Phosphodiester models for cleavage of nucleic acids

• Satu Mikkola,
• Tuomas Lönnberg and
• Harri Lönnberg

Beilstein J. Org. Chem. 2018, 14, 803–837, doi:10.3762/bjoc.14.68

• ribozymes [7]. The length of these catalytic sequences varies from 70–150 nucleotides of the so-called small ribozymes to hundreds of nucleotides of large ribozymes. Their catalytic efficiency is somewhat more modest than that of protein enzymes. The remarkable catalytic efficiency has made the action of

• protein nucleases and ribozymes a subject of intensive mechanistic studies. pH-Rate dependency, X-ray structures, amino acid/nucleotide substitution experiments and the effect of thiosubstitution of phosphate oxygens on the binding of metal ion cofactors have given invaluable information about the

• residues that participate in substrate binding or contribute to formation of high-energy intermediates or transition states during the PO-bond cleavage by protein nucleases [8] or ribozymes [9][10]. Based on this data, energetics of various pathways from the reactants to products may be compared by

Enzyme-free genetic copying of DNA and RNA sequences

• Marilyne Sosson and
• Clemens Richert

Beilstein J. Org. Chem. 2018, 14, 603–617, doi:10.3762/bjoc.14.47

• what started replication when life emerged on planet Earth. A solution to the chicken/egg dilemma of replication might be found in RNA, as oligo- and polyribonucleotides can encode genetic information and can catalyze biochemical reactions as ribozymes. More than 30 years ago, it was observed that RNA

• strands catalyze splicing or ligation of longer oligonucleotides [3][4]. Ancient ribozymes might have acted as polymerases [5], inducing either the oligomerization of activated ribonucleotides or the replication of the first RNA genomes. But ribozymes are usually too long to be likely to emerge from

• enzymes and ribozymes, relying on solely on base pairing for molecular recognition and chemical reactivity to drive the formation of phosphodiester bonds in aqueous media. This is what is usually referred to as "enzyme-free copying" (Figure 1). Studies on enzyme-free copying of genetic polymers date back

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

• bind to mRNA targets through Watson–Crick base pairing and form a RNA/DNA duplex [4]. This can result in either mRNA cleavage mediated by RNase H or mRNA translational arrest through steric blocking. Another strategy for gene inhibition involves ribozymes [5] and DNAzymes [6], which are nucleic acid

• molecules with enzymatic activity. These catalytic RNAs and DNAs trigger the cleavage of RNA substrates at a specific position. Additionally, ribozymes can catalyze the ligation of target mRNA, extending their therapeutic potential to RNA repair applications. Finally, another promising ON-based therapy

Chemical systems, chemical contiguity and the emergence of life

• Terrence P. Kee and
• Pierre-Alain Monnard

Beilstein J. Org. Chem. 2017, 13, 1551–1563, doi:10.3762/bjoc.13.155

• ]. Such vesicles with associated ribozymes could eventually prove to be novel functional chemical systems. The production of fatty acids from non-amphiphilic picolylesters performed using a photochemical reaction involving a ruthenium tris(bipyridine), functioning as photosensitizer and redox catalyst

• , Chen et al. [87] established that an inorganic catalyst itself, magnesium ions, could be delivered to non-functional hammerhead ribozymes with consequent induction of activity (self-cleavage). The enzymatic reactions were conducted within vesicles formed by long chained fatty acids, such as

• harvest light (here a ruthenium tris(bipyridine) and catalyse reactions, or polymers such RNA ribozymes that are both genotype (information component) and phenotype (catalyst). (C) The systems approach offers insight into the increased level of cooperativity necessary to grasp the complexity of living

Towards open-ended evolution in self-replicating molecular systems

• Herman Duim and
• Sijbren Otto

Beilstein J. Org. Chem. 2017, 13, 1189–1203, doi:10.3762/bjoc.13.118

• and RNA molecules are disposed of. In this way molecules are evolved based on their ability to bind to a specific target [42][43]. However, these in vitro evolution experiments all exploit RNA-based enzymes (ribozymes) or proteins in their replication process to obtain exponential growth and are

