Toxicity of Antineoplastic Chemotherapy in Children
Sam Kacew in Drug Toxicity and Metabolism in Pediatrics, 1990
Hydroxyurea is a water-soluble compound with the molecular weight of 76. Hydroxyurea putatively inhibits DNA synthesis by acting on ribonucleotide synthetase and blocks cell cycle progression through G,.135 This enzyme is important in the reduction of ribonucleotides to deoxyribonucleotides. Hydroxyurea apparently binds to the ribonucleotide synthetase in a nonreversible manner which thus inhibits enzymatic reductive capacity. Cells are thus unable to synthesize DNA, although RNA and protein synthesis are unimpeded at least for a limited time. Iron may reverse the effects of hydroxyurea as does the exogenous infusion of deoxyribonucleotides. Other DNA changes, such as fragmentation and template destruction, have also been reported as possible mechanisms of action for this drug. By these mechanisms, cells are synchronized between the G-l and S phases. Many cell lines show increased radiosensitivity or susceptibility in the G-l phase and this may account for the in vitro observation that the combination of radiation and hydroxyurea results in increased cell kill.
Gallium and Other Main Group Metal Compounds as Antitumor Agents
Astrid Sigel, Helmut Sigel in Metal Ions in Biological Systems, 2004
Due to its inability to shift between the trivalent and a divalent oxidation state as well as certain aspects of its coordinative behavior, gallium is not incorporated into heme-iron-containing proteins such as hemoglobin or cytochromes, but it is able to compete for iron binding sites on Fe3+-dependent enzymes such as ribonucleotide reductase. Enzymatic reduction of ribonucleotides to deoxyribonucleotides is the rate-limiting step in DNA synthesis. The enzyme is highly activated in proliferating tumor cells and is thus an excellent target for tumor chemotherapy. The activity of this enzyme is dependent on a tyrosyl free radical which is located in the R2 subunit and stabilized by ferric iron but destabilized in cells exposed to transferrin-bound gallium [103,104]. This spectroscopically detectable destabilization may in part be explained by the decreased intracellular iron availability, but cell-free experiments have demonstrated that gallium is also able to interact directly with the enzyme [105], and immunoprecipitation studies suggest that gallium indeed displaces iron from the R2 subunit [106]. Consistent with this mode of action, gallium causes a reduction of ribonucleoside flow into the dTTP pool and DNA as compared to that of deoxyribonucleosides and a reduction of dNTP pools, similar to the effect of the well-known ribonucleotide reductase inhibitor hydroxyurea [103,107].
Hydroxycarbamide
Sarah H. Wakelin, Howard I. Maibach, Clive B. Archer in Handbook of Systemic Drug Treatment in Dermatology, 2015
Hydroxycarbamide is an S-phase specific antimetabolite that inhibits DNA synthesis (but not RNA synthesis) through its action on ribonucleotide diphosphate reductase. This enzyme catalyses formation of deoxyribonucleotides from ribonucleotides, which in turn are used in the synthesis of DNA. Repair of DNA damaged by chemicals or irradiation is also inhibited. It is postulated that hydroxycarbamide’s effects in psoriasis are due to a reduction in keratinocyte proliferation in the basal layer of the epidermis or on proliferating lymphoid cells. It also has antiretroviral effects in human immunodeficiency virus (HIV) infection, inhibiting viral DNA synthesis, and acts in synergy with nucleoside reverse transcriptase inhibitors (NRTIs). Some effects of hydroxycarbamide may be mediated by nitric oxide.
siRNA: an alternative treatment for diabetes and associated conditions
Published in Journal of Drug Targeting, 2019
Ribonucleic acid (RNA) consists of a single stranded linear structure has crucial role in regulation and expression of specific gene and also stores genetic information. RNA structure consists of four ribonucleotide base pairs namely, adenine, guanine, cytosine and uracil in which purines like adenine and guanine binds which complementary pyridines like uracil and cytosine, respectively [8]. RNA is classified into three types, messenger RNA (mRNA), ribosomal RNA (rRNA) and transfer RNA (tRNA) which are involved in protein synthesis in human body, whereas RNA like short interfering RNA (siRNA) and micro RNA (miRNA) are mainly involved in regulation and expression of genes. Both siRNA and miRNA are similar in their structure as well as in their function of silencing and regulation of gene expression by binding with complementary messenger RNA (Figure 2). In contrast, they differ in their mechanism of action and also siRNA targets only one specific mRNA while miRNA has multiple complementary targets [9].
Strategies for targeting RNA with small molecule drugs
Published in Expert Opinion on Drug Discovery, 2023
Christopher L. Haga, Donald G. Phinney
Although single-stranded RNA [1] forms complicated secondary structures [2] through classic canonical Watson–Crick base pairing and [3] three-dimensional tertiary structures through non-canonical interactions [4]. Whereas the major and minor grooves of DNA are more accessible to small molecule binding, the major and minor grooves of paired RNA sterically preclude interactions with small molecules [5]. RNA structure is ultimately dictated by the primary ribonucleotide sequence with the base pairing of the primary sequence determining the secondary structure and the internal base pairing of the secondary structure ultimately determining the tertiary structure. In contrast to targeting tertiary or quaternary structures of proteins, targeting RNA with small molecules has largely focused on binding to secondary structures. These secondary structures can be viewed as RNA ‘motifs’ consisting of internal loops (Figure 1(a)), bulges (Figure 1(b)), hairpins (Figure 1(c)), and pseudoknots (Figure 1(d)) in three-dimensional space that are prime candidates for small molecule drug targeting [6,7]. These intricate structures or motifs regulate interactions with RNA-binding proteins and, particularly in the case of noncoding RNAs, such as microRNAs, directly contribute to the biogenesis and functionality of the RNA.
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).
Related Knowledge Centers
- Adenine
- Adenosine Monophosphate
- Cell Signaling
- Cyclic Adenosine Monophosphate
- Deoxyribonucleotide
- DNA
- Nucleic Acid
- Nucleotide
- Rna
- Adenosine Triphosphate