for developing targeted drug delivery systems. Molecules 2020, 25, 3 2 of 51 molecules [2]. Nowadays, the aptamer field covers various biomedical applications, including [3], therapeutic [4-6], aptasensors [7], biosensors [8,9], diagnostic [10,11], and imaging systems [12].Aptamers need to be stabilized for in vivo use against nuclease degradation, and their small size makes them susceptible to renal filtration. Aptamers' stabilization can be attained by chemically modifying them using different approaches. Moreover, introducing chemical modifications into nucleic acid libraries increases the interaction capabilities of aptamers and thereby their target spectrum [12]. Modified aptamers may show improved chemical diversity relative to aptamers composed entirely of natural DNA or RNA nucleotides and expand their applications in diagnostics, therapeutics, and nanotechnology [1].Chemical modifications of aptamer oligonucleotides are needed mainly to enhance their resistance to nuclease degradation and lowering their renal filtration. Additionally, chemical modifications, in some cases, may increase the aptamer-binding affinity [13]. Many approaches have been introduced to promote the stability of aptamers without altering their binding affinity and specificity against their targets. These approaches include chemical modification of the phosphate...

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Section: Locked and Unlocked Nucleic Acidmentioning

confidence: 99%

Aptamers Chemistry: Chemical Modifications and Conjugation Strategies

et al. 2019

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“…Kotkowiak et al recently modified a previously identified thrombin binding aptamer RE31 with unlocked nucleic acid (UNA), locked nucleic acid (LNA), and β-L-RNA [28,42]. Modifications with UNA at position 15 T residual and LNAs altered the melting temperature of RE31 and generated twofold higher anticoagulation activity.…”

Section: Aptamer Clinical Research In Anticoagulationmentioning

confidence: 99%

“…Modifications with UNA at position 15 T residual and LNAs altered the melting temperature of RE31 and generated twofold higher anticoagulation activity. All of the tested bases modifications did not change the G-quadruplex structure, and also increased the aptamer stability in human serum [28].…”

Section: Aptamer Clinical Research In Anticoagulationmentioning

confidence: 99%

A Mini-Review: Clinical Development and Potential of Aptamers for Thrombotic Events Treatment and Monitoring

Ponce

Hong

2019

Biomedicines

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The unique opportunity for aptamer uses in thrombotic events has sparked a considerable amount of research in the area. The short half-lives of unmodified aptamers in vivo remain one of the major challenges in therapeutic aptamers. Much of the incremental successful therapeutic aptamer stories were due to modifications in the aptamer bases. This mini-review briefly summarizes the successes and challenges in the clinical development of aptamers for thrombotic events, and highlights some of the most recent developments in using aptamers for anticoagulation monitoring.

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“…The success and advantages of LNA-containing oligomers for diverse applications stimulated the search for similar compounds, improving their properties. Many derivatives were recently introduced, like BNA NC with different substitutions at the N atom (of which a methyl group is the most commonly used to date) (Figure 1) [87], 2′- O ,4′- C -ethylene-bridged nucleic acid (ENA) [88], 2′- O ,4′- C -methylenoxymethylene-bridged nucleic acid [89], or unlocked nucleic acids (UNA) [90,91]. The bridge in the different BNA compounds can have a different number of members in the ring, the most widely used to date being BNA NC , a six-member ring [30,31].…”

Section: Bnancmentioning

confidence: 99%

Bridged Nucleic Acids Reloaded

2019

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Oligonucleotides are key compounds widely used for research, diagnostics, and therapeutics. The rapid increase in oligonucleotide-based applications, together with the progress in nucleic acids research, has led to the design of nucleotide analogs that, when part of these oligomers, enhance their efficiency, bioavailability, or stability. One of the most useful nucleotide analogs is the first-generation bridged nucleic acids (BNA), also known as locked nucleic acids (LNA), which were used in combination with ribonucleotides, deoxyribonucleotides, or other analogs to construct oligomers with diverse applications. However, there is still room to improve their efficiency, bioavailability, stability, and, importantly, toxicity. A second-generation BNA, BNANC (2′-O,4′-aminoethylene bridged nucleic acid), has been recently made available. Oligomers containing these analogs not only showed less toxicity when compared to LNA-containing compounds but, in some cases, also exhibited higher specificity. Although there are still few applications where BNANC-containing compounds have been researched, the promising results warrant more effort in incorporating these analogs for other applications. Furthermore, newer BNA compounds will be introduced in the near future, offering great hope to oligonucleotide-based fields of research and applications.

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Improved RE31 Analogues Containing Modified Nucleic Acid Monomers: Thermodynamic, Structural, and Biological Effects

Cited by 27 publications

References 43 publications

Aptamers Chemistry: Chemical Modifications and Conjugation Strategies

Aptamers Chemistry: Chemical Modifications and Conjugation Strategies

A Mini-Review: Clinical Development and Potential of Aptamers for Thrombotic Events Treatment and Monitoring

Bridged Nucleic Acids Reloaded

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