Synthesis of electrophile-tethered preQ₁ analogs for covalent attachment to preQ₁ RNA

• Laurin Flemmich and
• Ronald Micura

Beilstein J. Org. Chem. 2025, 21, 483–489, doi:10.3762/bjoc.21.35

• Laurin Flemmich Ronald Micura Institute of Organic Chemistry, Center for Molecular Biosciences Innsbruck (CMBI), Innrain 80-82, 6020 Innsbruck, Austria 10.3762/bjoc.21.35 Abstract The preQ1 cIass-I riboswitch aptamer can utilize 7-aminomethyl-7-deazaguanine (preQ1) ligands that are equipped with

• aqueous hydrobromic acid provided 3c. Conclusion We have developed a divergent synthesis of 7-aminomethyl-7-deazapurines (preQ1 and DPQ1) with various electrophilic handles extending the aminomethyl moiety. These derivatives are capable of covalent tethering to the preQ1-I RNA aptamer. This aptamer occurs

Synthesis of O⁶-alkylated preQ₁ derivatives

• Laurin Flemmich,
• Sarah Moreno and
• Ronald Micura

Beilstein J. Org. Chem. 2021, 17, 2295–2301, doi:10.3762/bjoc.17.147

• class-I riboswitch [1]. This riboswitch acts as a ribozyme by using 7-aminomethyl-O6-methyl-7-deazaguanine (m6preQ1) as methyl group donor; it catalyzes self-methylation of a specific cytidine in the aptamer binding pocket, yielding N3-methyl cytidine (m3C) under release of 7-aminomethyl-7-deazaguanine

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

• Christopher Liczner,
• Kieran Duke,
• Gabrielle Juneau,
• Martin Egli and
• Christopher J. Wilds

Beilstein J. Org. Chem. 2021, 17, 908–931, doi:10.3762/bjoc.17.76

• seen in the complex between PS2-modified anti-thrombin aptamer and thrombin [94] (Figure 3). Commonly, internucleotide-modified oligonucleotides are coupled with 2'-substitutions in order to enhance or regain desirable therapeutic properties. For example, not only did introducing a 2'-OMe modification

Enhanced target cell specificity and uptake of lipid nanoparticles using RNA aptamers and peptides

• Roslyn M. Ray,
• Anders Højgaard Hansen,
• Maria Taskova,
• Bernhard Jandl,
• Jonas Hansen,
• Citra Soemardy,
• Kevin V. Morris and
• Kira Astakhova

Beilstein J. Org. Chem. 2021, 17, 891–907, doi:10.3762/bjoc.17.75

• receptor type 5 (CCR5), a HIV-1 coreceptor. We report herein a CCR5-selective RNA aptamer that acts to facilitate entry through a simplified BBB model and that drives the uptake of LNPs into CCR5-expressing cells, while the gp160 aptamer did not. We further observed that the addition of cell-penetrating

• peptides, Tat and T7, did not increase BBB penetration above the aptamer-loaded LNPs alone. Moreover, we found that these targeted LNPs exhibit low immunogenic and low toxic profiles and that targeted LNPs can traverse the BBB to potentially deliver drugs into the target tissue. This approach highlights

• the usefulness of aptamer-loaded LNPs to increase target cell specificity and potentially deliverability of central-nervous-system-active RNAi therapeutics across the BBB. Keywords: aptamer; blood–brain barrier; gene therapy; HIV-1; lipid nanoparticle; Introduction Lipid nanoparticles (LNPs

¹⁹F NMR as a tool in chemical biology

• Diana Gimenez,
• Aoife Phelan,
• Cormac D. Murphy and
• Steven L. Cobb

Beilstein J. Org. Chem. 2021, 17, 293–318, doi:10.3762/bjoc.17.28

• -based G‐quadruplex complexes with different ligand molecules. This was exemplified by the Xu group who investigated the interaction of a RNA G‐quadruplex and the telomeric protein TRF2 [103] and the interaction of the DNA thrombin binding aptamer (TBA) G-quadruplex with thrombin [100]. Overall, these

