Finding a chink in the armor: Update, limitations, and challenges toward successful antivirals against flaviviruses

Abstract

Flaviviruses have caused large epidemics and ongoing outbreaks for centuries. They are now distributed in every continent infecting up to millions of people annually and may emerge to cause future epidemics. Some of the viruses from this group cause severe illnesses ranging from hemorrhagic to neurological manifestations. Despite decades of research, there are currently no approved antiviral drugs against flaviviruses, urging for new strategies and antiviral targets. In recent years, integrated omics data-based drug repurposing paired with novel drug validation methodologies and appropriate animal models has substantially aided in the discovery of new antiviral medicines. Here, we aim to review the latest progress in the development of both new and repurposed (i) direct-acting antivirals; (ii) host-targeting antivirals; and (iii) multitarget antivirals against flaviviruses, which have been evaluated both in vitro and in vivo, with an emphasis on their targets and mechanisms. The search yielded 37 compounds that have been evaluated for their efficacy against flaviviruses in animal models; 20 of them are repurposed drugs, and the majority of them exhibit broad-spectrum antiviral activity. The review also highlighted the major limitations and challenges faced in the current in vitro and in vivo evaluations that hamper the development of successful antiviral drugs for flaviviruses. We provided an analysis of what can be learned from some of the approved antiviral drugs as well as drugs that failed clinical trials. Potent in vitro and in vivo antiviral efficacy alone does not warrant successful antiviral drugs; current gaps in studies need to be addressed to improve efficacy and safety in clinical trials.

Effects of Statin Combinations on Zika Virus Infection in Vero Cells

“…They have indicated that certain conditions warrant the continuous use of statins during pregnancy; however, this recommendation does not necessarily translate to fully endorsing the use of statins during pregnancy due to their safety concerns. Given that significant morbidities from ZIKV infections occur in fetuses and neonates, protecting fetuses from complications due to ZIKV infections during pregnancy and keeping them safe from the adverse effects of drugs are the goals of anti-ZIKV therapy [ 17 ]. Additionally, lipophilic statins have been associated with muscle toxicity collectively called statin-associated muscle symptoms (SAMS), which, in rare severe cases, may require drug discontinuation [ 18 , 19 ].…”

Inhibition of the DENV2 and ZIKV RNA polymerases by Galidesivir triphosphate measured using a continuous fluorescence assay

“…However, existing flavivirus vaccines are of variable efficacy, and their development has not always been straightforward, because of the complex immunological response to infection by different flaviviruses, and the presence of multiple endemic flaviviruses in tropical regions (Fischer et al, 2020; Sridhar et al, 2018). Despite more than 60 years of research, there are currently no FDA-approved antivirals to treat flavivirus infection, and there is an urgent need for these to be developed (Komarasamy et al, 2022).…”

Japanese encephalitis disease: overview of the virus, its risk to Australia and the need for better surveillance

“…There are currently no approved JEV antiviral drugs despite decades of research and several compounds showing efficacy in vitro and in mouse models 29 . This is partly due to the difficulty of conducting clinical trials for JEV since outbreaks are unpredictable and occur in remote settings and recruitment is challenging due to a lack of good‐quality diagnostics.…”

“…The JEV antiviral drug pipeline includes newly developed compounds and repurposed existing drugs, such as prochlorperazine, niclosamide, nitazoxanide and ivermectin 9,29–31 . Drug repurposing is attractive as registered drugs already have regulatory approval and their safety has been established, whereas bringing a novel tropical disease drug to market is a financial risk for pharmaceutical companies.…”

“…The JEV antiviral drug pipeline includes newly developed compounds and repurposed existing drugs, such as prochlorperazine, niclosamide, nitazoxanide and ivermectin. 9,[29][30][31] Drug repurposing is attractive as registered drugs already have regulatory approval and their safety has been established, whereas bringing a novel tropical disease drug to market is a financial risk for pharmaceutical companies. Potential new JEV antiviral therapies targeting the envelope protein, the NS2B-NS3 protease, the replication complex or the RNA-dependent RNA polymerase have demonstrated JEV inhibition, either in vitro or in mouse models.…”