The role of chemistry in the success of oligonucleotides as therapeutics

• Pawan Kumar and
• Tom Brown

Beilstein J. Org. Chem. 2022, 18, 197–199, doi:10.3762/bjoc.18.22

• Pawan Kumar Tom Brown Takeda Development Center Americas, Inc. (TDCA), 9625 Town Centre Drive, San Diego, CA 92121, USA Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK 10.3762/bjoc.18.22 Keywords: antisense oligonucleotides; chemically modified

• messenger (mRNA) to stop the synthesis of proteins using short strands of DNA, now known as antisense oligonucleotides, was first coined about 40 years ago [1]. Almost 20 years later, another endogenous mechanism, known as RNA interference (RNAi) was discovered when it was shown that short stretches of

• double-stranded nucleotides, which are called short interfering RNA or “siRNA,” can target mRNA and prevent it from being translated to make proteins [2]. While the mechanism by which antisense oligonucleotides (single stranded oligonucleotide) and siRNA (short RNA duplexes) work are completely different

Cationic oligonucleotide derivatives and conjugates: A favorable approach for enhanced DNA and RNA targeting oligonucleotides

• Mathias B. Danielsen and
• Jesper Wengel

Beilstein J. Org. Chem. 2021, 17, 1828–1848, doi:10.3762/bjoc.17.125

• Mathias B. Danielsen Jesper Wengel Biomolecular Nanoscale Engineering Center, Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark 10.3762/bjoc.17.125 Abstract Antisense oligonucleotides (ASOs) have the ability of binding to

• , and examining the future design for ASOs. Keywords: antisense oligonucleotides; backbone modifications; cations; nucleobase modifications; sugar modifications; Introduction Antisense oligonucleotides (ASOs) are single-stranded (ss) oligomers composed of typically 10–25 nucleotides linked by

Chemical approaches to discover the full potential of peptide nucleic acids in biomedical applications

• Nikita Brodyagin,
• Martins Katkevics,
• Venubabu Kotikam,
• Christopher A. Ryan and
• Eriks Rozners

Beilstein J. Org. Chem. 2021, 17, 1641–1688, doi:10.3762/bjoc.17.116

Double-headed nucleosides: Synthesis and applications

• Vineet Verma,
• Jyotirmoy Maity,
• Vipin K. Maikhuri,
• Ritika Sharma,
• Himal K. Ganguly and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2021, 17, 1392–1439, doi:10.3762/bjoc.17.98

• simulations [15][22]. The double-headed nucleoside 157a was further used for the synthesis of 5-(phenyltriazol)-2′-deoxyuridine-modified 2′-O-methyl mixmer antisense oligonucleotides (AOs). The obtained AOs were investigated for their potential to induce exon skipping in DMD (Duchenne muscular dystrophy

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

• ]. In combination with the high selectivity for RNA sequences, this makes LNA-modified oligonucleotides well suited for use as antisense therapeutics. Recent publications have used LNA’s high affinity for RNA sequences in gapmer-designed antisense oligonucleotides for successful targeting of a key gene

• [148], and in the use of antisense oligonucleotides for splice modulation through the induction of Dmd exon-23 skipping in mice in vitro [149]. Recently, a lot of attention has been paid to modifying the LNA scaffold to incorporate various heteroatoms, modify the bicyclic framework, and to change the

• compared to second generation 2'-O-MOE antisense oligonucleotides [162][163]. The cEt also demonstrate an improved toxicity profile in comparison to standard LNA ASOs [162]. The arduous synthesis of the nucleoside analogues has been refined to minimize the number of needed stereochemical adjustments and

DNA with zwitterionic and negatively charged phosphate modifications: Formation of DNA triplexes, duplexes and cell uptake studies

• Yongdong Su,
• Maitsetseg Bayarjargal,
• Tracy K. Hale and
• Vyacheslav V. Filichev

