Abstract
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.
Highlights
Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that has spread to more than 60 countries worldwide
Baicalin was shown to interact with the CHIKV E glycoprotein using molecular docking, which led to discrepancy with the previous study suggesting that nsP3 is the viral target of this compound
CONCLUDING REMARKS The lack of effective control measures and the spread of new vectors and increased human travel and urbanization greatly contributed to CHIKV reemergence between 2004 and 2020
Summary
A comprehensive overview of small-molecule inhibitors of CHIKV is presented in Tables 1 to 4 grouped by the approach by which they were identified. Several approaches have been used for identification of potential CHIKV inhibitors, including cell-based high-throughput screening (HTS) campaigns, rational and structure-based drug design using crystal structures, and homology modeling of viral proteins. The CPE reduction assay screens can provide information on antiviral activity of compounds, and their cytotoxicity can be assessed in parallel using uninfected cells in the same plate Such screens are often deployed to test known clinically approved drugs, in a process referred to as drug repurposing. The emergence of computer-aided drug design has greatly contributed to the development of CHIKV inhibitors These approaches are based on the structure of a viral protein to perform in silico virtual screens.
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