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Conventional Pharmacological Strategies, Investigational Drugs, and Immunotherapies for COVID–19
Published in Srijan Goswami, Chiranjeeb Dey, COVID-19 and SARS-CoV-2, 2022
Subhra Bhattacharya, Srijan Goswami, Chiranjeeb Dey
Originally developed for treating Ebola complications, this experimental antiviral drug is currently undergoing clinical trials for its effectiveness against COVID-19. Remdesivir, the antiviral pro-drug (inactive form of medicine) developed by Gilead Sciences is an adenosine analog. Being an adenosine analog, it mimics natural adenosine in its structure and function and is known to inhibit RNA synthesis. This unapproved drug was initially used to treat COVID-19 patients under emergency use authorization based on data available from in vitro and in vivo studies against Filoviridae, Paramyxoviridae, and Coronaviridae viruses. Being a pro-drug, remdesivir is metabolized in cells and tissues to become an active nucleoside triphosphate that interferes with RNA polymerase activity of the virus. So, when remdesivir (GS-5734) is administered, it enters target cells and is metabolized into its active form (GS-441524). GS-441524 is an adenosine analog, meaning it is not real adenosine but looks and acts like adenosine. RNA is made up of four types of nucleotide adenine (A), guanine (G), cytosine (C), and uracil (U). As GS-441524 acts like adenosine, the viral RdRp is misdirected and picks up GS-441524 and incorporates it into the viral RNA strand. As the synthesis of viral RNA continues, GS-441524 keeps adding artificial adenosine into the growing chain, thus making it defective. This sequence of events disrupts the formation of normal viral RNA (see Figure 9.3). An important aspect to be considered is 3'-5' exoribonuclease (proofreading) activity. It is a viral protein produced from the original viral RNA template. This protein possesses the ability to detect and fix abnormalities in the viral RNA strand. If RdRp is making viral RNA with artificial adenosine, it detects the anomaly and corrects it. The adverse reactions caused by remdesivir include severe headaches, tachycardia or bradycardia, wheezing and shortness of breath, acute respiratory failure, facial swelling, nausea and vomiting, fever with chills and shivering, dizziness, increase in aminotransferase level, liver complications, and renal complications. On November 20, 2020, the World Health Organization issued a report recommending against the use of remdesivir in hospitalized patients regardless of disease severity as there is currently no evidence that remdesivir improves survival and other outcomes in these patients, but there is ample evidence showing adverse drug reactions and iatrogenic complications associated with its use (Dey et al., 2020; Wang et al., 2020; Lo et al., 2019; WHO, 2020b).
Cross-testing of direct-action antivirals, universal vaccines, or search for host-level antivirals: what will sooner lead to a generic capability to combat the emerging viral pandemics?
Published in Expert Review of Anti-infective Therapy, 2022
Viruses were found to be structurally conserved despite sequence diversity, and the binding pockets of evolutionally distant viral enzymes can bind the same agents [14]. The structural conservation in viruses nominates the direct-action antivirals (DAA) to the roles of broad-spectrum agents. For example, mortality in the tenofovir (hepatitis C inhibitor) treated group is 8.8% vs. 50% in the hydroxychloroquine control in severe COVID-19 cases [15]. Remdesivir and favipiravir were originally developed as anti-influenza treatments but were approved for COVID-19 treatment with mixed positive results. Remdesivir parent compound GS-441524 successfully treats feline infectious peritonitis (FIP) – a fatal systemic coronaviral disease – and promises to be a superior agent vs. remdesivir for coronavirus treatments in humans [16]. Other potential anti-coronavirus treatments: GC376 and GC373 were also borrowed from the veterinary field and represent promising protease-inhibiting anti-CoviD-19 drugs [17]. While being tested and used in felines, they are also active in murine models, demonstrating the requested generic character [17]. See Table S2 of the Supplemental Material for more examples.
Hepatic manifestations of COVID-19 and effect of remdesivir on liver function in patients with COVID-19 illness
Published in Baylor University Medical Center Proceedings, 2021
Abdul Aleem, Guruprasad Mahadevaiah, Nasir Shariff, Jiten P. Kothadia
Remdesivir (GS-5734) is a pro-drug of a monophosphate nucleoside analog (GS-441524) and manifests as a viral RNA-dependent RNA polymerase (RdRp) inhibitor that targets the viral genome replication process. Hypothetically, nucleoside analogs are unable to permeate the cell wall easily. Upon gaining entry into the host cell, the adenosine nucleotide pro-drug is metabolized to a nucleoside monophosphate intermediate by carboxyesterase 1 and/or cathepsin A. The nucleoside monophosphate undergoes subsequent phosphorylation to produce nucleoside triphosphate, which resembles adenosine triphosphate and can be used by the RdRp enzymes or complexes for genome replication. After remdesivir is metabolized into the pharmacologic active analog adenosine triphosphate (GS-443902) by the host cells, it vies with adenosine triphosphate for integration by the RdRp complex into the nascent RNA strand and, upon subsequent integration of a few more nucleotides, results in termination of viral RNA synthesis.17–21
An overview of the recent progress in Middle East Respiratory Syndrome Coronavirus (MERS-CoV) drug discovery
Published in Expert Opinion on Drug Discovery, 2023
Remdesivir (GS-5734) is a new drug with broad-spectrum possibilities that may include RNA viruses [103]. Even in conditions with an intact exonuclease proofreading capacity, remdesivir disturbed the pan-CoV RdRp function by reducing the replication of SARS and MERS [104]. Remdesivir was one of the first drugs to inhibit MERS-CoV-RdRp [105]. Remdesivir can be phosphorylated to generate a triphosphate form, RDV-TP, that inhibits MERS-CoV-RdRp [105]. RDV-TP competes with ATP for binding sites and is more selective for MERS-CoV-RdRp than ATP. The inhibition conferred by RDV-TP is quite strong, as the RDV-TP is resistant to the excisions caused by 3’-5’ exonucleases. In human amniotic epithelial (HAE) cells, remdesivir efficiently suppresses MERS-CoV replication with an EC50 value of 0.074 ± 0.023 µM and a CC50 value of greater than 10 µM [106]. Additionally, remdesivir reduced viral RNA concentrations in the initial phase of infection, and the delayed administration of remdesivir until 24 hours after infection began reduced viral titers in HAE cell lines at 48 and 72 hours after infection [106]. In HAE-cultured cells, the nucleotide analog GS-441524 likewise inhibited the replication of MERS-CoV with an EC50 value of 0.9 µM and a CC50 value of greater than 100 µM [106]. The administration of remdesivir as a therapeutic and preventive agent in vivo enhanced respiratory function and lowered lung virus levels and serious respiratory disease in mice [107]. Remdesivir administered prophylactically to rhesus macaques 24 hours before inoculation with MERS-CoV prevented clinical disease, significantly decreased MERS-CoV multiplication in respiratory tissues, and halted the development of lung lesions [108].