Lamivudine (β-L-2′,3′-dideoxy-3′-thiacytidine, 3TC) is a nucleoside-based anti-HIV/HBV drug that has provided insights into the nucleic acid double-stranded helix assembly. Two crystal structures thereof assembled with nucleobase pairing and helical stacking as mimicries of DNA have recently demonstrated that nucleosides bring themselves the chemical information to assemble DNA duplexes even if the covalent backbone is absent. Here, we report the third structural example in which nucleosides are basepaired and helically base-stacked. A DNA-like double stranded helix was prepared by cocrystallizing lamivudine with fumaric acid. We have named it lamivudine duplex III. When the maleic acid present in the first example of lamivudine duplex is substituted for its transstereoisomer, the formation of a DNA-mimic is still observed. Lamivudine duplex III exhibits both base pairing motifs present in the antecedent duplexes. In this structure, there are four protonated lamivudine molecules paired in-plane with four neutral ones. These base pairs are held together through three hydrogen bonds as occurs in lamivudine duplex I. But, contrary to duplex I with pairing between neutral and cationic drug units only, duplex III has one neutral 3TC3TC pair in its asymmetric unit. These molecules are kept in contact through only two peripheral N−H•••O hydrogen bonds as in two of the three neutral lamivudine pairs of the second example of lamivudine duplex. In both structures, each neutral pair is face-to-face stacked on top of one another and face-to-tail stacked on bottom of another one. Another remarkable feature of duplex III is in its fiber periphery. There are hydrogen bonds between the 5′-OH moieties of neighbor pairs pointing in the direction of the missing phosphodiester linkages that would covalently bond two adjacent monomers in the strand. Furthermore, the geometry of these interactions reveals the antiparallel orientation of each strand relative to one another. 13 C CP/MAS NMR and powder X-ray diffraction analyses have also revealed loss of long-range order upon grounding lamivudine duplex III crystals. Such phenomenon can be related to its low melting temperature. In addition, solid state 15 N NMR spectra have reinforced the protonation pattern of lamivudine duplex III. At last, this study adds knowledge on lamivudine versatility to assemble a DNAmimic in crystals even without the covalent phosphodiester linkages, and duplex formation with rational counterion replacement means base-paired and helically base-stacked structures of nucleosides can be successfully engineered.

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Chiral recognition, even when there is not chiral resolution, observed in two crystal forms of lamivudine with mandelic acid.

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