Nucleic acid chemistry

Networks of interacting DNA oligomers have various applications in molecular biology, chemistry and materials science, however, kinetic dispersions during DNA hybridization can be problematic for some applications. Here, the authors reveal that limiting unnecessary duplexes using in-silico optimization can reduce in-vitro kinetic dispersions by as much as 96%.

DNA aptamers can be selected against a wide range of therapeutic targets, however, the success rate of selective binding remains low due to the highly hydrophilic nature of the DNA backbone. Here, the authors design a hydrophobic 7-phenylbutyl-7-deazaadenine-modified DNA aptamer showing high binding affinity for the heat shock protein 70.

Controlled enzymatic DNA synthesis represents an alternative synthetic methodology that circumvents the limitations of traditional soild-phase synthesis. Here, the authors explore the use of 3’-phosphate as a transient protecting group for the controlled enzymatic synthesis of DNA and XNA oligonucleotides.

RNA-cleaving DNAzymes exhibit potential as biosensors and in vivo knockdown agents, however, the structures of DNAzymes remain underexplored. Here, the authors report the 2.7 Å X-Ray crystal structure of a 10-23 DNAzyme–substrate complex in a homodimer conformation.

The oligonucleotide d(TC₅) forms a well-characterized tetrameric i-motif in solution; however, the isolation of dimeric and trimeric intermediates remains challenging. Here, the authors report that 2′-deoxy-2′-fluoroarabinocytidine substitutions can prompt TC₅ to form dimeric i-motif folding intermediates through fluorine and oxygen hydrogen bonds.

Serinol nucleic acid and L-threoninol nucleic acid can bind to RNA and DNA, endowing them with potential as nucleic acid-based drugs. Here the authors prepare single crystals of L-aTNA/RNA and SNA/RNA heteroduplexes to further our structural understanding of how synthetic nucleic acids hybridize with natural nucleic acids.

Conventional structure-based design of M^pro inhibitors of SARS-CoV-2 often starts from the structural information of M^pro and their binders; however, the continual rise of resistant strains requires innovative routes to discover new inhibitors. Here, the authors develop a DNA-encoded chemical library screening to produce non-covalent, non-peptidic small molecule inhibitors for SARS-CoV-2 M^pro independently of preliminary knowledge regarding suitable starting points.

Light-activated antisense oligonucleotides have been developed to induce gene knockdown in living cells, however, their synthesis remains challenging and application in cell-free systems is underexplored. Here, the authors report a one-step method for selectively attaching photocages onto phosphorothioate linkages of antisense oligonucleotides that can knockdown cell-free protein synthesis using light.

Next-generation genome sequencing technologies have revolutionized the life sciences, however all sequencing platforms require nucleic acid pre-processing to generate suitable libraries for sequencing. Here, oligonucleotide-tethered 2′,3′-dideoxynucleotide terminators bearing universal priming sites are synthesised and incorporated by DNA polymerases, allowing integration of the fragmentation step into the library preparation workflow while also enabling the obtained fragments to be readily labeled by platform-specific adapters.