Condensing the information in DNA with double-headed nucleotides

Abstract

A normal duplex holds as many Watson-Crick base pairs as the number of nucleotides in its constituent strands. Here we establish that single nucleotides can be designed to functionally imitate dinucleotides without compromising binding affinity. This effectively allows sequence information to be more compact and concentrated to fewer phosphates.

Base‐Pairing Properties of Double‐Headed Nucleotides

“…The double-headed nucleosides ( Figure 2) were constructed according to our previously described methodology, 24,28 and incorporated into oligonucleotides using conventional phosphoramidite chemistry. The syntheses of the phosphoramidite building blocks are illustrated in Scheme 1.…”

“…Such bifurcated structures can function to condense the genetic information in DNA by comprising two Watson-Crick base pairs per each nucleotide unit. 24 This design can be used to e.g. improve cellular uptake, since the same molecular infor-mation can be delivered using a shorter sequence and decreased polyanionic charge.…”

“…The C2′-exo position of β-nucleosides emerges as the most reasonable site for introducing an additional base and enable dual Watson-Crick contacts. 18 In our preceding studies, we have gauged the potential of three designs (double-headed β-ᴅ-ribosides, 25 β-ᴅ-deoxyribosides 26,27 and β-ᴅarabinosides; 24,28,29 see Figure 1) in terms of their synthetic feasibility and dinucleotide potential. For convenience, uracil has invariably been used as the C1′-linked base.…”

“…In the present work, we focus on the arabino structure, which is essentially isosteric to the deoxyribo structure, yet we have shown that it can be obtained in remarkably improved yields over fewer steps. 24,28 Favorably, the 2′-OH group is shielded and does not necessitate a protecting group for oligonucleotide synthesis. 28 In this report, we take advantage of the synthetic ease offered by the arabino design to gain a deeper insight into doubleheaded nucleotides' base-pairing efficiency compared to natural dinucleotides.…”

Double‐Headed Nucleotides with Non‐Native Nucleobases: Synthesis and Duplex Studies

“…In practice, it can form two sets of Watson-Crick base pairs with two individual nucleotides of the opposite strand: one through its 1'-base to give a 1'•1' base pair, and another through its 2'-base to give a 2'•1' base pair. [24][25][26] This feature allows for the condensation of genetic information to smaller entities with fewer phosphates, which might be an effective approach for e. g. enhancing cellular uptake or target recognition in future nucleic acid-based therapeutics.…”