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Special Issue "Nucleic Acid Chemistry and Nucleic Acid Drugs: A Themed Issue in Honor of Professor Lihe Zhang on the Occasion of His 80th Birthday"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (20 June 2017)

Special Issue Editor

Guest Editor
Prof. Dr. Zhenjun Yang

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
Website | E-Mail
Interests: siRNA; Aptamer; Cyclic nucleotide; nucleoside

Special Issue Information

Dear Colleagues,

In the past three decades, the chemistry and biology of nucleosides, nucleotides and oligonucleotides have played an important role in epigenetic regulation, post-transcription regulation, gene edition and signaling transduction as second messenger, as well as anti-cancer and anti-viral agents, etc. Among them, nucleoside, cyclic nucleotide, antisense oligonucleotide, siRNA, miRNA, lncRNA, DNAzyme, aptamer, and CRISPR/Cas, etc, have been the hot topics. However, there still remain many unsolved problems in this field. For instance, rational modifications and suitable pharmaceutical preparations in vivo then in clinic is not well realized, off-target effects, enzymatic stability and immunoreaction of oligonucleotides are still questionares. Professor Lihe Zhang (born in 1937) is a Professor at State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Academician of Chinese Academy of Sciences (1995). He graduated from Department of Pharmacy, Beijing Medical College in 1958 and got graduate diploma of medicinal chemistry in 1967 from the same college (major in organic chemistry under the guidance of Professor Xu Wang, Academician of CAS). He worked in Department of Chemistry, University of Virginia, USA, as research associate from 1981–1983. In 1985, he became professor of medicinal chemistry in School of Pharmaceutical Sciences, Beijing Medical University and was appointed dean of School of pharmaceutical Sciences, Beijing Medical University (1987–1999) and Director of Chemistry Division of National Natural Science Foundation of China (1999-2006). He is on the Editorial boards of a number of scientific journals including Med. Res. Rev., Curr. Top. Med. Chem. and Orga. Biomol. Chem., ChemMedChem. He is the Associate Editor of Eur. J. Med. Chem.; Editor in Chief of J. Chin. Med. Chem.; Associate Editor of J. Chem. Chin. Univ. His research interests include chemistry of nucleosides and nucleotides. He made a systematic study in the chemical and biological activity of intracellular messenger cADPR and cAMP. He made outstanding contributions to the research areas of ribozyme cleavage mechanism, the nature and recognition of artificial oligonucleotides, and anticancer and antiviral drugs of nucleosides and nucleotides. The journal is pleased to be publishing a commemorative issue in honor of Professor Li-he Zhang for his outstanding contributions on “nucleosides, nucleotides and oligonucleotides” on the occasion of his 80th birthday in 2017. This special issue of Molecules welcomes submission of unpublished manuscripts of original work or reviews on “Nucleosides, Nucleotides and Oligonucleotides”. 

Prof. Dr. Zhenjun Yang
Guest Editor

Manuscript Submission Information

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Keywords

  • nucleoside
  • cyclic nucleotide
  • antisense oligonucleotide
  • siRNA
  • aptamer
  • miRNA
  • lncRNA
  • DNAzyme
  • CRISPR/Cas

Published Papers (10 papers)