Beilstein J. Org. Chem. 2021, 17, 749–761, doi:10.3762/bjoc.17.65

• [47][48], a sugar [49][50], or the DNA backbone [51][52][53] leading to the formation of more stable duplexes and triplexes [54]. The introduction of sulfonamide RNA (SaRNA monomers) to replace the phosphodiester backbone led to charge-neutral sulfonamide antisense oligonucleotides (SaASOs), which

Synthesis and properties of oligonucleotides modified with an N-methylguanidine-bridged nucleic acid (GuNA[Me]) bearing adenine, guanine, or 5-methylcytosine nucleobases

• Naohiro Horie,
• Takao Yamaguchi,
• Shinji Kumagai and
• Satoshi Obika

Beilstein J. Org. Chem. 2021, 17, 622–629, doi:10.3762/bjoc.17.54

• data indicate that GuNA[Me] could be a useful modification for therapeutic antisense oligonucleotides. Keywords: artificial nucleic acid; duplex-forming ability; oligonucleotide synthesis; Introduction The efficacy and safety of therapeutic oligonucleotides can be controlled by chemical modifications

• . For applications in antisense technology, chemical modifications aimed at enhancing the duplex-forming ability toward a target RNA (i.e., a complementary single-stranded RNA) and improving the stability against enzymatic degradations are commonly utilized. For instance, antisense oligonucleotides

Synthesis, biophysical properties, and RNase H activity of 6’-difluoro[4.3.0]bicyclo-DNA

• Sibylle Frei,
• Adam K. Katolik and
• Christian J. Leumann

Beilstein J. Org. Chem. 2019, 15, 79–88, doi:10.3762/bjoc.15.9

• oligonucleotides (AONs) [6]. An effective way to tune the properties of antisense oligonucleotides is by the insertion of the fluorine atom in the sugar moiety of the nucleoside. In this way, the sugar pucker can be controlled which ideally results in an increased affinity towards complementary RNA [7]. An

• ; Introduction The fluorine atom is a very attractive substituent in medicinal chemistry due to the beneficial biological effects induced by this atom on the overall drug behaviour [1][2][3][4][5]. The positive influences on the drug behaviour is not limited to small molecules but is also valid for antisense

6’-Fluoro[4.3.0]bicyclo nucleic acid: synthesis, biophysical properties and molecular dynamics simulations

• Sibylle Frei,
• Andrei Istrate and
• Christian J. Leumann

Beilstein J. Org. Chem. 2018, 14, 3088–3097, doi:10.3762/bjoc.14.288

• use of therapeutic antisense oligonucleotides (AONs) [1][2][3][4]. These short, synthetic fragments bind through Watson–Crick base pairing to cellular RNA, thus modulating or silencing the gene expression through various mechanisms [5][6][7]. One mode of action is the recruitment of the endonuclease

Synthesis and photophysical studies of a multivalent photoreactive Ru^II-calix[4]arene complex bearing RGD-containing cyclopentapeptides

• Sofia Kajouj,
• Lionel Marcelis,
• Alice Mattiuzzi,
• Adrien Grassin,
• Damien Dufour,
• Pierre Van Antwerpen,
• Didier Boturyn,
• Eric Defrancq,
• Mathieu Surin,
• Julien De Winter,
• Pascal Gerbaux,
• Ivan Jabin and
• Cécile Moucheron

Beilstein J. Org. Chem. 2018, 14, 1758–1768, doi:10.3762/bjoc.14.150

• activity of enzymes such as RNA polymerase or endonuclease is inhibited in vitro at the level of the photoadduct [23][24]. In order to target a specific DNA sequence, photoreactive RuII complexes have been anchored to specific antisense oligonucleotides to inhibit the expression of the complementary

Oligonucleotide analogues with cationic backbone linkages

• Melissa Meng and
• Christian Ducho

Beilstein J. Org. Chem. 2018, 14, 1293–1308, doi:10.3762/bjoc.14.111

• competition of the cationic antigene oligonucleotide with cellular histones for DNA binding [43]. Vasseur, Debart and co-workers have combined a variant of Letsinger's linkages with an α-configuration at the anomeric centers of antisense oligonucleotides [44][45]. They have found that such zwitterionic to

