Reaching beyond HIV/HCV: nelfinavir as a potential starting point for broad-spectrum protease inhibitors against dengue and chikungunya virus
Reaching beyond HIV/HCV: nelfinavir as a potential starting point for broad-spectrum protease inhibitors against dengue and chikungunya virus
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DOI：
10.1039/c5ra14469h
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发表时间：
2015-01-01
期刊：
影响因子：
3.9
通讯作者：
Jayaprakash, Venkatesan
中科院分区：
文献类型：
--
作者：
Bhakat, Soumendranath;Delang, Leen;Jayaprakash, Venkatesan
药物再利用或重新分析已成为确定已批准药物新适应症的有效策略。在这项研究中，研究了FDA批准的拟肽HIV/HCV抑制剂通过分别靶向NS 2B-NS 3和NSP 2蛋白酶而重新用于抑制登革热（DENV）和基孔肯雅病毒（CHIKV）复制的潜力。基于MM/GBSA的结合自由能结果提出奈非那韦作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检测中进一步探索了这两种病毒。奈非那韦对CHIKV显示出适度的抗病毒活性（EC 50 = 14 +/- 1 μ M，选择性指数为1.6），对DENV-2的活性略高（EC 50 = 3.5 +/- 0.4 μ M，选择性指数为4.6）。尽管抗病毒效力有限，但在这些试验中观察到一些活性的事实使得值得探索奈非那韦作为踏脚石化合物的潜力和性质：进行更详细的计算分析以了解结合模式、相互作用、氢键距离、占有率和最小药效特征。从这些分析中得到的综合数据集可能被证明可用于开发新型DENV和CHIKV蛋白酶抑制剂。
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.