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Research

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Open AccessArticle Construction of a Bivalent Thrombin Binding Aptamer and Its Antidote with Improved Properties
Molecules 2017, 22(10), 1770; doi:10.3390/molecules22101770
Received: 27 September 2017 / Revised: 18 October 2017 / Accepted: 19 October 2017 / Published: 19 October 2017
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Abstract
Aptamers are short synthetic DNA or RNA oligonucleotides that adopt secondary and tertiary conformations based on Watson–Crick base-pairing interactions and can be used to target a range of different molecules. Two aptamers, HD1 and HD22, that bind to exosites I and II of
[...] Read more.
Aptamers are short synthetic DNA or RNA oligonucleotides that adopt secondary and tertiary conformations based on Watson–Crick base-pairing interactions and can be used to target a range of different molecules. Two aptamers, HD1 and HD22, that bind to exosites I and II of the human thrombin molecule, respectively, have been extensively studied due to their anticoagulant potentials. However, a fundamental issue preventing the clinical translation of many aptamers is degradation by nucleases and reduced pharmacokinetic properties requiring higher dosing regimens more often. In this study, we have chemically modified the design of previously described thrombin binding aptamers targeting exosites I, HD1, and exosite II, HD22. The individual aptamers were first modified with an inverted deoxythymidine nucleotide, and then constructed bivalent aptamers by connecting the HD1 and HD22 aptamers either through a triethylene glycol (TEG) linkage or four consecutive deoxythymidines together with an inverted deoxythymidine nucleotide at the 3′-end. The anticoagulation potential, the reversal of coagulation with different antidote sequences, and the nuclease stability of the aptamers were then investigated. The results showed that a bivalent aptamer RNV220 containing an inverted deoxythymidine and a TEG linkage chemistry significantly enhanced the anticoagulation properties in blood plasma and nuclease stability compared to the existing aptamer designs. Furthermore, a bivalent antidote sequence RNV220AD efficiently reversed the anticoagulation effect of RNV220 in blood plasma. Based on our results, we believe that RNV220 could be developed as a potential anticoagulant therapeutic molecule. Full article
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Open AccessArticle ADP-ribosyl-N3: A Versatile Precursor for Divergent Syntheses of ADP-ribosylated Compounds
Molecules 2017, 22(8), 1346; doi:10.3390/molecules22081346
Received: 29 June 2017 / Revised: 11 August 2017 / Accepted: 11 August 2017 / Published: 14 August 2017
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Abstract
Adenosine diphosphate-ribose (ADP-ribose) and its derivatives play important roles in a series of complex physiological procedures. The design and synthesis of artificial ADP-ribosylated compounds is an efficient way to develop valuable chemical biology tools and discover new drug candidates. However, the synthesis of
[...] Read more.
Adenosine diphosphate-ribose (ADP-ribose) and its derivatives play important roles in a series of complex physiological procedures. The design and synthesis of artificial ADP-ribosylated compounds is an efficient way to develop valuable chemical biology tools and discover new drug candidates. However, the synthesis of ADP-ribosylated compounds is currently difficult due to structural complexity, easily broken pyrophosphate bond and high hydrophilicity. In this paper, ADP-ribosyl-N3 was designed and synthesized for the first time. With ADP-ribosyl-N3 as the key precursor, a divergent post-modification strategy was developed to prepare structurally diverse ADP-ribosylated compounds including novel nucleotides and peptides bearing ADP-ribosyl moieties. Full article
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Open AccessArticle Application of Ammonium Persulfate for Selective Oxidation of Guanines for Nucleic Acid Sequencing
Molecules 2017, 22(7), 1222; doi:10.3390/molecules22071222
Received: 12 June 2017 / Revised: 14 July 2017 / Accepted: 17 July 2017 / Published: 21 July 2017
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Abstract
Nucleic acids can be sequenced by a chemical procedure that partially damages the nucleotide positions at their base repetition. Many methods have been reported for the selective recognition of guanine. The accurate identification of guanine in both single and double regions of DNA
[...] Read more.
Nucleic acids can be sequenced by a chemical procedure that partially damages the nucleotide positions at their base repetition. Many methods have been reported for the selective recognition of guanine. The accurate identification of guanine in both single and double regions of DNA and RNA remains a challenging task. Herein, we present a new, non-toxic and simple method for the selective recognition of guanine in both DNA and RNA sequences via ammonium persulfate modification. This strategy can be further successfully applied to the detection of 5-methylcytosine by using PCR. Full article
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Open AccessArticle Structure-Activity Relationships of Acyclic Selenopurine Nucleosides as Antiviral Agents
Molecules 2017, 22(7), 1167; doi:10.3390/molecules22071167
Received: 17 June 2017 / Revised: 8 July 2017 / Accepted: 10 July 2017 / Published: 12 July 2017
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Abstract
A series of acyclic selenopurine nucleosides 3af and 4ag were synthesized based on the bioisosteric rationale between oxygen and selenium, and then evaluated for antiviral activity. Among the compounds tested, seleno-acyclovir (4a) exhibited the most potent anti-herpes
[...] Read more.
A series of acyclic selenopurine nucleosides 3af and 4ag were synthesized based on the bioisosteric rationale between oxygen and selenium, and then evaluated for antiviral activity. Among the compounds tested, seleno-acyclovir (4a) exhibited the most potent anti-herpes simplex virus (HSV)-1 (EC50 = 1.47 µM) and HSV-2 (EC50 = 6.34 µM) activities without cytotoxicity up to 100 µM, while 2,6-diaminopurine derivatives 4eg exhibited significant anti-human cytomegalovirus (HCMV) activity, which is slightly more potent than the guanine derivative 4d, indicating that they might act as prodrugs of seleno-ganciclovir (4d). Full article
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Open AccessArticle Site-Specific PEGylated Adeno-Associated Viruses with Increased Serum Stability and Reduced Immunogenicity
Molecules 2017, 22(7), 1155; doi:10.3390/molecules22071155
Received: 16 June 2017 / Revised: 5 July 2017 / Accepted: 7 July 2017 / Published: 11 July 2017
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Abstract
