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首页> 外文期刊>RSC Advances >Reaching beyond HIV/HCV: nelfinavir as a potential starting point for broad-spectrum protease inhibitors against dengue and chikungunya virus
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Reaching beyond HIV/HCV: nelfinavir as a potential starting point for broad-spectrum protease inhibitors against dengue and chikungunya virus

机译：超越HIV / HCV：奈非那韦是广谱蛋白酶抑制剂对登革热和基孔肯雅病毒的潜在起点

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摘要

Drug repurposing or re-profiling has become an effective strategy to identify novel indications for already-approved drugs. In this study, peptidomimetic FDA-approved HIV/HCV inhibitors were explored for their potential to be repurposed for the inhibition of the replication of dengue (DENV) and chikungunya virus (CHIKV) by targeting the NS2B-NS3 and NSP2 protease, respectively. MM/GBSA-based binding free energy results put nelfinavir forward as a potential inhibitor of both dengue and chikungunya virus, which subsequently was further explored in a virus-cell-based assay for both viruses. Nelfinavir showed modest antiviral activity against CHIKV (EC50 = 14 +/- 1 mu M and a selectivity index of 1.6) and was slightly more active against DENV-2 (EC50 = 3.5 +/- 0.4 mu M and a selectivity index of 4.6). Even though the antiviral potency was limited, the fact that some activity was observed in these assays made it worthwhile exploring the potential and properties of nelfinavir as a stepping-stone compound: a more detailed computational analysis was performed to understand the binding mode, interaction, hydrogen bond distance, occupancy and minimum pharmacophoric features. The comprehensive data set that resulted from these analyses may prove to be useful for the development of novel DENV and CHIKV protease inhibitors.
机译：重新设定药物用途或重新配置文件已成为识别已批准药物的新适应症的有效策略。在这项研究中，对拟肽FDA批准的HIV / HCV抑制剂进行了研究，探讨了它们有可能通过分别靶向NS2B-NS3和NSP2蛋白酶而被重新用于抑制登革热（DENV）和基孔肯雅病毒（CHIKV）的复制。基于MM / GBSA的结合自由能结果使奈芬那韦成为登革热和基孔肯雅病毒的潜在抑制剂，随后在基于病毒细胞的两种病毒分析中进一步探索了奈非那韦。奈非那韦对CHIKV表现出适度的抗病毒活性（EC50 = 14 +/- 1μM，选择性指数为1.6），对DENV-2的活性稍强（EC50 = 3.5 +/- 0.4μM，选择性指数为4.6）。 。尽管抗病毒效力有限，但在这些检测方法中观察到一些活性这一事实使我们有必要探索奈非那韦作为垫脚石化合物的潜力和性质：进行了更详细的计算分析以了解结合方式，相互作用，氢键距离，占有率和最小药效学特征。这些分析得出的综合数据集可能被证明对开发新型DENV和CHIKV蛋白酶抑制剂有用。

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