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Current Inhibitors of Dengue Virus
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
J. Jonathan Harburn, G. Stuart Cockerill
One of the main things hampering drug discovery for Dengue is that at present there is no existing animal model that approximates the human disease (Zompi and Harris 2012). The most widely used model to evaluate vaccines and antivirals is the AG129 mouse which is deficient in types I and II interferon receptors which would normally be required for an antiviral response (Schul et al. 2007). Recent examples of pitfalls of using this model was the clinical trials of repurposed Celgosivir (ER-associated α-glucosidase inhibitor) and Lovastatin (cholesterol synthesis inhibitor), both compounds showing reduction in viral load and increased survival rates in mice; neither compound met efficacy end point in clinical trials (Martinez- Guiterrez et al. 2014, Rathore et al. 2011). Drug dose timing could be a possible cause of inconsistency between animal studies versus clinical outcomes. Typically, in animal studies first dose begins at the point of detection of viremia whereas in clinical trials with patients the viral load is typically in decline due to presentation timings of the study. Although non-human primates (NHP, such as rhesus macaques) are natural hosts to DENV infection and develop viremia of similar time frame to humans, they rarely show clinical signs or symptoms (Halstead et al. 1973). NHP models addressing different DENV manifestations utility is limited to various factors (cost, scarce laboratory expertise); they could be invaluable as part of rational drug development for the advancement of novel drugs, especially direct-acting antiviral agents (Whitehorn et al. 2014).
Biologics for dengue prevention: up-to-date
Published in Expert Opinion on Biological Therapy, 2023
Adam T Waickman, Krista Newell, Timothy P Endy, Stephen J Thomas
Celgosivir is an iminosugar derived from the seeds of Castanospermum australe and has an antiviral effect by inhibiting the α-glucosidase I enzyme on the host cell endoplasmic reticulum which glycosylated viruses such as DENV require for the proper packaging of the viral outer E protein [98]. Pre-clinical studies of Celgosivir demonstrated inhibition of all DENV types [99,100]. In a phase 1b study in Singapore of adults with acute dengue using Celgosivir and placebo, there was a non-significant reduction in DENV viral load with the authors concluding that the drug was safe and well tolerated but does not appear to reduce viral load or fever burden during acute DENV infection [98]. This study is registered on ClnicalTrials.gov as an active clinical trial in Singapore, ClinicalTrials.gov Identifier NCT02569827.
New avenues for therapeutic discovery against West Nile virus
Published in Expert Opinion on Drug Discovery, 2020
Alessandro Sinigaglia, Elektra Peta, Silvia Riccetti, Luisa Barzon
Since flaviviruses have crucial interactions with the host ER for genome replication, ER-associated proteins can be important drug targets [171,172]. Genome-wide CRISPR screening identified (ER)-membrane multiprotein complexes, including the oligosaccharyltransferase (OST) complex, as critical flavivirus host factors [171]. Actually, NGI-1, a small-molecule inhibitor of ER-associated OST, caused an impressive suppression of RNA replication in vitro of several flaviviruses, including ZIKV, DENV, YFV, and WNV, with a mechanism independent of inhibition of the N-glycosylation function of the OST [173]. Another ER group of proteins, α-glucosidases, were shown to be relevant for virion assembly. Their inhibition with iminosugar derivatives led to in vitro and in vivo antiviral effects against enveloped viruses, including flaviviruses, HCV, and influenza virus [174,175]. Among candidate iminosugar derivatives, the prodrug celgosivir demonstrated high antiviral activity in vitro and in vivo [176–178]. However, a randomized phase I proof-of-concept clinical trial did not show any benefit of celgosivir in reducing viral load or fever in patients with dengue fever [179].
Murine models of dengue virus infection for novel drug discovery
Published in Expert Opinion on Drug Discovery, 2022
Alana B. Byrne, Cybele C. García, Elsa B. Damonte, Laura B. Talarico
Celgosivir (6-O-butanoyl castanospermine) is alkylated on its nitrogen ring and has been shown to be more effective than its parent compound against all four DENV serotypes [101,106,107]. Experiments conducted in AG129 mice infected with a lethal viral dose in primary or ADE infection confirmed the in vivo efficacy of this compound as shown by enhanced survival, reduced viremia and robust immune response, reflected by serum cytokine analysis, even when a post-infection treatment was used [106,108]. With this promising background celgosivir was evaluated in a clinical trial (NCT01619969) named CLADEN. Patients with uncomplicated dengue fever (fever ≥38◦C for less than 48 h) received celgosivir at an initial dose of 400 mg within 6 h. Later, they received maintenance doses of 200 mg every 12 h for a total of nine doses. In this trial, celgosivir showed a modest antiviral effect, reflected as reduced NS1 protein amounts in the serum of the patients compared to placebo. Failure of the efficacy of celgosivir in humans could be due to virus strain and cell type dependency of this drug as well as to the treatment schedule of two daily doses [109,110]. With these premises, later studies performed in AG129 mice infected with the mouse-adapted DENV-2 strain S221 and clinical isolates from DENV-1 and DENV-2 demonstrated the higher efficacy of four daily doses of celgosivir in comparison to the twice daily treatment, particularly when therapy was initiated at the peak of viremia [107]. On this basis, another clinical trial to evaluate the efficacy of a revised dosing regimen of celgosivir (150 mg every 6 h for a total of 20 doses) is currently on-going and is expected to finish in 2021 (NCT02569827) [109].