Adeno-associated virus (AAV) is one of the most extensively studied and utilized viral vectors in clinical gene transfer research. However, the serum instability and immunogenicity of AAV vectors significantly limit their application. Here, we endeavored to overcome these limitations by developing a straightforward
[...] Read more.
Adeno-associated virus (AAV) is one of the most extensively studied and utilized viral vectors in clinical gene transfer research. However, the serum instability and immunogenicity of AAV vectors significantly limit their application. Here, we endeavored to overcome these limitations by developing a straightforward approach for site-specific PEGylation of AAV via genetic code expansion. This technique includes incorporation of the azide moiety into the AAV capsid protein followed by orthogonal and stoichiometric conjugation of a variety of polyethylene glycols (PEGs) through click chemistry. Using this approach, only the chosen site(s) was consistently PEGylated under mild conditions, preventing nonselective conjugation. Upon a series of in vitro examinations, AAVs conjugated with 20-kD PEG at sites Q325+1, S452+1, and R585+1 showed a 1.7- to 2.4-fold stability improvement in pooled human serum and a nearly twofold reduction in antibody recognition. Subsequent animal research on Sprague Dawley rats displayed a promising 20% reduction in antibody inducement and a higher virus titer in the blood. Together, our data demonstrate successful protection of an AAV vector from antibody neutralization and blood clearance, thereby increasing the efficiency of therapeutic gene delivery. Full article
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Open AccessArticle Synthesis and In Vitro Anti-Influenza Virus Evaluation of Novel Sialic Acid (C-5 and C-9)-Pentacyclic Triterpene Derivatives
Molecules 2017, 22(7), 1018; doi:10.3390/molecules22071018
Received: 16 May 2017 / Revised: 16 June 2017 / Accepted: 16 June 2017 / Published: 22 June 2017
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Abstract
The emergence of drug resistant variants of the influenza virus has led to a great need to identify novel and effective antiviral agents. In our previous study, a series of sialic acid (C-2 and C-4)-pentacyclic triterpene conjugates have been synthesized, and a five-fold
[...] Read more.
The emergence of drug resistant variants of the influenza virus has led to a great need to identify novel and effective antiviral agents. In our previous study, a series of sialic acid (C-2 and C-4)-pentacyclic triterpene conjugates have been synthesized, and a five-fold more potent antiviral activity was observed when sialic acid was conjugated with pentacyclic triterpene via C-4 than C-2. It was here that we further reported the synthesis and anti-influenza activity of novel sialic acid (C-5 and C-9)-pentacyclic triterpene conjugates. Their structures were confirmed by ESI-HRMS, 1H-NMR, and 13C-NMR spectroscopic analyses. Two conjugates (26 and 42) showed strong cytotoxicity to MDCK cells in the CellTiter-Glo assay at a concentration of 100 μM. However, they showed no significant cytotoxicity to HL-60, Hela, and A549 cell lines in MTT assay under the concentration of 10 μM (except compound 42 showed weak cytotoxicity to HL-60 cell line (10 μM, ~53%)). Compounds 20, 28, 36, and 44 displayed weak potency to influenza A/WSN/33 (H1N1) virus (100 μM, ~20–30%), and no significant anti-influenza activity was found for the other conjugates. The data suggested that both the C-5 acetylamide and C-9 hydroxy of sialic acid were important for its binding with hemagglutinin during viral entry into host cells, while C-4 and C-2 hydroxy were not critical for the binding process and could be replaced with hydrophobic moieties. The research presented herein had significant implications for the design of novel antiviral inhibitors based on a sialic acid scaffold. Full article
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Open AccessArticle Studies on the Two Thymine Residues in the Catalytic Core of 10-23 DNAzyme: The Impact on the Catalysis of Their 5-Substituted Functional Groups
Molecules 2017, 22(7), 1011; doi:10.3390/molecules22071011
Received: 26 May 2017 / Revised: 9 June 2017 / Accepted: 15 June 2017 / Published: 22 June 2017
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Abstract
In the 15-mer catalytic core of 10-23 DNAzyme, each residue contributes to the catalytic conformation differently. Here, the critically conserved T4 and the least conserved T8 were modified on their 5-position with hydroxyl, imidazolyl, and amino groups with a hydrogen-bonding ability. These external
[...] Read more.
In the 15-mer catalytic core of 10-23 DNAzyme, each residue contributes to the catalytic conformation differently. Here, the critically conserved T4 and the least conserved T8 were modified on their 5-position with hydroxyl, imidazolyl, and amino groups with a hydrogen-bonding ability. These external functional groups induced new interactions within the catalytic core, resulting in both negative and positive effects on the catalytic activity of 10-23 DNAzyme, and the different linkages could be used to modulate the effect of the functional groups. The conservation of T4 and T8 could be recognized at the level of the nucleobase, but at the level of the functional group, T4 is not completely conserved. Their 5-methyl groups could be modified for a better performance in terms of the DNAzyme. Full article
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Open AccessArticle Synthesis, Biological Activity and Preliminary in Silico ADMET Screening of Polyamine Conjugates with Bicyclic Systems
Molecules 2017, 22(5), 794; doi:10.3390/molecules22050794
Received: 20 March 2017 / Revised: 28 April 2017 / Accepted: 9 May 2017 / Published: 12 May 2017
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Abstract
Polyamine conjugates with bicyclic terminal groups including quinazoline, naphthalene, quinoline, coumarine and indole have been obtained and their cytotoxic activity against PC–3, DU–145 and MCF–7 cell lines was evaluated in vitro. Their antiproliferative potential differed markedly and depended on both their chemical structure
[...] Read more.
Polyamine conjugates with bicyclic terminal groups including quinazoline, naphthalene, quinoline, coumarine and indole have been obtained and their cytotoxic activity against PC–3, DU–145 and MCF–7 cell lines was evaluated in vitro. Their antiproliferative potential differed markedly and depended on both their chemical structure and the type of cancer cell line. Noncovalent DNA-binding properties of the most active compounds have been examined using ds–DNA thermal melting studies and topo I activity assay. The promising biological activity, DNA intercalative binding mode and favorable drug-like properties of bis(naphthalene-2-carboxamides) make them a good lead for further development of potential anticancer drugs. Full article
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Review

