Increasing the functional density of threose nucleic acid

Abstract

Chemical strategies that augment genetic polymers with amino acid residues that are overrepresented on the paratope surface of an antibody offer a promising route for enhancing the binding properties of nucleic acid aptamers.

Expanding the Horizon of the Xeno Nucleic Acid Space: Threose Nucleic Acids with Increased Information Storage

“…Advances in enhancing the chemical diversity of nuclease-resistant sugar-modified XNAs were recently made by Chaput and co-workers. Enzymatic synthesis of a functionally enhanced TNA was reported. − To augment the functional density of TNA, the nuclease-resistant threose backbone was combined with canonical nucleobases modified with hydrophobic groups at the C-5 position of pyrimidine nucleobases − to resemble the nonpolar side chains that are prevalent in paratopes of antibodies . Notably, these functionalized canonical nucleobases were well accommodated by Kod-RSGA polymerase. − With this technique, TNA aptamers with enhanced functional density were selected. , Notably, TNA aptamers modified with two different aromatic side chains showed accelerated on-rates and tighter binding affinity constants compared to TNA aptamers bearing only one nucleobase modification …”

“…15−17 With this technique, TNA aptamers with enhanced functional density were selected. 15,16 Notably, TNA aptamers modified with two different aromatic side chains showed accelerated on-rates and tighter binding affinity constants compared to TNA aptamers bearing only one nucleobase modification. 16 This work emphasizes the profound significance of the development of novel XNAs with a dual modification pattern in both the sugar backbone and the nucleobase.…”

“…15,16 Notably, TNA aptamers modified with two different aromatic side chains showed accelerated on-rates and tighter binding affinity constants compared to TNA aptamers bearing only one nucleobase modification. 16 This work emphasizes the profound significance of the development of novel XNAs with a dual modification pattern in both the sugar backbone and the nucleobase. 32 However, the approach itself is still limited to the recognition of the four canonical nucleobases by Watson−Crick base pairing.…”

“…One prominent sugar-modified nucleic acid that has been thoroughly studied with a particular focus on additional modifications to its xeno nucleic acid (XNA) structure, encompassing alterations in the phosphodiester backbone or the nucleobase moiety, is threofuranosyl-based nucleic acid (TNA). − TNA was first proposed as a progenitor of RNA by Eschenmoser. , TNA, characterized by a 4-carbon atom threose sugar moiety and a 3′–2′ connected phosphodiester backbone, exhibits increased biological stability under simulated physiological conditions compared to DNA and RNA . Despite these distinct structural differences to DNA and RNA, TNA is still able to form stable antiparallel Watson–Crick duplexes with canonical nucleic acids. − Furthermore, TNA synthesis is achieved by commercially available Therminator polymerase as well as laboratory-evolved Kod-RI , and Kod-RSGA polymerases, engineered mutants of archaeal B-family DNA polymerase KOD isolated fromThermococcus kodakarensis.…”

Organometallic modification confers oligonucleotides new functionalities

“…40–48 Similar strategies have also met with considerable success in increasing the binding affinity and specificity of aptamers. 49–57 Chemical modification of ribozymes and DNAzymes 17,18 has largely focused on biostability but recently rationally designed changes based on high-resolution 3D structures have been shown to also improve the catalytic activity. 58 As long as the modifications are confined to the sugar moieties, such engineered nucleic acid catalysts still usually retain their reliance on metal ion cofactors.…”