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. 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. 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. 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. Despite decades of research, there are currently no approved antiviral drugs against flaviviruses, urging for new strategies and antiviral targets. Some of the viruses from this group cause severe illnesses ranging from hemorrhagic to neurological manifestations. They are now distributed in every continent infecting up to millions of people annually and may emerge to cause future epidemics. Flaviviruses have caused large epidemics and ongoing outbreaks for centuries.
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