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Open AccessReview Enhancing the Therapeutic Delivery of Oligonucleotides by Chemical Modification and Nanoparticle Encapsulation
Molecules 2017, 22(10), 1724; doi:10.3390/molecules22101724
Received: 20 August 2017 / Revised: 22 September 2017 / Accepted: 9 October 2017 / Published: 13 October 2017
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Abstract
Oligonucleotide (ON) drugs, including small interfering RNA (siRNA), microRNA (miRNA) and antisense oligonucleotides, are promising therapeutic agents. However, their low membrane permeability and sensitivity to nucleases present challenges to in vivo delivery. Chemical modifications of the ON offer a potential solution to improve
[...] Read more.
Oligonucleotide (ON) drugs, including small interfering RNA (siRNA), microRNA (miRNA) and antisense oligonucleotides, are promising therapeutic agents. However, their low membrane permeability and sensitivity to nucleases present challenges to in vivo delivery. Chemical modifications of the ON offer a potential solution to improve the stability and efficacy of ON drugs. Combined with nanoparticle encapsulation, delivery at the site of action and gene silencing activity of chemically modified ON drugs can be further enhanced. In the present review, several types of ON drugs, selection of chemical modification, and nanoparticle-based delivery systems to deliver these ON drugs are discussed. Full article
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Open AccessReview Targeted Magnetic Nanotheranostics of Cancer
Molecules 2017, 22(6), 975; doi:10.3390/molecules22060975
Received: 19 April 2017 / Revised: 2 June 2017 / Accepted: 6 June 2017 / Published: 12 June 2017
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Abstract
Current advances in targeted magnetic nanotheranostics are summarized in this review. Unique structural, optical, electronic and thermal properties of magnetic materials in nanometer scale are attractive in the field of biomedicine. Magnetic nanoparticles functionalized with therapeutic molecules, ligands for targeted delivery, fluorescent and
[...] Read more.
Current advances in targeted magnetic nanotheranostics are summarized in this review. Unique structural, optical, electronic and thermal properties of magnetic materials in nanometer scale are attractive in the field of biomedicine. Magnetic nanoparticles functionalized with therapeutic molecules, ligands for targeted delivery, fluorescent and other chemical agents can be used for cancer diagnostic and therapeutic purposes. High selectivity, small size, and low immunogenicity of synthetic nucleic acid aptamers make them attractive delivery agents for therapeutic purposes. Properties, production and functionalization of magnetic nanoparticles and aptamers as ligands for targeted delivery are discussed herein. In recent years, magnetic nanoparticles have been widely used in diagnostic methods, such as scintigraphy, single photon emission computed tomography (SPECT), positron emission tomography (PET), magnetic resonance imaging (MRI), and Raman spectroscopy. Therapeutic purposes of magnetic nanoconstructions are also promising. They are used for effective drug delivery, magnetic mediated hypertermia, and megnetodynamic triggering of apoptosis. Thus, magnetic nanotheranostics opens a new venue for complex differential diagnostics, and therapy of metastatic cancer. Full article
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