Abstract
Nucleic-acid-based small molecule and oligonucleotide therapies are attractive topics due to their potential for effective target of disease-related modules and specific control of disease gene expression. As the non-naturally occurring biomolecules, modified DNA/RNA nucleoside and oligonucleotide analogues composed of L-(deoxy)riboses, have been designed and applied as innovative therapeutics with superior plasma stability, weakened cytotoxicity, and inexistent immunogenicity. Although all the chiral centers in the backbone are mirror converted from the natural D-nucleic acids, L-nucleic acids are equipped with the same nucleobases (A, G, C and U or T), which are critical to maintain the programmability and form adaptable tertiary structures for target binding. The types of L-nucleic acid drugs are increasingly varied, from chemically modified nucleoside analogues that interact with pathogenic polymerases to nanoparticles containing hundreds of repeating L-nucleotides that circulate durably in vivo. This article mainly reviews three different aspects of L-nucleic acid therapies, including pharmacological L-nucleosides, Spiegelmers as specific target-binding aptamers, and L-nanostructures as effective drug-delivery devices.
Highlights
The genetic information of the human genome is stored in nucleic acids, which are constituted by only four major nucleobases (A, G, C, and T)
The current application of L -nucleic acids as therapeutic agents in clinical trials mainly focuses on the L -aptamer development, and it utilizes the versatile secondary/tertiary structures of L -nucleic acids to recognize the disease relevant target with high specificity and affinity
L-enantiomer of natural D-ImmH, and its of purine nucleosideL-ribitol. It has been extensively studied for the treathydrochloride complex was revealed to be a slow-onset tight-binding inhibitor of ment of patients with T-cell acute lymphoblastic leukemia (T-ALL), and its C-nucleoside
Summary
The genetic information of the human genome is stored in nucleic acids, which are constituted by only four major nucleobases (A, G, C, and T). Only L -proteins can contact D -DNAs/RNAs in vivo to ensure the central dogma [7] This scenario would be closely related to the molecular evolution of life. We are interested in another actuality: L -DNAs/RNAs, as the completely orthogonal biomolecules of native nucleic acids, are featured due to their resistance to nuclease degradation, nontoxicity, and nonimmunogenicity [10] Those are the properties an ideal nucleic acid drug is expected to possess. L -DNAs/RNAs are incapable of base pairing with native nucleic acids in vivo or interacting with native nucleic-acid-processing enzymes. The current application of L -nucleic acids as therapeutic agents in clinical trials mainly focuses on the L -aptamer development, and it utilizes the versatile secondary/tertiary structures of L -nucleic acids to recognize the disease relevant target with high specificity and affinity. Those related contents have been summarized in other review articles [17,18]
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