Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that has spread to more than 60 countries worldwide. CHIKV infection leads to a febrile illness known as chikungunya fever (CHIKF), which is characterized by long-lasting and debilitating joint and muscle pain. CHIKV can cause large-scale epidemics with high attack rates, which substantiates the need for development of effective therapeutics suitable for outbreak containment. In this review, we highlight the different strategies used for developing CHIKV small-molecule inhibitors, ranging from high-throughput cell-based screening to in silico screens and enzymatic assays with purified viral proteins. We further discuss the current status of the most promising molecules, including in vitro and in vivo findings. In particular, we focus on describing host and/or viral targets, mode of action, and mechanisms of antiviral drug resistance and associated mutations. Knowledge of the key molecular determinants of drug resistance will aid selection of the most promising antiviral agent(s) for clinical use. For these reasons, we also summarize the available information about drug-resistant phenotypes in Aedes mosquito vectors. From this review, it is evident that more of the active molecules need to be evaluated in preclinical and clinical models to address the current lack of antiviral treatment for CHIKF.

中文翻译：

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基孔肯雅病毒的小分子抑制剂：作用机理和抗病毒药物耐药性。

基孔肯雅病毒（CHIKV）是一种蚊子传播的甲型病毒，已传播到全球60多个国家。CHIKV感染会导致发热性疾病，称为基孔肯雅热（CHIKF），其特征是关节和肌肉疼痛持久且使人衰弱。CHIKV可以引起高流行率的大规模流行病，从而证实了对开发适用于疫情遏制的有效疗法的需求。在这篇综述中，我们重点介绍了用于开发CHIKV小分子抑制剂的不同策略，从基于高通量细胞的筛选到计算机筛选以及纯化病毒蛋白的酶促测定。我们进一步讨论了最有前途的分子的当前状态，包括体外和体内发现。特别是，我们专注于描述宿主和/或病毒靶标，作用方式以及抗病毒药物耐药性和相关突变的机制。了解耐药性的关键分子决定因素将有助于选择最有希望的临床抗病毒药物。由于这些原因，我们还总结了伊蚊蚊载体中有关耐药表型的可用信息。从这篇评论中，很明显，需要在临床前和临床模型中评估更多的活性分子，以解决当前缺乏针对CHIKF的抗病毒治疗的问题。