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Recent Developments in Therapies and Strategies Against COVID-19
Published in Hanadi Talal Ahmedah, Muhammad Riaz, Sagheer Ahmed, Marius Alexandru Moga, The Covid-19 Pandemic, 2023
Misbah Hameed, M. Zia-Ul-Haq, Marius Moga
Nucleoside analogs are a class of antiviral drugs that proves to be effective against different viruses such as hepatitis B, C, and HIV. Nucleoside analogs are further classified into three classes: Mutagenic Nucleosides: This targets the viral dependence on RdRp that cause the replication of RNA from RNA template like ribavirin.Obligate Chain Terminators: This targets additional DNA synthesis and incorporation as it lacks the reactive 3′-hydroxyl group needed for this process like azidothymidine (AZT).Delayed Chain Terminators: This targets the process of transcription like Remdesivir.
The Viruses
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
Despite the difficulty of the problem some effective antiviral drugs have been developed against herpesviruses and retroviruses. The nucleoside analogue acycloguanosine (Acyclovir) is activated by phosphorylation via thymidine kinase, a herpesvirus encoded enzyme. The phosphorylated analogue acts then to inhibit the activity of the virus-encoded polymerase. Nucleoside and nonnucleoside inhibitors have been developed against retroviral infections as a result of the massive efforts developed in response to the AIDS epidemic (see below). Nucleoside analogues such as azidothymidine (AZT) selectively inhibit reverse transcriptase (RT) and thereby inhibit the replication of the retroviruses including HIV. A variety of nucleoside analogs have been produced to combat HIV infections (e.g., ddl, didanosine). The need for additional antiviral drugs against HIV has been driven, in part, by the ability of retroviruses like HIV to mutate and become resistant to the effects of drugs that have been developed. The introduction of protease inhibitors like nelfinavir has provided additional types of drugs active against HIV infection. These drugs in combination with RT inhibitors have provided new hope in the battle against AIDS. However, before long-term success against HIV is achieved elimination of sites of latent virus production and continued development of drugs against resistant strains will be required.
HIV
Published in Vincenzo Berghella, Maternal-Fetal Evidence Based Guidelines, 2022
Jenani Jayakumaran, William R. Short
Nucleoside analogue drugs—mitochondrial toxicity and clinical disorders: Clinical disorders include neuropathy, cardiomyopathy, myopathy, pancreatitis, hepatic steatosis, and lactic acidosis which could be confused with HELLP syndrome or acute fatty liver of pregnancy. Monitor liver enzymes and electrolytes in the third trimester. Fatalities due to lactic acidosis during pregnancy or in the early postpartum period have been reported in women on ART regimens that included the combination of d4T and ddI.
Gastroprotective effects of water extract of domesticated Amauroderma rugosum against several gastric ulcer models in rats
Published in Pharmaceutical Biology, 2022
Yanzhen Mai, Siyuan Xu, Ru Shen, Bairu Feng, Hong He, Yifei Xu
Dried domesticated A. rugosum was purchased from Longmen Maling Ganoderma lucidum planting base (Huizhou, China) and identified by morphological, microscopic and gene sequencing (the internal transcribed spacer (ITS). Sequence analysis showed that the similarity between the sample (GenBank accession number: MK660145) and A. rugosum (GenBank accession number: MG021113.1) was 99%. The authenticated voucher specimen (voucher 20-07-02) was kept in Huizhou Health Sciences Polytechnic. Dried domesticated A. rugosum mycelia powder as above was extracted for 1 h in hot water (98 °C) in proportion (1:17, w/v) by heating reflux, thrice. The extracting solution was mixed, filtered, concentrated and lyophilized to obtain WEA. The powder of WEA was dissolved in appropriate distilled water to prepare the extract solution (1 mL equivalent to 1 g of A. rugosum mycelia powder) for test. The polysaccharide content was determined according to Chinese Pharmacopoeia (version 2020) based on the method of Ganoderma lucidum (Curtis: Fr.) P. Karst. (Ganodermataceae) polysaccharide quantification. The nucleosides were determined by high-performance liquid chromatography (HPLC). The total polysaccharides of WEA were analysed by anthrone-sulphuric acid colorimetry at 625 nm. The contents of four nucleosides, namely, including cytidine, uridine, guanosine and adenosine, were determined by HPLC.
The preclinical discovery and development of molnupiravir for the treatment of SARS-CoV-2 (COVID-19)
Published in Expert Opinion on Drug Discovery, 2022
Pasquale Pagliano, Carmine Sellitto, Tiziana Ascione, Giuliana Scarpati, Veronica Folliero, Ornella Piazza, Gianluigi Franci, Amelia Filippelli, Valeria Conti
Many nucleoside analogues have been used in the treatment of viral diseases, some of these have historical value only, but other retain their antiviral efficacy years after their introduction. Antiviral activity of nucleoside analog is driven by the interaction with viral DNA/RNA polymerase or reverse transcriptase, which finally inhibits nucleic acid elongation or causes loss of viral information [19]. Active triphosphate nucleosides have poor chemical stability and cannot cross cellular barrier and penetrate the cell due to their negative charge. Drugs interacting with RdRp must be administered as nucleosides and converted into their triphosphate form, which is finally incorporated into the growing RNA chain. As conversion of a nucleoside to its monophosphate form can be a limiting passage, stable protected monophosphate nucleosides have been developed. RDV, Sofosbuvir, and Tenofovir, well-known drugs currently administered to patients with COVID-19, HCV, or HIV infection, are available as the prodrugs of their monophosphate (ProTide), which can be finally converted into the active compound once they reach the targeted cell [20,21].
A patent review of pharmaceutical and therapeutic applications of oxadiazole derivatives for the treatment of chronic diseases (2013–2021)
Published in Expert Opinion on Therapeutic Patents, 2022
Abbas Hassan, Abid Hussain Khan, Faiza Saleem, Haseen Ahmad, Khalid Mohammed Khan
Chris D et al. developed oxadiazole-based compounds as ribonucleotide reductase modulators (RRmod). These compounds are effective at inhibiting neoplastic cell growth. Ribonucleotide reductase (RR) is directly involved in metathesis, neoplastic tumor growth, and drug resistance. RR is an important target in cancer therapy as it performs a critical role in DNA synthesis. Existing chemotherapies are nucleoside-based analogs that target ribonucleotide reductase [25]. However, the nucleoside-based analogs cause unwanted side effects due to the non-specific binding of other nucleoside-binding proteins. 1,2,4-Oxadiazole-based compounds are more suitable ribonucleotide reductase modulators compared to nucleoside-based analogs. 1,2,4-Oxadiazole compounds bind to epitopes (e.g. M-site or C-site) of the large α-subunit of RR1 and inhibit the growth of multiple cancer cell types in vitro. A variety of 1,2,4-oxadiazoles were tested in cell growth inhibition assays against the HTC116 cell line and the Panel cell line. Two novel hRRM1 inhibitors 13 and 14 shown in Figure 6 were identified using in silico docking, and growth inhibition.