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The Scientific Basis of Medicine
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
Chris O'Callaghan, Rachel Allen
DNA strands consist of nucleotides joined by phosphodiester bonds linking the sugar of one nucleotide to the phosphate group of the next. DNA coils into a double helix of two antiparallel strands (Figure 2.1). Complementary base pairing of adenine with thymine and guanine with cytosine ensures the fidelity of DNA transcription and replication. When DNA is copied, each parental strand acts as a template for replication: incoming nucleotides form hydrogen bonds with an appropriate base on the template strand. Base mispairing, induced by damage or mutation, introduces structural alterations which can be detected and/or removed by DNA repair proteins.
Development of an Oligodeoxynucleotide Pharmaceutical for the Treatment of Human Leukemia
Published in Eric Wickstrom, Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors, 2020
Alan M. Gewirtz, Deborah Lee Sokol
The studies described above were carried out primarily with unmodified DNA. Such molecules are subject to endonuclease and exonuclease attack at the phosphodiester bonds and are therefore of little utility in vivo. We therefore needed to address two questions at this point. First, we needed to know if a more stable, chemically modified ODN would give similar results. Second, we needed to know if these materials would have effectiveness in an in vivo system against human leukemia cells. Since we could not give this material to patients we established a human leukemia/SCID mouse model system which would allow us to address both questions simultaneously (Ratajczak et al., 1992b).
Translation
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
The circular permutation analysis was employed further to examine binding effects caused by a single break in the phosphodiester backbone (Gott et al. 1993). This method revealed that breakage of all but one phosphodiester bond within a well-defined binding site substantially reduced the binding affinity. This was probably due to the destabilization of the hairpin structure upon breaking the ribose phosphates at these positions. One circularly permuted isomer with the 5′ and 3′ ends at the bulged nucleotide bound with wild-type affinity. However, extending the 5′ end of this coat isomer greatly reduced binding, making it unlikely that this circularly permuted binding site would be active when embedded in a larger RNA. The circular permutation analysis located the 5′ and 3′ boundaries of protein binding sites on the RNA: the 5′ boundary of the R17 coat protein site was defined two nucleotides shorter (nucleotides −15 to +2) than the previously determined site (−17 to +2). It is necessary to note here that Carey et al. (1983b) mapped this region by −17 to +1, as stated above. The smaller binding site was verified by terminal truncation experiments. Then, a minimal binding fragment (−14 to +2) was synthesized and was found to bind tightly to the coat protein. The site size determined by the 3-ethyl-1-nitrosourea-modification interference was larger at the 5′ end (−16 to +1), probably due, however, to steric effects of ethylation of phosphate oxygens. These impressive permutation data were reviewed by Pan and Uhlenbeck (1993).
Plant-Derived Natural Non-Nucleoside Analog Inhibitors (NNAIs) against RNA-Dependent RNA Polymerase Complex (nsp7/nsp8/nsp12) of SARS-CoV-2
Published in Journal of Dietary Supplements, 2023
Sreus A. G. Naidu, Ghulam Mustafa, Roger A. Clemens, A. Satyanarayan Naidu
In CoVs, RdRp catalyzes the synthesis of the RNA genome using the (+)RNA strand as a template to produce a complementary (−)RNA strand starting from 3′-poly-A tail (19). There are two plausible molecular mechanisms to initiate the genomic RNA synthesis by RdRp: i) the primer-independent (de novo) synthesizes the genomic RNA by forming a phosphodiester bond with 3′-hydroxyl group linked to 5′-phosphate group of the adjacent nucleotide (49); and ii) the primer-dependent synthesis generates a new RNA complementary to the template with base pairing under the guidance of either an oligonucleotide or a protein primer (50). Furthermore, four cellular ribonucleotide triphosphates (rNTPs), ATP, GTP, CTP, and UTP provide the template substrates, which are recognized by RdRp. Divalent metal ions magnesium (Mg2+) and manganese (Mn2+) act as essential cofactors in the polymerization reaction and coordinate the catalytic aspartates to promote reactivity with rNTPs (51).
Advances and challenges in drug design against tuberculosis: application of in silico approaches
Published in Expert Opinion on Drug Discovery, 2019
Alexey Aleksandrov, Hannu Myllykallio
DNA ligase plays a central role in DNA metabolism and catalyzes phosphodiester-bond formation in the backbones of DNA. Bacterial ligases are substantially different from eukaryotic ligases in structure and function as they use nicotinamide adenine dinucleotide as a co-factor, while eukaryotic ligases use adenosine-5ʹ-triphosphate. Korycka-Machala et al. [88] screened a library of 1,592 compounds from the National Cancer Institute Diversity Set against the catalytic center of Mtb ligA using the AutoDock 4.2 suite [89]. Out of 200 compounds selected by docking, 23 compounds were shortlisted for the experimental tests based on the burial inside the protein. Seven compounds out of 23 tested inhibited the activity of bacterial ligA. The most active in vitro compound also demonstrated antituberculosis activity in vivo with MIC50 of 15 µM.
Antisense techniques provide robust decrease in GnRH receptor expression with minimal cytotoxicity in GT1-7 cells
Published in Systems Biology in Reproductive Medicine, 2018
Maurice Andre Recanati, Hongling Du, Katherine J. Kramer, Maik Hüttemann, Robert A. Welch
Unlike the nonspecific inhibitors, antisense oligonucleotides reduce the expression of a single protein product without disrupting other proteins responsible for normal cell function. Phosphorothioates are oligonucleotides with a sulfur substituted for one of the oxygens in the phosphodiester bonds between the nucleotides. This modification increases the stability of the oligonucleotides, especially in aqueous solutions, and prevents cellular nuclease enzymes from rapidly degrading them. Phosphorothioates can function in vivo by a number of mechanisms. At the RNA level they generate a substrate for RNase H activity by forming a thermally stable DNA-RNA duplex with a specific sequence and thus render the mRNA accessible for RNase-H cleavage (Stein 1998). In addition, antisense oligonucleotides can form triple helices that interfere directly with transcription and may also inhibit translation (Cazenave et al. 1989). In general, HPLC purified oligonucleotides ranging in size from 14 to 28 bases offer excellent specificity without being subject to self-annealing (Sczakiel 1997).