Exploring the Role of Chirality in Nucleic Acid Recognition

Abstract

The study of the base-pairing properties of nucleic acids with sugar moieties in the backbone belonging to the L-series (β-L-DNA, β-L-RNA, and their analogs) are reviewed. The major structural factors underlying the formation of stable heterochiral complexes obtained by incorporation of modified nucleotides into natural duplexes, or by hybridization between homochiral strands of opposite sense of chirality are highlighted. In addition, the perspective use of L-nucleic acids as candidates for various therapeutic applications, or as tools for both synthetic biology and etiology-oriented investigations on the structure and stereochemistry of natural nucleic acids is discussed.

Oligonucleotides containing a ribo-configured cyclohexanyl nucleoside: probing the role of sugar conformation in base pairing selectivity

“…As widely reported, the strong and selective affinity for RNA (ΔT m /mod up to +3°C) relies on a pre-organized conformation of the non-hydrolyzable hexitol ring, closely resembling the C3′-endo sugar ring pucker of natural ribonucleotides. 19b, 25 In this context, we herein introduce a novel synthetic nucleic acid composed of D-ribo-configured 26 cyclohexanyl nucleotides (r-CNA, ribo-Cyclohexanyl Nucleic Acids; Fig. 2 The analysis of the physicochemical properties of oligonucleotide systems composed of pyranyl (α-HNA, 8 ANA, 9 MNA, F-HNA, 10 cANA 11 ), pyranosyl (homoDNA, 12 MANA, 13 DMANA 14 ) and carbocyclic (CNA, 15 CeNA, 16 F-CeNA 17 ) nucleotides, quite often evaluated in both enantiomeric forms, 15,[18][19][20] has led to the identification of HNA congeners endowed with even superior hybridization properties, 9,10,13,16 thus acting, along with HNA, as excellent candidates for applications in therapy, 21 diagnostics 22 and chemical genetics.…”

Propagation of Chirality in Mixtures of Natural and Enantiomeric DNA Oligomers

“…Specifically, we adopt here the new strategy of mixing natural D-DNA oligomers and their L-DNA enantiomers having perfectly mirror symmetrical structures. Because of the enantioselectivity of WatsonCrick interactions [9,10], L and D-oligomers do not bind. Thus when self complementary L and D oligomers are put together in solution, a mixture of mirror symmetric right-and left-handed helices is obtained [11] (see Fig.…”

Enantiomeric Selection Properties of β‐homoDNA: Enhanced Pairing for Heterochiral Complexes

“…In all cases, structural changes of natural (deoxy)ribose cores have been established to determine profound consequences in the pairing potential of the resulting artificial nucleic acids 6. 7 In some noteworthy examples, oligonucleotide systems endowed with six‐membered sugars in the backbone have been observed8–10 to hold the singular property (unique of its kind) of pairing with homochiral complements having opposite sense of chirality. Relevant to etiology‐oriented investigations on nucleic acid structure,5 these findings could suggest the existence of a relationship between nature of the sugar backbone and chiral‐selection properties of nucleic acids, thereby providing insights to enrich our understanding of the structural prerequisites for base pairing.…”

“…Relevant to etiology‐oriented investigations on nucleic acid structure,5 these findings could suggest the existence of a relationship between nature of the sugar backbone and chiral‐selection properties of nucleic acids, thereby providing insights to enrich our understanding of the structural prerequisites for base pairing. From a comparative analysis of the pairing behavior of six‐membered nucleic acids2, 5–7 we perceived that, despite the large structural differences, oligonucleotide systems capable of iso‐ and heterochiral hybridization (Figure 1) shared preorganized carbohydrate conformations with equatorially‐oriented nucleobases 11. This observation took us to wonder if such an arrangement of the aglycon moiety, especially whereas inducing strong backbone‐base inclination6 or even enabling formation of quasilinear oligomeric structures,5–8 could lead sugar chirality not to be crucial in hybridization processes.…”