Incorporation of a metal-mediated base pair into an ATP aptamer – using silver(I) ions to modulate aptamer function

• Marius H. Heddinga and
• Jens Müller

Beilstein J. Org. Chem. 2020, 16, 2870–2879, doi:10.3762/bjoc.16.236

• modulate the affinity of an aptamer towards its target. In particular, two artificial imidazole 2’-deoxyribonucleosides (Im) were incorporated into various positions of an established ATP-binding aptamer (ATP, adenosine triphosphate), resulting in the formation of three aptamer derivatives bearing Im:Im

• mispairs with a reduced ATP affinity. A fluorescence spectroscopy assay and a binding assay with immobilized ATP were used to evaluate the aptamer derivatives. Upon the addition of one Ag(I) ion per mispair, stabilizing Im–Ag(I)–Im base pairs were formed. As a result, the affinity of the aptamer derivative

• towards ATP is restored again. The silver(I)-mediated base-pair formation was particularly suitable to modulate the aptamer function when the Im:Im mispairs (and hence the resulting metal-mediated base pairs) were located close to the ATP-binding pocket of the aptamer. Being able to trigger the aptamer

Changed reactivity of secondary hydroxy groups in C8-modified adenosine – lessons learned from silylation

• Jennifer Frommer and
• Sabine Müller

Beilstein J. Org. Chem. 2020, 16, 2854–2861, doi:10.3762/bjoc.16.234

• entities in our ribozyme design projects [21][22]. Strikingly, the C8-position of a specific adenosine in the loop region of the flavine mononucleotide (FMN) aptamer is a highly favorable position for covalent attachment of FMN to study regulation of an FMN dependent hairpin aptazyme in response to RNA

A smart deoxyribozyme-based fluorescent sensor for in vitro detection of androgen receptor mRNA

• Ekaterina A. Bryushkova,
• Erik R. Gandalipov and
• Julia V. Nuzhina

Beilstein J. Org. Chem. 2020, 16, 1135–1141, doi:10.3762/bjoc.16.100

• receptor mRNA was developed. It consists of several functional modules including two deoxyribozymes 10–23, an RNA-dependent split malachite green aptamer, and an oligonucleotide platform. Deoxyribozymes specifically release a 27-nucleotide RNA fragment that is readily available for the interaction with the

• aptamer module. This solves a problem of secondary structure in hybridization with the target sequence of full-length mRNA. It was shown that within 24 hours the proposed sensor specifically recognized both a synthetic 60-nucleotide RNA fragment (LOD is 1.4 nM of RNA fragment at 37 °C) and a full-sized

• diagnosis. Keywords: androgen receptor; 10–23 deoxyribozyme; nucleic acid sensor; malachite green aptamer; RNA cleavage; Introduction The fast and precise diagnostics of diseases are one of the key factors that allow choosing the most effective method of treatment. Disease markers can be found at a few

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

• Françoise Debart,
• Christelle Dupouy and
• Jean-Jacques Vasseur

Beilstein J. Org. Chem. 2018, 14, 436–469, doi:10.3762/bjoc.14.32

• normal cells. A nitrobenzyl (NB) group has also been introduced at O6 of a guanine to modulate the conformational properties of a G-quadruplex structure-forming single-stranded DNA [28]. The dGNB phosphoramidite was synthesized and incorporated into the sequence of a thrombin-binding DNA aptamer (TBA, at

Fluorogenic PNA probes

• Tirayut Vilaivan

Beilstein J. Org. Chem. 2018, 14, 253–281, doi:10.3762/bjoc.14.17

• proteins and other non-nucleic acid targets by employing aptamer technology [2]. However, ordinary fluorescent oligonucleotide probes generally show indistinguishable signals between the free and target-bound states. This means that additional treatments are required in order to separate the bound and

