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The Application of Fragment-based Approaches to the Discovery of Drugs for Neglected Tropical Diseases
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Christina Spry, Anthony G. Coyne
Nucleoside 2-deoxyribosyltransferase functions in the nucleoside salvage pathway, catalyzing the transfer of deoxyribose between nucleobases. As T. brucei lacks the enzymes required for de novo purine synthesis and is dependent on purine nucleoside scavenging, the enzyme was proposed as a potential drug target (Bosch et al. 2006). This enzyme is particularly attractive as a target because humans are devoid of nucleoside 2-deoxyribosyltransferases (and instead rely on purine and pyrimidine phosphorylases), and as such it should be possible to design inhibitors that selectively target the pathogen. After solving the X-ray crystal structure of T. brucei nucleoside 2-deoxyribosyltransferase (TbNDRT) in the apo form (to 1.8 Å), Bosch et al. (2006) performed an X-ray crystallographic fragment screen against the enzyme.
Therapeutic Medicinal Mushroom (Ganoderma Lucidum): A Review of Bioactive Compounds and their Applications
Published in Megh R. Goyal, Durgesh Nandini Chauhan, Plant- and Marine-Based Phytochemicals for Human Health, 2018
Huang et al. (1999) designed a study to determine total nucleoside (s) in sporophores of G. lucidum produced in different Asian localities by UV-spectrophotometry. They found that the contents of total nucleosides in sporophore were found to be higher in G. lucidum of Taiwan, Jiangsu, and Guangdong origin than from China and Vietnam. Thin layer chromatography (TLC) identification of adenine, adenosine, uracil, and uridine in sporophore of G. lucidum was also performed.53 In another study, a high-performance liquid chromatography-diode array detector-mass spectrometry (HPLC– DAD-MS) analytical method was employed for detection of nucleosides and nucleobases in G. lucidum fruiting bodies by Gao et al.35 The method qualitatively identified six nucleosides namely adenosine, cytidine, guanosine, inosine, thymidine, uridine, and five nucleobases namely adenine, guanine, hypoxanthine, thymine, and uracil.97, 133
Overview of Drug Development
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
James A. Popp, Jeffery A. Engelhardt
The development of DNA/RNA-based therapeutics has been an active area of investigation for over 20 years. These oligodeoxynucleotide (ODN) drugs fall under the auspices of small molecules for development rather than as biologics in spite of their chemical structure. The two most advanced classes are the single-stranded antisense oligonucleotides (ASOs) and the double-stranded silencing RNAs (siRNAs). The overall toxicity profile of these agents does not vary as much as with small molecules, though. More often, there are common toxicities to the class related primarily to protein binding, backbone chemistry, and sequence. The phosphorothioate ASOs are regarded as the first generation of antisense drugs. Modifications to the 2′-position on ribose sugar of nucleobases has improved potency by increasing hybridization affinity with the target mRNA and improved the pharmacokinetic profile through decreasing metabolism, giving rise to the so-called second generation antisense therapeutics (Henry et al. 2008). Similar chemical modification may also be made to siRNAs to improve their stability or otherwise optimize their drug-like properties.
Strategies for targeting RNA with small molecule drugs
Published in Expert Opinion on Drug Discovery, 2023
Christopher L. Haga, Donald G. Phinney
To overcome limitations of enzyme-based RNA footprinting, chemical modifiers of solvent-accessible nucleobases were adopted to probe RNA secondary structures. Perhaps the most well-established reagent is dimethyl sulfate (DMS), a compound that alkylates the N-7 cyclic amine of unpaired guanosine residues, which following reduction and cleavage by analine treatment may be detected by PAGE analysis [21]. DMS has also been shown to alkylate the N1 and N3 positions of unpaired adenine and cytosine, respectively [22]. Since these modifications result in early termination of cDNA elongation, their location can be probed by primer extension using reverse transcriptase. Combining this approach with RNA sequencing permits massively multiplexed RNA secondary structural determination on the level of the entire RNA transcriptome (DMS-Seq and DMS-MaPseq) [23,24]. Because DMS is a small molecule capable of permeating cell membranes, probing RNA secondary structures in cellulo is also possible.
Protective effect of rutin and β-cyclodextrin against hepatotoxicity and nephrotoxicity induced by lambda-cyhalothrin in Wistar rats: biochemical, pathological indices and molecular analysis
Published in Biomarkers, 2022
Walaa A. Ali, Walaa A. Moselhy, Marwa A. Ibrahim, Maha M. Amin, Shaimaa Kamel, Ehab B. Eldomany
Histopathological damages to liver and kidney tissue were observed. These results are in agreement with those of (El-Bialy et al. 2019) and are supported by1 those who reported that LCT treatment caused liver damage through the generation of ROS and energizing oxidative stress; this consequently caused liver cell necrosis and loss of membrane integrity, leading to the elevation in levels of these enzymes due to the lack of cellular functional integrity of hepatocyte membranes. These effects are due to highly reactive free radicals that caused considerable damage to the liver leading to necrosis and fatty infiltration of methylate nucleobases that upset polysomal assembly (Khalaf et al. 2022). Furthermore Postulated that the correlation between liver biomarkers and histological alteration in liver tissues proved that these markers can be used for the early identification of acute liver damage. LCT also exhibits antioxidant activity and induces hepatotoxicity that can be histologically characterized by hypertrophy of hepatocytes, congestion, karyorrhexis, karyolysis, cloudy degeneration, and focal necrosis (Inyang et al. 2016).
Noninvasive urine metabolomics of prostate cancer and its therapeutic approaches: a current scenario and future perspective
Published in Expert Review of Proteomics, 2021
Deepak Kumar, Kavindra Nath, Hira Lal, Ashish Gupta
Malignant transformation has evidenced the perturbation of existing molecular cascades as well as the energetics. To fulfill the requirement of the malignant progression, amino acid biosynthesis and PC metabolism are more targeted on anaplerosis than on the energy production [83]. For rapidly proliferating cells, the intermediate required for nucleobases synthesis associated with the amino acid pool are mainly procured via folate metabolism, one carbon cycle; serine and glycine synthesis pathways [83]. To maintain the proliferative capacity, malignant cells can arrange the metabolic reprogramming by adjusting the catabolism and uptake of nutrients, enabling researchers to foster the bypassing immune-mediated destruction and resistance to oxidative stress [84]. Thus, identifying the altered metabolic pathway and the key molecules playing a major role in PC transformation and progression can pave a new vista for translational applications, including the development of treatment strategies.