Special Issue "Nucleoside Analogues"

Guest Editor
Prof. Dr. Ramachandra S. Hosmane
Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA
Website: http://research.umbc.edu/~hosmane
E-Mail:
Phone: +1 410 455 2520 (Lab Phones: x 3844; x2562, and x 3717)
Fax: +1 410 455 1148
Interests: heterocycles; nucleosides; nucleotides; medicinal chemistry; organic synthesis; purines; pyrimidines; enzymes of purine and pyrimidine metabolism; bioorganic synthesis

Dear Colleagues,

Analogues of natural nucleosides have long played pivotal roles in the treatment of viral infections and cancer.  A vast majority of FDA approved drugs to treat viral infections are nucleoside analogues, including but not limited to AZT, ddI, ddC, FTC, 3TC (HIV), entecavir, lamivudine, telbuvidine (HBV), and acyclovir (HSV).  In addition, a number of drugs currently under clinical development for treating HCV infection, which fall under the category of polymerase inhibitors, are nucleoside analogues.  With regard to chemotherapy, nucleoside or nucleobase analogues were among the first to be introduced for the treatment of cancer.  Some examples of FDA-approved anticancer nucleosides/nucleobases include Ara-C (AML/leukemia), 5-FU (skin cancer), and gemcitabine (breast, pancreatic, lung, and ovarian cancers).  A number of these nucleoside analogues act as antimetabolites, compete with natural nucleosides, and interact with a large number of intracellular targets to induce cytotoxicity.  A lot of work is currently underway in identification and characterization of nucleoside transporters and the enzymes of nucleoside metabolism.  Many of these enzyme inhibitors are derived from nucleoside framework, and are targeted to reverse transcriptases and other polymerases, deaminases, kinases, and hydrolases, and have found additional uses in a wide variety of bacterial infections such as malaria and tuberculosis. A number of nucleoside analogues get incorporated during replication or DNA excision repair synthesis, leading to chain termination.  Recent research on DNAzymes, which cleave at predetermined sequences within RNA, suggests that incorporation of locked nucleoside analogues into DNAzymes improves their ability to gain access and cleave at highly-structured RNA targets.  Furthermore, biophysical investigations of certain locked nucleoside analogues have revealed that they possess hybridization and mismatch discrimination attributes similar to those of locked nucleic acid (LNA) but with greatly improved resistance to exonuclease digestion.  Considerable advances have also been made in the area of adenosine receptor agonists/antagonists, which play significant roles in regulation of myocardial oxygen consumption, coronary blood flow, antiinflammatory effects, release of neurotransmitters, and control of immune responses. A vast majority of these agonists/antagonists are derived from adenosine or xanthine family. Finally, a lot of research of mainly academic interest is being carried out on nucleoside analogues as potentially new genetic alphabets. With non-standard hydrogen-bonding topologies, shape complementarity, and/or hydrophobic interfaces, these unnatural bases could pair with complementary natural or unnatural bases to confer enough selectivity and efficiency during transcription, translation, and replication, thus expanding the genetic information.  Articles falling in any of these described or related areas are welcome for inclusion of this special issue of Molecules on Nucleoside Analogues, to be published by MDPI, Switzerland.

Prof. Dr. Ramachandra S. Hosmane
Guest Editor

Submission

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• nucleosides
• analogues
• antiviral compounds
• anticancer compounds
• enzyme inhibitors
• receptor agonists/antagonists
• DNA/RNA building blocks
• biophysical applications

Type of Paper: Review
Title: Nucleoside/Nucleotide Analogues in the Treatment of Chronic Hepatitis B
Authors: James Fung, Ching-Lung Lai, Man-Fung Yuen
Affiliation: Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China;
E-Mail: mfyuen@hkucc.hku.hk (M.-F.Y.)
Abstract: The current available agents for the treatment of chronic hepatitis B (CHB) include immunomodulatory agents such as interferon-α and pegylated interferon-α, and oral nucleoside/nucleotide analogues (NAs), including lamivudine, adefovir, telbivudine, entecavir, and tenofovir. The NAs work mainly by inhibiting HBV DNA polymerase activity and therefore suppressing hepatitis B virus replication. Oral NAs have become the mainstay of CHB treatment, due to mainly their profound viral suppressive effects and in part the ease of single daily dosing and lack of significant side-effects. One major drawback of NA therapy is the development of drug-resistant mutations with long-term treatment. Lamivudine, the first oral NA approved for CHB patients, was associated with high rates of drug resistance, with resultant virological relapse and biochemical flare. Fortunately, newer and more potent NA such as entecavir and tenofovir have lower resistance rate, with high rates of durable viral suppression.
The current review is aimed at the current developments in NAs for CHB treatment, detailing the mechanisms of antiviral activity of the different agents, and also focusing on viral suppression, achieving treatment end-points, development of drug resistance, and optimal strategies in using these drugs.

Type of Paper: Review
Title: Thymidine Analogues for Tracking DNA Synthesis
Authors: Brenton L Cavanagh, Tom Walker, Anwar Norazit and Adrian C. B. Meedeniya
Affiliation: Health Institute and Eskitis Institute, Griffith University, Queensland, Australia; E-Mail: a.meedeniya@griffith.edu.au (A.C.B.M.)
Abstract: Replicating / dividing cells undergo DNA synthesis in the highly regulated, S-phase of the cell cycle. Several arms of biomedical research use analogues of the pyrimidine deoxynucleoside base thymidine, to quantify or track cell proliferation. These “Unnatural bases” may be inserted into replicating DNA, effectively tagging the dividing cells during S-phase by evading multiple cellular safety mechanisms. Tritiated thymidine, targeted using autoradiography was technically demanding and superseded by 5-bromo-2-deoxyuridine (BrdU) and related halogenated analogues, which are detected using antibodies. The detection of these unique bases following their incorporation into the DNA backbone requires denaturation of the DNA, often constraining the outcome of investigations. Despite these limitations BrdU alone has been used to target newly synthesised DNA in over 20,000 biomedical studies in the reviewed literature. A recent breakthrough for targeting dividing cells is the application of the thymidine analogue 5-ethynyl-2′-deoxyuridine (EdU). An alkyne group is uniquely present in EdU which allows its ready detection by a fluorescent azide probe in the presence of copper using the well established ‘Huisgen’s reaction’ also known as 1,3-dipolar Cycloaddition or ‘click chemistry’. This two-step biolabelling approach allows the tagging and imaging of DNA within cells whilst preserving the structural and molecular integrity of the cells. The bio-orthogonal detection of EdU allows its application in many more experimental assays than was previously possible with other “unnatural bases”. These include cell biological; anatomical and molecular biological experimentation in fields spaning developmental biology; stem cell research; cancer biology; and parasitology. The full potential of EdU and related molecules in biology and medicine remains to be explored.