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

• ) histopathological examination [64]. Alternatively, serological testing has been proposed and promising results were obtained in a case control study in Ghana [65]. More recently, the detection of mycolactone from patient biopsy samples via LC–MS [66] and RNA aptamer binding [67] has been suggested, but the

Learning from the unexpected in life and DNA self-assembly

• Jennifer M. Heemstra

Beilstein J. Org. Chem. 2015, 11, 2713–2720, doi:10.3762/bjoc.11.292

• at equilibrium [7]. Building upon this work, we were intrigued by the question of whether these DNA assembly events could be covalently trapped, which would allow the initial binding event to be “remembered” even if the target became unbound from the split aptamer. We reasoned that this might improve

• the sensitivity of split aptamer-based detection assays, and also that by converting the presence of a target molecule into the output of a DNA ligation event, we might be able to use split aptamers in assay formats that were previously inaccessible with these affinity reagents. In our first attempt

• to demonstrate this principle of split aptamer ligation, we functionalized one fragment of the cocaine-binding DNA split aptamer [8] with a cyclooctyne and the other fragment with an azide. Although the cyclooctyne and azide are inherently reactive towards one another [9], we hypothesized that in the

DNA display of glycoconjugates to emulate oligomeric interactions of glycans

• Alexandre Novoa and
• Nicolas Winssinger

Beilstein J. Org. Chem. 2015, 11, 707–719, doi:10.3762/bjoc.11.81

• high mannose epitope of gp120. For this purpose, the aptamer library was functionalized with oligomannoses (Man4-azide or Man9-azide) leading to the selection of glycan-functionalized aptamers bearing 7–14 glycan units and with a KD below 220 nM. A mutagenesis study showed that the affinity was also

• could be harnessed to combine a DNA-based aptamer with a glycan. Glycan arrays prepared by hybridization to a DNA microarray Microarray technologies have enjoyed tremendous success based on the miniaturization and the high information content that this format provides. The DNA microarray is now a

A comparative study of the interactions of cationic hetarenes with quadruplex-DNA forming oligonucleotide sequences of the insulin-linked polymorphic region (ILPR)

• Darinka Dzubiel,
• Heiko Ihmels,
• Mohamed M. A. Mahmoud and
• Laura Thomas

Beilstein J. Org. Chem. 2014, 10, 2963–2974, doi:10.3762/bjoc.10.314

• -quartet planes that is formed by the thrombin binding aptamer (TBA) [d(G2T2G2TGTG2T2G2)], though with varying intensities and slightly different shifts [32]. In addition, it has been suggested that the porphyrin 4 also binds to an antiparallel quadruplex form that consists of just two stacked G-quartets

Syntheses of ¹⁵N-labeled pre-queuosine nucleobase derivatives

• Jasmin Levic and
• Ronald Micura

Beilstein J. Org. Chem. 2014, 10, 1914–1918, doi:10.3762/bjoc.10.199

• preQ1 base. The new derivatives carry the potential for modern NMR spectroscopic applications to study the recognition process of these small molecules with RNA aptamer domains from the three preQ1 riboswitch classes known to this date [4][5][18]. Experimental General.Chemical reagents and solvents were

Glycosystems in nanotechnology: Gold glyconanoparticles as carrier for anti-HIV prodrugs

• Fabrizio Chiodo,
• Marco Marradi,
• Javier Calvo,
• Eloisa Yuste and
• Soledad Penadés

Beilstein J. Org. Chem. 2014, 10, 1339–1346, doi:10.3762/bjoc.10.136

• )pyrrolidone were found to be effective against different HIV-strains [16]. Aptamer-conjugated gold nanoparticles were also exploited as effective inhibitors of viral enzymes [17]. We have previously described the usefulness of carbohydrate-coated gold nanoparticles (GNPs) as a carrier for different structures