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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
The clinical landscape for DENV is sparse with only five small molecule potential anti-DENV drugs- Balapiravir (ClinicalTrials.gov Identifier: NCT01096576), Chloroquine (NCT00849602), Celgosivir (NCT01619969, NCT02569827), Prednisolone (ISRCTN Registry No. 39575233) and UV-4B9 (NCT02061358, NCT02696291) have entered Phase I or Phase II clinical trials. These repurposed or off-patent drugs have been subjected to standard double-blinded, randomized trials with placebo-controlled design and showed good safety profiles in patients with acute dengue but failed to meet trial endpoints including reducing viral load. Future trials are recruiting for the use of the platelet activating factor Modipafant and the leukotriene antagonist Ketotefin to prevent vascular leakage in DHF and DSS.
Hepatitis C Virus and Its Inhibitors
Published in Satya Prakash Gupta, Cancer-Causing Viruses and Their Inhibitors, 2014
Based on its potent and specific inhibition of HCV replication invitro, 4′-azidocytidine was selected for development, and a 2′-,3′-,5′-isobutyric acid triester (balapiravir, R1626, 25) was prepared in order to improve bioavailability (Li et al. 2008). This prodrug was efficiently converted to R1479 after uptake from the gastrointestinal tract and showed dose-dependent mean viral load reductions with a maximum of 3.7 log10 IU/mL at the highest dose of 4500 mg bid in a 14-day monotherapy phase 1b clinical study in treatment-naïve individuals infected with HCV GT1 (Table 3.2). No drug-resistant strains emerged during this trial (Roberts et al. 2008). A phase 2a clinical study in HCV GT1-infected patients revealed a synergistic effect of balapiravir in combination with PEG-IFNα-2a (IFN) with or without RBV. After four weeks of treatment, the mean viral load reduction was 3.6 log10 IU/mL in the group receiving 1500 mg bid R1626 plus IFN and 5.2 log10 IU/mL for 1500 mg bid R1626 plus IFN and RBV compared to 2.6 log10 IU/mL for SOC alone (Table 3.2). At the end of the triple therapy, 74% of individuals in that group had achieved a virologic response, that is, HCV RNA levels less than 15 IU/mL (Pockros et al. 2008). Viral resistance to balapiravir did not occur during the four-week treatment period; however, combination therapy was associated with significant hematologic changes, particularly in neutropenia. These adverse events could not be prevented by adjusting drug dosing, and the development of balapiravir was discontinued (Nelson et al. 2012).
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
Balapiravir is a nucleoside analog originally developed for chronic hepatitis C virus (HCV) infection. Against HCV it was found to be a potent inhibitor of ribonucleic acid (RNA) synthesis mediated by the RNA polymerase non-structural protein 5B (NS5B) [101]. Both HCV and DENV are flaviviruses and share genetic commonality in the nonstructural proteins. Balapiravir was then evaluated for the treatment of DENV as a potential inhibitor of the RNA polymerase in infected patients in Vietnam [102]. Patients received doses of balapiravir at 1,500 or 3,000 mg for 5 days. There were no virologic or clinical difference between those treated and placebo controls with the authors concluding Balapiravir was not an effective antiviral against clinical DENV infection (Clinical Trials Registration. NCT01096576). Lower doses failed to produce measurable reductions in viral load, while higher doses produced serious side effects [102].