De Novo Nucleic Acids: A Review of Synthetic Alternatives to DNA and RNA That Could Act as Bio-Information Storage Molecules

Abstract

Modern terran life uses several essential biopolymers like nucleic acids, proteins and polysaccharides. The nucleic acids, DNA and RNA are arguably life’s most important, acting as the stores and translators of genetic information contained in their base sequences, which ultimately manifest themselves in the amino acid sequences of proteins. But just what is it about their structures; an aromatic heterocyclic base appended to a (five-atom ring) sugar-phosphate backbone that enables them to carry out these functions with such high fidelity? In the past three decades, leading chemists have created in their laboratories synthetic analogues of nucleic acids which differ from their natural counterparts in three key areas as follows: (a) replacement of the phosphate moiety with an uncharged analogue, (b) replacement of the pentose sugars ribose and deoxyribose with alternative acyclic, pentose and hexose derivatives and, finally, (c) replacement of the two heterocyclic base pairs adenine/thymine and guanine/cytosine with non-standard analogues that obey the Watson–Crick pairing rules. This manuscript will examine in detail the physical and chemical properties of these synthetic nucleic acid analogues, in particular on their abilities to serve as conveyors of genetic information. If life exists elsewhere in the universe, will it also use DNA and RNA?

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

“…The chemical make-up of RNA, i.e., the ribose-phosphate backbone, has inspired countless strategies to chemically modify either the sugar [12,[41][42][43][44], or the phosphate (e.g., amide-RNA [45]), or both [46,47]. In addition, the ribose has been replaced with alternative sugar moieties, such as a tetrose (ʟ-α-threofuranose, TNA [48]), and hexoses (e.g., hexitol, HNA [49]; altritol AtNA [50]; xylol XyNA [51]), or cyclohexene (CeNA [52]), a morpholino moiety (PMO [53]), and an acyclic, chiral glycol linker (GNA [54]), to generate so-called xeno nucleic acids (XNAs [55,56]). In arguably the most radical alternative nucleic acid pairing system, peptide nucleic acid (PNA), the sugarphosphate backbone is replaced by an amide-based, neutral and achiral scaffold that allows cross-pairing with both DNA and RNA as well as formation of double-and triple-stranded species [57].…”

From polymerase engineering to semi-synthetic life: artificial expansion of the central dogma

“…Introduction of chemical modifications into natural nucleobases adds new functionalities to DNA and RNA, while introduction of UBPs pairing orthogonally to natural base pairs increases genetic information capacity of DNA and RNA 14,15 . Modification or replacement of sugar-phosphate backbones with unnatural components usually leads to significant change of the overall properties of nucleic acids, including increase of chemical or biological stabilities and change of electronegativity 16 . Combination of modifications on different moieties led to successful production of nucleic acid analogs with combined properties and functions added 17,18 .…”

“…14,15 Modification or replacement of sugar-phosphate backbones with unnatural components usually leads to a significant change of the overall properties of nucleic acids, including an increase of chemical or biological stabilities and a change of electronegativity. 16 Combination of modifications on different moieties led to the successful production of nucleic acid analogs with combined properties and functions added. 17,18…”

“…14,15 Modification or replacement of sugar-phosphate backbones with unnatural components usually leads to a significant change of the overall properties of nucleic acids, including an increase of chemical or biological stabilities and a change of electronegativity. 16 Combination of modifications on different moieties led to the successful production of nucleic acid analogs with combined properties and functions added. 17,18 Unnatural nucleic acids with modified nucleobases Chemical modifications of nucleobases are achieved via direct replacement of atoms in the nucleobases or attachment of functional groups onto the atoms in the nucleobases (Fig.…”

Water-Soluble Supramolecular Polymers of Paired and Stacked Heterocycles: Assembly, Structure, Properties, and a Possible Path to Pre-RNA

“…It has been proposed that early life on Earth used RNA to carry out both the informational and catalytic functions now performed by DNA and protein enzymes. − Accordingly, chemists have long sought, and in some cases demonstrated, model prebiotic syntheses for the canonical RNA nucleotides − and mechanisms for their polymerization, both de novo − and with the aid of pre-existing polymers. − Despite these advances, there remain chemical and biological challenges to the historical validity of RNA spontaneously emerging as the first informational polymer of life. − Additionally, chemists have now prepared numerous non-natural nucleic acids, so-called XNAs, which demonstrate that RNA is not unique in its ability to act as both an informational and a functional polymer. − We have proposed that RNA was preceded by an ancestral polymer, or proto-RNA, that more readily self-assembled on the prebiotic Earth and that this polymer was converted by chemical and/or biological evolution into RNA. − …”