Browsing by Author "Dantsu, Yuliya"

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    Advances in Therapeutic L-Nucleosides and L-Nucleic Acids with Unusual Handedness
    (MDPI, 2021-12-24) Dantsu, Yuliya; Zhang, Ying; Zhang, Wen; Biochemistry and Molecular Biology, School of Medicine
    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.
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    Insight into the structures of unusual base pairs in RNA complexes containing a primer/template/adenosine ligand
    (Royal Society of Chemistry, 2023-08-30) Dantsu, Yuliya; Zhang, Ying; Zhang, Wen; Biochemistry and Molecular Biology, School of Medicine
    In the prebiotic RNA world, the self-replication of RNA without enzymes can be achieved through the utilization of 2-aminoimidazole activated nucleotides as efficient substrates. The mechanism of RNA nonenzymatic polymerization has been extensively investigated biophysically and structurally by using the model of an RNA primer/template complex which is bound by the imidazolium-bridged or triphosphate-bridged diguanosine intermediate. However, beyond the realm of the guanosine substrate, the structural insight into how alternative activated nucleotides bind and interact with the RNA primer/template complex remains unexplored, which is important for understanding the low reactivity of adenosine and uridine substrates in RNA primer extension, as well as its relationship with the structures. Here we use crystallography as a method and determine a series of high-resolution structures of RNA primer/template complexes bound by ApppG, a close analog of the dinucleotide intermediate containing adenosine and guanosine. The structures show that ApppG ligands bind to the RNA template through both Watson-Crick and noncanonical base pairs, with the primer 3'-OH group far from the adjacent phosphorus atom of the incoming substrate. The structures indicate that when adenosine is included in the imidazolium-bridged intermediate, the complexes are likely preorganized in a suboptimal conformation, making it difficult for the primer to in-line attack the substrate. Moreover, by co-crystallizing the RNA primer/template with chemically activated adenosine and guanosine monomers, we successfully observe the slow formation of the imidazolium-bridged intermediate (Ap-AI-pG) and the preorganized structure for RNA primer extension. Overall, our studies offer a structural explanation for the slow rate of RNA primer extension when using adenosine-5'-phosphoro-2-aminoimidazolide as a substrate during nonenzymatic polymerization.
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    Syntheses of Pyrimidine-Modified Seleno-DNAs as Stable Antisense Molecules
    (bioRxiv, 2023-05-03) Fang, Ziyuan; Dantsu, Yuliya; Chen, Cen; Zhang, Wen; Huang, Zhen; Biochemistry and Molecular Biology, School of Medicine
    Chemically modified antisense oligonucleotides (ASO) currently in pre-clinical and clinical experiments mainly focus on the 2'-position derivatizations to enhance stability and targeting affinity. Considering the possible incompatibility of 2'-modifications with RNase H stimulation and activity, we have hypothesized that the atom specific modifications on nucleobases can retain the complex structure and RNase H activity, while enhancing ASO's binding affinity, specificity, and stability against nucleases. Herein we report a novel strategy to explore our hypothesis by synthesizing the deoxynucleoside phosphoramidite building block with the seleno-modification at 5-position of thymidine, as well as its Se-oligonucleotides. Via X-ray crystal structural study, we found that the Se-modification was located in the major groove of nucleic acid duplex and didn't cause the thermal and structural perturbations. Surprisingly, our nucleobase-modified Se-DNAs were exceptionally resistant to nuclease digestion, while compatible with RNase H activity. This affords a novel avenue for potential antisense modification in the form of Se-antisense oligonucleotides (Se-ASO).
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    Synthesis and Structural Characterization of 2′-Deoxy-2′-fluoro-l-uridine Nucleic Acids
    (ACS, 2021-06) Dantsu, Yuliya; Zhang, Ying; Zhang, Wen; Biochemistry and Molecular Biology, School of Medicine
    Despite the development of artificial l-RNA/DNA as therapeutic molecules, the in-depth investigation on their chemical modifications is still limited. Here, we synthesize a chemically derivatized 2′-deoxy-2′-fluoro-l-uridine building block and incorporate it into oligonucleotides. Our thermo-denaturization and enzymatic digestion experiments reveal their superior stability. Furthermore, one crystal structure of l-type fluoro-DNA is determined to characterize its handedness. Our results reveal the increase of l-helix stability by fluoro-modification and provide the foundation for its future functional application.
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    Synthesis of 2′-Deoxy-2′-fluoro-L-cytidine and Fluorinated L-Nucleic Acids for Structural Studies
    (Wiley, 2021-10) Dantsu, Yuliya; Zhang, Ying; Zhang, Wen; Biochemistry and Molecular Biology, School of Medicine
    The unique properties of fluorine atom on nucleic acid backbone can offer stricking functional and structural features. In order to extend the biological applications of L-type nucleic acid, we chemically incorporate the fluoro-modification into 2′-position of L-cytidine, and obtain a series of fluoro-modified L-DNAs/ L-RNAs. Our melting study indicates that the 2′-fluoro-modification does not disrupt the thermostabilities of wild-type L-nucleic acids. Consistently, our X-ray crystal structure reveals that fluoro-moiety cause no structural perturbation, and the fluoro-L-cytidine forms the Watson-Crick base pair with L-guanosine virtually identical to nonmodified L-type CG pair. This fluoro-modified cytidine provides a useful biochemical strategy to investigate L-nucleic acid as advanced molecular therapy.