• -replicating molecules. Lehman et al. showed that a mixture of relatively short RNA segments can self-assemble to form self-replicating ribozymes [46]. These ribozymes in turn gave rise to spontaneous formation of cooperative networks that were shown to grow faster than the autocatalytic replication rate of

• the individual ribozymes. Moreover, cooperative systems are generally more stable towards parasites then autocatalytic self-replicators and are, in principle, able to gain in complexity [46][47]. In the study a ribozyme of around 200 nucleotides called Azoarcus was used. This ribozyme is made from

From chemical metabolism to life: the origin of the genetic coding process

• Antoine Danchin

Beilstein J. Org. Chem. 2017, 13, 1119–1135, doi:10.3762/bjoc.13.111

• considerable number of works about RNAs involved in a large number of functions, including catalytic activities (ribozymes). It can therefore be expected that primeval metabolism was developed at this point as a mixture of peptide- and RNA-mediated catalytic activities, within protocells. Because of their

• tRNA has been proposed recently [61]. With ribozymes involved in the catalysis of peptide-bond formation, and primal tRNAs as handles carrying amino acids used in the process, an alternative or complement to the swinging-arm peptide synthesis would have evolved in parallel, with RNA-dependent peptide

• ribonucleotides resulted in the emergence of a new function. Polypeptide synthesis used RNA substrates carrying amino acids and RNA ribozymes (the forerunner of the ribosomal RNA peptide centre) for peptide formation. Subsequently, another class of RNA molecules complementary to part of the tRNA ancestors

Facile synthesis of a 3-deazaadenosine phosphoramidite for RNA solid-phase synthesis

• Elisabeth Mairhofer,
• Elisabeth Fuchs and
• Ronald Micura

Beilstein J. Org. Chem. 2016, 12, 2556–2562, doi:10.3762/bjoc.12.250

• -amino-3-deazapurine and benzoyl-protected 1-O-acetylribose. The novel path is superior to previously described syntheses in terms of efficacy and ease of laboratory handling. Keywords: deazapurine nucleoside; nucleosidation; protection groups; ribozymes; Introduction The synthesis of 3-deazaadenosine

• motives [1][2]. Selected adenines in their active sites have been discussed to participate in acid base catalysis, thereby contributing to accelerate the specific phosphodiester cleavage of these nucleolytic ribozymes. Concerning the twister ribozyme, structural analyses suggest that an adenine N3 atom

• nucleobases can be significantly shifted within a well-structured RNA fold [12][13][14][15]. To address RNA phenomena of that kind, comparative atomic mutagenesis is an indispensable means, and with respect to ribozymes, can deliver important insights into the RNA catalyzed chemical reactions and underlying

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

Synthesis of a bifunctional cytidine derivative and its conjugation to RNA for in vitro selection of a cytidine deaminase ribozyme

• Nico Rublack and
• Sabine Müller

Beilstein J. Org. Chem. 2014, 10, 1906–1913, doi:10.3762/bjoc.10.198

• ; SELEX; Introduction Since the discovery of the first catalytic RNA in the ciliate Tetrahymena thermophilia in 1982 [1], a number of naturally occurring ribozymes have been described [2]. Whereas all of these natural ribozymes accelerate transesterifications or, as in the case of the ribosome, the

• peptide bond formation, artificial ribonucleic acids developed by in vitro selection have been shown to catalyze a wide variety of organic chemical reactions [3][4][5]. Moreover, several of these developed ribozymes promote reactions of metabolic relevance in modern life organisms. Impressive examples are

• RNA catalysts that support an aldol reaction between an aldehyde and a ketone, relevant to the synthesis of sugars [6], or the linkage of ribose to nucleobases to generate nucleotides [7]. Such ribozymes are seen as important functional entities underscoring the RNA world theory, where ribonucleic