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

• strategies include antisense oligonucleotides (AONs), ribozymes, DNAzymes, small interfering RNAs (siRNAs) and micro RNAs (miRNAs) that specifically target the complementary mRNA sequence of the relevant undesired gene before translation. AONs are single-stranded DNA of 15 to 25 nucleotides in length that

A postsynthetically 2’-“clickable” uridine with arabino configuration and its application for fluorescent labeling and imaging of DNA

• Heidi-Kristin Walter,
• Bettina Olshausen,
• Ute Schepers and
• Hans-Achim Wagenknecht

Beilstein J. Org. Chem. 2017, 13, 127–137, doi:10.3762/bjoc.13.16

• structure of double-helical DNA elucidates that the positioning of the fluorophores in the major groove may be improved by inversion of the configuration at the 2’-position of the anchor nucleoside sugar. In fact, arabino nucleic acids are an important class of antisense oligonucleotides [20] since their

Preparation of a disulfide-linked precipitative soluble support for solution-phase synthesis of trimeric oligodeoxyribonucleotide 3´-(2-chlorophenylphosphate) building blocks

• Amit M. Jabgunde,
• Alejandro Gimenez Molina,
• Pasi Virta and
• Harri Lönnberg

Beilstein J. Org. Chem. 2015, 11, 1553–1560, doi:10.3762/bjoc.11.171

• acids have been used to regulate gene expression through different mechanisms of action, such as antisense oligonucleotides [1][2], ribozymes [3], interfering RNAs (siRNA) [4][5] and immunostimulatory CpG [6] based therapeutics. At the same time, the interest in detailed understanding of the factors

Sequence-specific RNA cleavage by PNA conjugates of the metal-free artificial ribonuclease tris(2-aminobenzimidazole)

• Friederike Danneberg,
• Alice Ghidini,
• Plamena Dogandzhiyski,
• Elisabeth Kalden,
• Roger Strömberg and
• Michael W. Göbel

Beilstein J. Org. Chem. 2015, 11, 493–498, doi:10.3762/bjoc.11.55

• and Nutrition, Novum, SE-141 83 Huddinge, Sweden 10.3762/bjoc.11.55 Abstract Tris(2-aminobenzimidazole) conjugates with antisense oligonucleotides are effective site-specific RNA cleavers. Their mechanism of action is independent of metal ions. Here we investigate conjugates with peptide nucleic

Synthesis of dinucleoside acylphosphonites by phosphonodiamidite chemistry and investigation of phosphorus epimerization

• William H. Hersh

Beilstein J. Org. Chem. 2015, 11, 184–191, doi:10.3762/bjoc.11.19

• barrier was found to be high as no epimerization was detected up to 150 °C, and consistent with this, density functional theory calculations give an inversion barrier of over 40 kcal/mol. Keywords: acylphosphine; acyl phosphite; chiral; DFT; NMR; nucleic acids; oligonucleotides; Introduction Antisense

• oligonucleotides, which are modified oligonucleotides that bind to mRNA in order to inhibit translation to proteins, have been intensively investigated for decades [1][2]. Modifications of native DNA or RNA are required to permit pharmaceutical use, for example, for conferring nuclease resistance, enhanced binding

Structure/affinity studies in the bicyclo-DNA series: Synthesis and properties of oligonucleotides containing bc^en-T and iso-tricyclo-T nucleosides

• Branislav Dugovic,
• Michael Wagner and
• Christian J. Leumann

Beilstein J. Org. Chem. 2014, 10, 1840–1847, doi:10.3762/bjoc.10.194

• ; Introduction Antisense oligonucleotides (ASOs) can interfere with gene expression via various biological mechanisms, depending on the nature of the cellular RNA target [1]. First and foremost they can inhibit translation by targeting a mature mRNA in either its coding or non-coding part of the sequence by a