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Is the ADP ribose site of the Chikungunya virus NSP3 Macro domain a target for antiviral approaches?
Acta Tropica ( IF 2.1 ) Pub Date : 2020-04-23 , DOI: 10.1016/j.actatropica.2020.105490 Jacqueline Farinha Shimizu 1 , Daniel Oliveira Silva Martins 1 , Martin J McPhillie 2 , Grace C Roberts 3 , Carsten Zothner 3 , Andres Merits 4 , Mark Harris 3 , Ana Carolina Gomes Jardim 1
Acta Tropica ( IF 2.1 ) Pub Date : 2020-04-23 , DOI: 10.1016/j.actatropica.2020.105490 Jacqueline Farinha Shimizu 1 , Daniel Oliveira Silva Martins 1 , Martin J McPhillie 2 , Grace C Roberts 3 , Carsten Zothner 3 , Andres Merits 4 , Mark Harris 3 , Ana Carolina Gomes Jardim 1
Affiliation
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Chikungunya virus (CHIKV) is a mosquito-transmitted virus of special concern as it causes Chikungunya fever, characterized by an acute febrile illness, rash, and arthralgia that can progress to chronic and debilitating arthritic symptoms. The effects of climate change on the geographic distribution of the mosquito vector has the potential to expose more of the globe to this virus. No antiviral agents or vaccines are currently available against CHIKV infection and the development of novel therapies that may lead to a future treatment is therefore necessary. In this context, the ADP-ribose binding site of the CHIKV nsP3 macro domain has been reported as a potential target for the development of antivirals. Mutations in the ADP-ribose binding site demonstrated decreased viral replication in cell culture and reduced virulence. In this study, 48,750 small molecules were screened in silico for their ability to bind to the ADP-ribose binding site of the CHIKV nsP3 macro domain. From this in silico analysis, 12 molecules were selected for in vitro analysis using a CHIKV subgenomic replicon in Huh-7 cells. Cell viability and CHIKV replication were evaluated and molecules C5 and C13 demonstrated 53 and 66% inhibition of CHIKV replication, respectively. By using a CHIKV-Dual luciferase replicon contain two reporter genes, we also demonstrated that the treatment with either compounds are probably interfering in the early replication rather than after RNA replication has occurred.
中文翻译：
基孔肯雅病毒 NSP3 宏结构域的 ADP 核糖位点是抗病毒方法的目标吗？
基孔肯雅病毒 (CHIKV) 是一种需要特别关注的蚊子传播病毒，因为它会引起基孔肯雅热，其特征是急性发热性疾病、皮疹和关节痛，可发展为慢性和衰弱性关节炎症状。气候变化对蚊媒地理分布的影响有可能使全球更多地区暴露于这种病毒。目前尚无针对 CHIKV 感染的抗病毒药物或疫苗，因此有必要开发可能导致未来治疗的新疗法。在此背景下，CHIKV nsP3 宏结构域的 ADP-核糖结合位点已被报道为开发抗病毒药物的潜在靶点。 ADP-核糖结合位点的突变表明细胞培养物中病毒复制减少并降低毒力。在这项研究中，通过计算机筛选了 48,750 个小分子与 CHIKV nsP3 宏结构域的 ADP-核糖结合位点结合的能力。通过计算机分析，选择 12 个分子用于在 Huh-7 细胞中使用 CHIKV 亚基因组复制子进行体外分析。对细胞活力和 CHIKV 复制进行了评估，分子 C5 和 C13 分别显示出对 CHIKV 复制的 53% 和 66% 抑制作用。通过使用包含两个报告基因的 CHIKV-双荧光素酶复制子，我们还证明用任一化合物进行处理可能会干扰早期复制，而不是在 RNA 复制发生后。
更新日期：2020-04-23
中文翻译：
基孔肯雅病毒 NSP3 宏结构域的 ADP 核糖位点是抗病毒方法的目标吗？
基孔肯雅病毒 (CHIKV) 是一种需要特别关注的蚊子传播病毒，因为它会引起基孔肯雅热，其特征是急性发热性疾病、皮疹和关节痛，可发展为慢性和衰弱性关节炎症状。气候变化对蚊媒地理分布的影响有可能使全球更多地区暴露于这种病毒。目前尚无针对 CHIKV 感染的抗病毒药物或疫苗，因此有必要开发可能导致未来治疗的新疗法。在此背景下，CHIKV nsP3 宏结构域的 ADP-核糖结合位点已被报道为开发抗病毒药物的潜在靶点。 ADP-核糖结合位点的突变表明细胞培养物中病毒复制减少并降低毒力。在这项研究中，通过计算机筛选了 48,750 个小分子与 CHIKV nsP3 宏结构域的 ADP-核糖结合位点结合的能力。通过计算机分析，选择 12 个分子用于在 Huh-7 细胞中使用 CHIKV 亚基因组复制子进行体外分析。对细胞活力和 CHIKV 复制进行了评估，分子 C5 和 C13 分别显示出对 CHIKV 复制的 53% 和 66% 抑制作用。通过使用包含两个报告基因的 CHIKV-双荧光素酶复制子，我们还证明用任一化合物进行处理可能会干扰早期复制，而不是在 RNA 复制发生后。
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