Advances in Therapeutic L-Nucleosides and L-Nucleic Acids with Unusual Handedness

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.

Advances in the mechanisms and applications of inhibitory oligodeoxynucleotides against immune-mediated inflammatory diseases

“…DNA aptamers can change the distribution of intracellular substances and inhibit biological functions by specifically binding to corresponding proteins, peptides and small molecules, which indicates their potential in the treatment of diseases ( Dantsu et al, 2021 ). DNA aptamers, especially those with targeting inflammatory cytokines, have a therapeutic effect on “hyperactive” immune diseases at the onset of the disease ( Zhu and Chen 2018 ).…”

SynBio 2.0, a new era for synthetic life: Neglected essential functions for resilience

“…While this work is currently developing in many interesting avenues, we can be sure that completely different chassis will be used before long. For example, lnucleotides have rarely been considered ( (Dantsu et al, 2021), and only 32 references at PubMed on 30 July, 2022). The chemistry of 4 0 -thioribonucleosides has been known for a long time (Haeberli et al, 2005), but the interest in these analogues has been revived recently (Betson et al, 2014).…”

Derivatization of Mirror‐Image l‐Nucleic Acids with 2′‐OMe Modification for Thermal and Structural Stabilization

“…[14] The lnucleic acid aptamers have the excellent stability against physiological degradation because of the inertness of l-(deoxy)ribose backbone, as well as the high specificity and binding affinity to target proteins, small molecules, metal ions and nucleic acids. [10,15] As the highly potential translational therapeutics, several Spiegelmers are currently in different clinical trials. [9] There is emerging evidence that l-DNAs and l-RNAs have properties to address long-standing bottlenecks in the field of nucleic acid biotechnology and therapeutic design.…”

“…Rapid advances in the l ‐nucleic acids related biotechnologies and drug design have been seen [7a,10] . l ‐DNAs and l ‐RNAs have been used as advanced biosensors to detect temperature changes [11] and various heavy metal pollutants [12] .…”

“…More promisingly, l ‐RNA molecules are used to select specific mirror‐image aptamers (Spiegelmers) to target a broad range of ligands by systematic evolution of ligands by exponential enrichment (SELEX) technique [14] . The l ‐nucleic acid aptamers have the excellent stability against physiological degradation because of the inertness of l ‐(deoxy)ribose backbone, as well as the high specificity and binding affinity to target proteins, small molecules, metal ions and nucleic acids [10,15] . As the highly potential translational therapeutics, several Spiegelmers are currently in different clinical trials [9] …”