Infection and Immunity Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia.
Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
PLoS Negl Trop Dis. 2022 Apr 28;16(4):e0010291. doi: 10.1371/journal.pntd.0010291. eCollection 2022 Apr.
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.
黄病毒在几个世纪以来引发了大规模的流行病和持续不断的疫情爆发。它们现在分布在每个大陆，每年感染多达数百万人，并可能出现导致未来的流行病。该病毒组中的一些病毒会引起严重的疾病，从出血性到神经表现都有。尽管经过几十年的研究，目前还没有针对黄病毒的批准的抗病毒药物，因此需要新的策略和抗病毒靶点。近年来，基于整合组学数据的药物再利用与新型药物验证方法学和适当的动物模型相结合，极大地促进了新抗病毒药物的发现。在这里，我们旨在综述新的和重新利用的（i）直接作用抗病毒药物；（ii）宿主靶向抗病毒药物；以及（iii）针对黄病毒的多靶抗病毒药物的最新进展，这些药物已在体外和体内进行了评估，重点介绍了它们的靶点和机制。搜索结果得到了 37 种已在动物模型中评估其对黄病毒疗效的化合物；其中 20 种是重新利用的药物，它们中的大多数具有广谱抗病毒活性。该综述还强调了当前在体外和体内评估中面临的主要限制和挑战，这些限制和挑战阻碍了针对黄病毒的成功抗病毒药物的开发。我们分析了从一些已批准的抗病毒药物以及临床试验失败的药物中可以学到什么。仅具有强大的体外和体内抗病毒功效并不能保证成功的抗病毒药物；需要解决当前研究中的差距，以提高临床试验中的疗效和安全性。
