Institute of Physics of Sao Carlos, University of Sao Paulo, Sao Carlos, SP, Brazil.
Physical Sciences Laboratory, State University of Northern Rio de Janeiro Darcy Ribeiro (UENF), Campos dos Goytacazes, RJ, Brazil.
Sci Rep. 2022 Jun 22;12(1):10601. doi: 10.1038/s41598-022-14790-x.
Chikungunya virus (CHIKV) is the causative agent of Chikungunya fever, an acute febrile and arthritogenic illness with no effective treatments available. The development of effective therapeutic strategies could be significantly accelerated with detailed knowledge of the molecular components behind CHIKV replication. However, drug discovery is hindered by our incomplete understanding of their main components. The RNA-dependent RNA-polymerase (nsP4-CHIKV) is considered the key enzyme of the CHIKV replication complex and a suitable target for antiviral therapy. Herein, the nsP4-CHIKV was extensively characterized through experimental and computational biophysical methods. In the search for new molecules against CHIKV, a compound designated LabMol-309 was identified as a strong ligand of the nsp4-CHIKV and mapped to bind to its active site. The antiviral activity of LabMol-309 was evaluated in cellular-based assays using a CHIKV replicon system and a reporter virus. In conclusion, this study highlights the biophysical features of nsP4-CHIKV and identifies a new compound as a promising antiviral agent against CHIKV infection.
基孔肯雅热病毒（CHIKV）是基孔肯雅热的病原体，这是一种急性发热性关节炎疾病，目前尚无有效的治疗方法。如果能详细了解 CHIKV 复制背后的分子成分，将能显著加快有效治疗策略的开发。然而，由于我们对其主要成分的了解并不完整，药物的发现受到了阻碍。RNA 依赖性 RNA 聚合酶（nsP4-CHIKV）被认为是 CHIKV 复制复合物的关键酶，也是抗病毒治疗的合适靶点。本文通过实验和计算生物物理方法对 nsP4-CHIKV 进行了广泛的研究。在寻找针对 CHIKV 的新分子的过程中，一种名为 LabMol-309 的化合物被鉴定为 nsp4-CHIKV 的强配体，并被定位到与它的活性位点结合。LabMol-309 的抗病毒活性在使用 CHIKV 复制子系统和报告病毒的细胞基础测定中进行了评估。总之，这项研究强调了 nsP4-CHIKV 的生物物理特征，并确定了一种新的化合物作为针对 CHIKV 感染的有前途的抗病毒药物。
