LNucleosides

Lnucleosides are nucleosides in which the sugar moiety is the enantiomer of the naturally occurring D-ribose, yielding mirror-image (L) nucleosides. In biochemical terms they are the enantiomers of the common D-nucleosides, and natural living systems predominantly use the D form. As a result, LNucleosides are rare in nature and are typically accessed through synthetic or semi-synthetic methods.

Structurally, lnucleosides consist of a nitrogenous base linked to an L-ribofuranose (or an L-containing sugar) via a beta-glycosidic bond. The L configuration profoundly alters how the molecule interacts with biological enzymes such as polymerases and kinases, often producing different pharmacokinetic and pharmacodynamic properties compared with their D counterparts. Synthesis is usually achieved by enantioselective construction from L-ribose or by resolution of racemic nucleosides.

Biological activity and applications have been most notable in antiviral drug development. Notable L-nucleoside analogs include lamivudine (3TC) and emtricitabine (FTC), which are L-cytidine derivatives used to treat HIV and hepatitis B virus infections. After cellular phosphorylation to their active triphosphate forms, they are recognized and incorporated by viral polymerases, typically acting as chain terminators, with selectivity favoring viral enzymes over host polymerases. L-nucleosides may also exhibit altered stability and resistance to certain nucleases, contributing to distinctive pharmacokinetic profiles.

Challenges include ensuring efficient phosphorylation by host kinases, adequate cellular uptake, and managing potential resistance. While L-nucleosides provide valuable alternatives in antiviral therapy, their development remains more specialized than that of natural D-nucleosides.